CA3221251A1

CA3221251A1 - Therapeutic methods employing noribogaine and related compounds

Info

Publication number: CA3221251A1
Application number: CA3221251A
Authority: CA
Inventors: Lawrence Friedhoff; Emeline Maillet; Holger Weis
Original assignee: DemeRx Inc
Current assignee: DemeRx Inc
Priority date: 2014-02-18
Filing date: 2015-02-17
Publication date: 2015-08-27
Also published as: IL247325A0; WO2015126836A2; CN106413718A; JP2017506244A; CA2977636A1; AU2020267217B2; AU2015219172A1; CA2977636C; EP3107546A4; KR20160124829A; EA201691656A2; AU2020267217A1; EP3107546A2; TW201534306A

Abstract

This invention is directed to the use of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof at a dosage that provides a therapeutic serum concentration for treating a disease or disorder as described herein in a patient.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

THERAPEUTIC METHODS EMPLOYING NORIBOGAINE AND RELATED
COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Nos.
61/941,387 filed February 18, 2014; 61/945,746 filed February 27, 2014; 61/941,390 filed February 18, 2014; 62/035,335 filed August 8,2014; 61/952,731 filed March 13, 2014;
61/952,727 filed March 13, 2014; 62/005,851 filed May 30, 2014; 61/952,733 filed March 13, 2014;
62/005,847 filed May 30, 2014; 61/952,738 filed March 13, 2014; 62/005,855 filed May 30, 2014; 61/952,741 March 13, 2014; 62/005,841 filed May 30, 2014; 61/952,744 March 13, 2014; 62/005,858 filed May 30, 2014; 62/007,346 filed June 3, 2014;
62/024,388 filed July 14, 2014; and 62/033,538 filed August 5, 2014; and U.S. Application Nos.
14/195,822 filed March 3, 2014, 14/292,632 filed May 30, 2014 and 14/485,514 filed September 12, 2014; and PCT Application No. PCT/US14/19692 filed February 28, 2014, each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION

[0002] This invention is directed to the use of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof at a dosage that provides a therapeutic serum concentration for treating a disease or disorder in a patient.
STATE OF THE ART

[0003] Noribogaine is sometimes referred to as 12-hydroxyibogaine. US Patent No.
2,813,873 claims noribogaine albeit as "12-0-demethylibogaine" while providing an incorrect structural formula for ibogaine. Noribogaine can be depicted by the following formula:

[0004] Noribogaine and its pharmaceutically acceptable salts have recently received significant attention as a non-addictive alkaloid useful in treating drug dependency (U.S.
Patent No. 6,348,456) and as a potent analgesic (U.S. Patent No. 7,220,737).
Such Date Recue/Date Received 2023-11-27 treatment generally requires administration of high doses of noribogaine, typically 0.1 mg to 100 mg per kg body weight.

[0005] Noribogaine is a metabolite of ibogaine found in human, dog, rat and monkey.
While the prior art suggests that ibogaine at higher doses is useful as a treatment for addiction, use of ibogaine is associated with hallucinations and other negative side effects.
In the United States, ibogaine is classified as a Schedule I controlled substance.
Noribogaine has been suggested to have a greater and longer lasting activity in humans than ibogaine for reducing craving for addictive substances and treating chemical dependency. U.S. Patent No. 6,348,456, incorporated by reference herein in its entirety, discloses highly purified noribogaine and teaches that it should be provided at dosages from about 0.01 to about 100 mg per kg body weight per day to treat addiction, although no human data was provided showing an effective dose to treat drug addiction.

[0006] The therapeutic dosing of noribogaine for long-term treatment in humans has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe. Indeed, prior to the instant invention, it was uncertain as to whether noribogaine could be administered at a dose which was therapeutic while at the same time safe for patients.
Addiction

[0007] Nicotine addiction relates generally to smoking, although other forms of nicotine addiction are common (e.g., chewing tobacco). Smoking and other forms of nicotine use pose a serious threat to global health. In the United States alone, annual mortality from smoking (including environmental exposure, i.e. "second-hand smoke") is greater than 440,000. Costs associated with smoking-related illness in the United States total $96 billion in medical costs and $97 billion in lost productivity each year.
Furthermore, smoking significantly increases the risk of a number of diseases, including coronary artery disease, stroke, lung cancer and other cancers, and chronic obstructive pulmonary disease.
An estimated 46 million people in the United States are smokers, 20.6 percent of the US
population.

[0008] More than 40 percent of existing smokers attempt to quit smoking annually.
Various approved therapies (varenicline, bupropion, nicotine patch/gum, nicotine nasal Date Recue/Date Received 2023-11-27 spray/inhaler, hypnotherapy, biofeedback) have long been in clinical use to treat nicotine dependence. Current therapies directed toward smoking cessation tend to focus on counseling, behavioral treatment such as hypnosis, ancUor pharmaceutical therapies.
Quitting smoking is difficult and may require multiple attempts, with success rates of 4%
to 25% depending on the technique used. Users often relapse because of stress, weight gain, and withdrawal symptoms. Furthermore, nicotine replacement therapies (e.g., nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler) do not directly treat nicotine addiction, as the patient remains addicted to nicotine throughout treatment.

[0009] A nicotine addict in remission may exhibit psychological symptoms of nicotine addiction long after the physical symptoms of nicotine addiction are gone.
Many ex-smokers relapse due to a trigger, such as stress or environmental cues. For example, approximately 50% of relapses occur when the ex-smoker has been drinking alcohol.

[0010] Given the immense harm of smoking and other forms of nicotine use to the human body, the high degree of cost to the health care system, the addictive nature of nicotine use, and the difficulty in quitting even when using conventional therapy, there remains an acute need for effective strategies for treating nicotine addiction. There also remains an acute need for effective strategies for preventing relapse of nicotine addiction in nicotine addicts who are in remission.

[0011] Alcohol dependence (also referred to alcohol abuse, alcohol addiction, or alcoholism) is also serious public health problem throughout the world. As many as 140 million people worldwide have an alcohol abuse problem, although only a small fraction of those receive treatment. Alcohol abuse can cause damage to almost every organ in the body, including the brain. Long-term alcohol abuse is known to cause or contribute to numerous diseases, including cirrhosis of the liver, pancreatitis, epilepsy, dementia, heart disease, peptic ulcers, damage to the central and/or peripheral nervous system, cancer, polyneuropathy, nutritional deficiencies, and death.

[0012] Complicating the treatment of alcohol dependence, alcohol-dependent patients generally experience significant, potentially fatal, withdrawal symptoms while attempting to quit using alcohol. Acute withdrawal lasts one to three weeks after cessation of alcohol consumption. Acute withdrawal symptoms include anxiety, seizures, delirium tremens, hallucinations, shakes, and heart failure. Post-acute withdrawal can last significantly Date Recue/Date Received 2023-11-27 longer, with symptoms such as anxiety, depression, sleep disturbance, fatigue, and tension being common.

[0013] Treatment for alcohol dependence generally includes detoxification followed by individual and/or group therapy. Detoxification may include treatment with medications (such as benzodiazepines) that reduce the symptoms of withdrawal. However, drugs such as benzodiazepines have numerous negative side effects, including adverse psychological effects and physical dependence. Benzodiazepines are also known to increase alcohol cravings in alcohol dependent people, and are thus not suitable for long-term treatment of alcohol dependence/addiction. Alcohol-dependent patients have a high rate of relapse.

[0014] Alcohol consumption has been shown to stimulate the release of endogenous opioids in the brains of both humans and experimental animals. Alcohol's effects on the opioid system are believed to be central to drug-induced reward and relapse to alcohol use, as well as sensitivity to alcohol.

[0015] Due to the severity and duration of withdrawal symptoms, alcohol-dependent patients have a high rate of relapse. There is a significant need for effective, non-addictive treatment for acute and post-acute withdrawal symptoms, as well as a method for preventing relapse to alcohol use by a detoxified patient.

[0016] Alcohol consumption has been shown to stimulate the release of endogenous opioids in the brains of both humans and experimental animals. Alcohol's effects on the opioid system are believed to be central to drug-induced reward and relapse to alcohol use, as well as sensitivity to alcohol.

[0017] Substance addiction is a serious public health problem throughout the world. As many as 23.5 million people in the US have a drug or alcohol abuse problem, although only a small fraction of those receive treatment.
100181 Complicating the treatment of drug addiction, drug-addicted patients generally experience significant withdrawal symptoms while attempting to quit using the drug.
Acute withdrawal from drug dependence is characterized by dramatic and traumatic symptoms, including sweating, racing heart, palpitations, muscle tension, tightness in the chest, difficulty breathing, tremor, nausea, vomiting, diarrhea, grand mal seizures, heart Date Recue/Date Received 2023-11-27 attacks, strokes, hallucinations and delirium tremens (DTs). Withdrawal symptoms can also include severe cravings for the drug, fatigue, lack of pleasure, anxiety, irritability, sleepiness, suicidal thoughts, and sometimes agitation or extreme suspicion or paranoia.
Once acute withdrawal symptoms have subsided, post-acute withdrawal syndrome can last for months or years. Post-acute withdrawal symptoms include physical, emotional, and psychological symptoms, such as fatigue, depression, lack of motivation, and increased pain sensitivity. Acute and post-acute withdrawal symptoms are the primary reason drug-addicted patients return to using the drug after treatment, even when the patient has been drug-free for a significant amount of time.
[0019] Although treatments have been developed in attempts to ameliorate acute and post-acute withdrawal symptoms, such treatments do not work for all types of drugs. In addition, treatment of withdrawal may require use of other addictive substances (e.g., morphine, buprenorphine, or methadone). Due to the severity and duration of withdrawal symptoms, addicted patients have a high rate of relapse. There is a significant need for effective, non-addictive treatment for acute and post-acute withdrawal symptoms.
[0020] While the prior art suggests that ibogaine at higher doses is useful as a treatment for addiction, use of ibogaine is associated with hallucinations and other negative side effects. In the United States, ibogaine is classified as a Schedule I
controlled substance.
Pain and Migraine [0021] Pain is broadly defined as an unpleasant sensory experience associated with actual or potential tissue damage, or described in terms of such damage. The interpretation of sensory pain occurs when peripheral nerve endings called nociceptors are stimulated and subsequently transmit signals through sensory neurons in the spinal cord.
The signals are then transmitted to the brain, at which point the individual becomes aware of the pain.
[0022] There are a number of pain categories and classifications, which for example, can be grouped into four categories according to the source and related nociceptors: (1) cutaneous pain; (2) somatic pain; (3) visceral pain; and (4) neuropathic pain.
Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates present damage to tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute pain is Date Recue/Date Received 2023-11-27 centralized in one area before becoming somewhat spread out. Acute pain generally responds well to medications (e.g., morphine).
[0023] Chronic pain may be medically defined as pain that has lasted six months or longer. This constant or intermittent pain has often outlived its purpose because it does not help the body to prevent injury. It is often more difficult to treat than acute pain. Expert care is generally necessary to treat any pain that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to control the pain. This can lead to drug dependency. For example, opioids are used in some instances for prolonged periods to control chronic pain. Drug tolerance, chemical dependency, and even psychological addiction may occur.
[0024] Debilitating chronic pain affects tens of millions of people annually and costs hundreds of millions of dollars in terms of medication, physical therapy, and lost production. Numerous treatments have been developed in attempts to ameliorate pain in its various categories. The current methods for treating chronic pain have a limited success rate and in some cases may result in chemical dependency.
[0025] Migraine headaches (also referred to as "headaches") are a neurological disorder whose symptoms include headaches of moderate to severe intensity, which may be accompanied by nausea, vomiting, sensitivity to sensatory inputs (light, sound, and/or smell), fatigue, irritability, and/or auras. Migraines can last for prolonged periods of time, usually between 4 and 72 hours. Migraines affect approximately 15% of the human population, with up to 2.2% of the population experiencing chronic migraines.
Costs associated with migraines (e.g., patient care, lost productivity, etc.) in the U.S. are estimated to be up to $17 billion per year.
[0026] Migraines are generally managed by trigger avoidance, control of symptoms, and prevention using pharmacologic agents. Acupuncture, acupressure, massage, and relaxation may also be used. Biofeedback, neurostimulators, or migraine surgery may be used in more severe cases, especially those that do not respond to other treatments. Given the prevalence of migraines and the difficulty in treatment and/or prevention, there remains an acute need for effective strategies for treating and preventing migraines and symptoms thereof.

Date Recue/Date Received 2023-11-27 Depression, Anxiety, Psychiatric Disorders, and Related Disorders [0027] The CDC estimates that about 1 in 10 adults in the United States suffer from depression. High levels of depression correlate with high rates of other diseases, including obesity, heart disease, and stroke.
[0028] Similarly, anxiety-related disorders are prevalent in the United States. Anxiety-related disorders include obsessive-compulsive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder.
[0029] PTSD affects approximately 8% of Americans at some point in their lives. More strikingly, up to 30% of people, including veterans, who spend time in war zones develop PTSD. PTSD is increasingly recognized as a major issue for U.S. troops returning from Iraq and Afghanistan, as well as those who served in previous wars, and is a potential contributor to the high rate of suicide among veterans.
[0030] Impulse control disorder is a class of psychiatric disorders involving the failure to resist a temptation, urge, or impulse (impulsivity) where such impulse is potentially harmful to the patient and/or others. The American Psychiatric Association's (May 2013) includes impulse control disorders "characterized by problems in emotional and behavioral self-control". These include borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, interne addiction, trichotillomania, pathological skin picking, and compulsive shopping. Impulse control disorder may be related to anxiety disorder and/or OCD.
[0031] Violence and anger, particularly when out of proportion to a stimulus and/or a result of pathological anger, are associated with a number of mental disorders. These include oppositional defiant disorder, attention-deficit/hyperactivity disorder and conduct disorder (in children and adolescents), psychotic disorder, bipolar disorder, antisocial, borderline, paranoid and narcissistic personality disorders, adjustment disorder with disturbance of conduct, and intermittent explosive disorder. Pathological anger and violence account for a significant portion of violent crimes, including many high-profile Date Recue/Date Received 2023-11-27 crimes involving multiple victims. Highly volatile individuals are over-represented in the prison system in the United States.
Food Intake [0032] Over 2/3 of adults in the U.S. are overweight, with about half of those being obese. The U.S. weight loss market is estimated to be worth over $60 billion;
diet pills alone account for around $1 billion. However, many diet pills contain ingredients that are at best of dubious efficacy and at worst dangerous. Obesity greatly increases a person's risk for a variety of diseases, including coronary heart disease, high blood pressure, stroke, type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, reproductive issues, and gallstones.
Opioid Analgesic Tolerance [0033] Addictive opioid analgesic agents such as morphine are well-known and exceptionally potent analgesics. Such opioids operate as mu receptor agonists.
Upon administration, opioids initiate a cascade of biological events including increased serotonin and dopamine expression. As is well known, continued use of many such opioids (especially at high doses) carries a significant risk of dependency/addiction.
Indeed, potential addiction to such opioids is a serious issue that limits the therapeutic use of addictive opioids as analgesic agents. For example, the use of morphine as an analgesic is common among end stage patients suffering from serious pain where addiction is no longer a concern.
[0034] Drug tolerance to opioid analgesics is common, and may be psychological and/or physiological. A patient who has developed tolerance to the opioid analgesic is not necessarily addicted to or misusing the analgesic. Drug tolerance occurs when the patient's reaction to the drug is reduced, requiring an increase in dose to achieve the same desired effect. There are several potential methods for how tolerance develops, including receptor desensitization, receptor phosphorylation, receptor internalization or down-regulation, and up-regulation of inhibitory pathways.
[0035] Drug tolerance requires that the dosage of analgesic be increased in order to provide sustained analgesic effect. However, high doses of opioids may lead to serious complications and side effects, including physical dependence, addiction, respiratory Date Recue/Date Received 2023-11-27 depression, nausea, sedation, euphoria or dysphoria, decreased gastrointestinal motility, and itching.
[0036] Noribogaine is a metabolite of ibogaine found in human, dog, rat and monkey.
The therapeutic dosing of noribogaine for treating drug addiction and other diseases in humans has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe. Indeed, prior to the instant invention, it was uncertain as to whether noribogaine could be administered at a dose which was therapeutic while at the same time safe for patients.
Depression [0037] Noribogaine is a well-known member of the ibogaine family of alkaloids and is sometimes referred to as 12-hydroxyibogaine. U.S. Patent No. 2,813,873 claims noribogaine, albeit as "12-0-demethylibogaine," while providing an incorrect structural formula for ibogaine. The structure of noribogaine has now been thoroughly evaluated and is found to combine the features of tryptamine, tetrahydrohavaine and indolazepines.
Noribogaine can be depicted by the following formula:

[0038] Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b).
Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes. A major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it can include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.

Date Recue/Date Received 2023-11-27 [0039] Post-traumatic stress disorder (PTSD), as defined by DSM-111-R/IV
(American Psychiatric Association, 1987; American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Although PTSD is classified as an anxiety disorder, PTSD is unique from other anxiety disorders because of the requirement of exposure to a traumatic event.
[0040] Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
[0041] Given the prevalence and impact of depression and PTSD, there is a need for treatments that address these issues. Prior to the embodiments described herein, the therapeutic dosing of noribogaine and its derivatives for treating depression and/or PTSD
in humans at an acceptable QT interval prolongation has not previously been addressed, especially as it relates to dosing protocols that are effective, as well as safe.
SUMMARY
[0042] While noribogaine has been disclosed for treatment of substance addiction, its use in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg/kg body weight). Furthermore, human clinical studies demonstrate that the lower dosing of noribogaine has minimal impact on withdrawal symptoms in addicted patients. Thus, the previously disclosed broad range has now been found to be insufficient for some human therapies at the lower end of this range.
Date Recue/Date Received 2023-11-27 [0043] Moreover, the use of noribogaine imparts a dose-dependent prolongation of the treated patient's QT interval, rendering higher dosing of noribogaine unacceptable. A
prolonged QT interval is a marker of potential Torsades de Pointes, a serious arrhythmia that can result in death.
[0044] The current invention is predicated, in part, on the surprising discovery that treatment with a narrow dosage range of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, between about 1 mg/kg body weight and about 4 mg/kg body weight, provides a therapeutic reduction in withdrawal symptoms and/or an increase in time to resumption of opioid use in opioid-addicted patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds in opioid and opioid-like drug addicted humans is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges. Opioid-like drugs, including cocaine, ketamine, and methamphetamine, are not opioids but act through the opioid receptors, and thus addiction to these drugs also can be treated with noribogaine.
[0045] In some embodiments, the unit dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds in opioid and opioid-like drug addicted humans is between about 60 mg and about 150 mg. In some embodiments, the unit dose that provides both therapeutic results and an acceptable QT
interval prolongation of less than about 50 milliseconds in opioid and opioid-like drug addicted humans is about 120 mg. In some embodiments, the unit dose that provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds in opioid and opioid-like drug addicted humans is about 2 mg/kg body weight.
[0046] In some embodiments, the patient is administered an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, followed by one or more additional doses. In one embodiment, the initial dose is from about 50 mg to about 120 mg. In one embodiment, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from Date Recue/Date Received 2023-11-27 about 5 mg to about 50 mg. In one embodiment, such a dosing regimen provides an average serum concentration of noribogaine of about 50 ng/mL to about 180 ng/mL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL over a period of time. In one embodiment, the one or more additional doses are administered periodically.
[0047] In a preferred embodiment, the narrow therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate described above unexpectedly do not prolong the QT interval to unacceptable levels in human addicted patients. It is expected that opioid or opioid-like drug addicted patients will be administered therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with noribogaine.
[0048] Some aspects of the current invention are further predicated on the discovery that even lower doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of opioid (or opioid-like drug) use in an opioid-addicted patient treated to ameliorate their opioid use. That is, a lower dose of noribogaine can prevent a patient who is no longer physically addicted to opioid from relapsing to opioid use. Without being bound by theory, it is believed that a patient who is no longer physically addicted to opioids or opioid-like drug requires less noribogaine to prevent relapse because the opioid or opioid-like drug does not compete with noribogaine for receptor binding, and/or because desensitization of one or more receptors in the brain by the opioid or opioid-like drug is reversed when the patient ceases to take the drug. This lower, maintenance dose of noribogaine results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0049] In some embodiments, the maintenance dose of noribogaine is about 5 mg to about 100 mg. In some embodiments, the maintenance dose of noribogaine is about 1.5 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 1 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is Date Recue/Date Received 2023-11-27 about 0.9 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.8 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.7 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.6 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.5 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.4 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.3 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.2 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.1 mg/kg body weight.
[0050] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide a serum concentration of about 1000 to about ng*hour/mL. In some embodiments the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide a maximum serum concentration (Cmax) of less than about 250 ng/mL. In a preferred embodiment, the therapeutic dose provides a Cmax of about 100 ng/mL to about 200 ng/mL.
[0051] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 180 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient provides an average serum concentration of about 80 ng/mL to about 100 ng/ml.
[0052] In some embodiments, the patient is administered a high (therapeutic) dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to opioid or opioid-like drug use. In some embodiments, the patient is administered a therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof for a period of time to ameliorate the most significant withdrawal symptoms, and then is administered Date Recue/Date Received 2023-11-27 a decreasing (tapered) amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof over time until the maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of noribogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0053] In some embodiments, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL is administered as a single dose. In some embodiments, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL is administered as multiple doses. In an embodiment, the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 1 mg/kg to about 3 mg/kg. In another preferred embodiment, the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 1 mg/kg to about 2.5 mg/kg.
[0054] In some embodiments, the serum concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 milliseconds (ms) during said treatment. In a preferred embodiment, the serum concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 450 ms during said treatment.
[0055] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides prolongation of the QT interval of less than about 80 ms. In an embodiment, the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides prolongation of the QT interval of less than about 50 ms. In some embodiments, the maintenance dose or therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides prolongation of the QT
interval of less than about 30 ms. In a preferred embodiment, the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides prolongation of the QT interval of less than about 20 ms. In one embodiment, the Date Recue/Date Received 2023-11-27 QT prolongation is equivalent to or less than that observed in patients receiving methadone treatment. In a preferred embodiment, the patient is tested to determine QT
interval before treatment with noribogaine, and if clinician determines that the QT
prolongation would be unacceptable risk, noribogaine therapy will be contraindicated.
[0056] In another embodiment, noribogaine or a pharmaceutically acceptable salt thereof is administered.
Opioid or Opioid Like Drug Abuse [0057] In one aspect, provided herein is a method for treating opioid or opioid-like drug abuse in a human patient addicted thereto, comprising administering to the patient a therapeutic dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the therapeutic dosage provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0058] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL for a period of time.
[0059] In another embodiment, the initial dose is from about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg.
In another embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from about 6 hours to about 24 hours after the previous dose. In another embodiment, the Date Recue/Date Received 2023-11-27 method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval. In another embodiment, the maximum serum concentration is between about 40 ng/mL and about 250 ng/mL. In another embodiment, the serum concentration of noribogaine is between about 1000 ng*hr/mL and about 5800 ng*hr/mL .
[0060] In another aspect, provided herein is a method for treating opioid or opioid-like drug abuse in a human patient addicted thereto, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL
to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval prolongation of less than about 20 ms during said treatment.
[0061] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
[0062] In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL for a period of time.
[0063] In another embodiment, the initial dose is from about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg.
In another embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from about 6 hours to about 24 hours after the previous dose.
[0064] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, comprising administering to the patient a dosage of noribogaine, Date Recue/Date Received 2023-11-27 noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0065] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL for a period of time.
[0066] In another embodiment, the initial dose is from about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg.
In another embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from about 6 hours to about 24 hours after the previous dose.
[0067] In another aspect, provided herein is a method to prevent relapse of opioid or opioid-like drug abuse in a patient previously treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the patient is no longer abusing the opioid or opioid-like drug, wherein the dosage is less than about 70% of a therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 30 ms.

Date Recue/Date Received 2023-11-27 [0068] In one embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 5 mg to about 100 mg per day.
Nicotine [0069] This invention is based, in part, on the discovery that at very low doses, direct blood stream delivery of noribogaine reduces the desire to smoke. Such dosing is well below that previously described. Direct blood stream delivery of noribogaine enhances the amount of noribogaine delivered to the brain, because noribogaine so administered does not initially pass through the liver before reaching the brain as it does when ingested.
Direct blood stream delivery of noribogaine includes sublingual, pulmonary and intranasal delivery where the noribogaine is absorbed directly into the blood stream and then into the brain. The rapid delivery of noribogaine into the brain causes a significant reduction in the craving to smoke on a rapid basis, typically less than 5 minutes after administration.
[0070] Noribogaine is believed to bind to several receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opiod receptors (e.g., vi-opiod receptors).
Without being bound by theory, it is believed that the nAChR has a greater binding affinity for noribogaine than other receptors in the brain. This allows treatment of nicotine addiction and/or nicotine cravings using much lower doses of noribogaine than are currently used for the treatment of other conditions, such as opiod withdrawal.
Furthermore, a nicotine addict in remission may not exhibit physical symptoms of addiction, but rather may have psychological cravings for cigarettes or other forms of nicotine, or may anticipate such cravings in certain situations. As such, and without being bound by theory, it is expected that lower amounts of noribogaine are required to treat or prevent nicotine cravings in such situations than would be required in a patient who is currently addicted to nicotine.
[0071] In one aspect, this invention relates to methods of treating nicotine addiction or preventing relapse of nicotine use, comprising administration of a therapeutic amount of noribogaine. As used herein, unless specified otherwise, noribogaine includes to noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.

18 Date Recue/Date Received 2023-11-27 [0072] In one aspect, this invention relates to treating nicotine addiction in a patient in need thereof comprising administering to the patient by direct blood stream delivery a therapeutically effective amount of noribogaine. In one aspect, a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 10 lig per kg of body weight. In some embodiments, the therapeutically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day.
[0073] In another aspect, this invention provides a method for treating nicotine addiction in a patient in need thereof comprising administering to the patient a therapeutic amount of noribogaine or a noribogaine derivative or pharmaceutically acceptable salt thereof, wherein the noribogaine or derivative or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0074] In one aspect, this invention relates to methods of preventing relapse of nicotine use, comprising administration of a prophylactic amount of noribogaine to inhibit a behavioral craving for nicotine. As used herein, unless specified otherwise, noribogaine includes to noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
[0075] In one aspect, this invention relates to preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient by direct blood stream delivery a prophylactically effective amount of noribogaine. In one aspect, a prophylactically effective amount of noribogaine is from about 50 ng to less than 10 pg per kg of body weight. In some embodiments, the prophylactically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day. In some embodiments, the prophylactically effective amount is administered when the patient feels a craving, or anticipates feeling a craving, for nicotine.
[0076] In another aspect, this invention provides a method for preventing relapse of nicotine use in a patient in need thereof comprising administering to the patient a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein the noribogaine, derivative, or salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery.

19 Date Recue/Date Received 2023-11-27 [0077] In one aspect, provided herein is a a method for treating nicotine addiction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is from about 50 ng to less than 10 g per kg body weight per day.
[0078] In one embodiment, the therapeutically effective amount is from about 50 ng to about 1 jig per kg body weight per day. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once a day. In another embodiment, the therapeutically effective amount is administered two or more times per day.
[0079] In one aspect, provided herein is a method for preventing a nicotine craving in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein said prophylactically effective amount is from about 50 ng to less than 10 1.1g per kg body weight per day.
[0080] In one embodiment, the patient is no longer physically addicted to nicotine. In another embodiment, the prophylactically effective amount is from about 50 ng to about 1 jig per kg body weight per day. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered on an as-needed basis as determined by the subject. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered before the nicotine craving occurs. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered after the nicotine craving occurs.
Alcohol Dependence [0081] While noribogaine has been disclosed for treatment of alcohol dependence, its use in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg/kg body weight). Furthermore, human clinical studies Date Recue/Date Received 2023-11-27 demonstrate that the lower dosing of noribogaine has minimal impact on withdrawal symptoms in addicted patients. Thus, the previously disclosed broad range has now been found to be insufficient for human therapy at the lower end of this range.
[0082] The current invention is predicated, in part, on the surprising discovery that treatment with a narrow dosage range of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, between greater than about 1 mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic reduction in withdrawal symptoms in alcohol dependent patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in addicted humans is between about 1.3 mg per kg body weight and no more than about 4 mg per kg body weight and, more preferably between about 1.3 mg per kg body weight and no more than about 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0083] In a preferred embodiment, the narrow therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate described above do not prolong the QT interval to unacceptable levels in human patients.
It is expected that alcohol dependent patients will be administered therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions or other indicators which would disqualify them from treatment with noribogaine. In one embodiment, a patient who exhibits a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof will not require further clinical monitoring.
[0084] Some aspects of the current invention are further predicated on the discovery that even lower doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of alcohol use in an addicted patient treated to ameliorate their alcohol dependence. That is, a lower dose of noribogaine can prevent a patient who is no longer physically dependent on alcohol from relapsing to use thereof.

Date Recue/Date Received 2023-11-27 Without being bound by theory, it is believed that a patient who is no longer physically dependent on alcohol requires less noribogaine to prevent relapse at least in part because the changes made to the brain by alcohol dependence at least partially reverse when the patient detoxifies from alcohol. This lower, maintenance dose of noribogaine results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0085] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
[0086] In some embodiments, the patient is administered a high (therapeutic) dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to alcohol use. In some embodiments, the patient is administered a therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of noribogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0087] In some embodiments, the dose of noribogaine, noribogaine derivative, or phatmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of noribogaine, noribogaine derivative, or Date Recue/Date Received 2023-11-27 pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 8 mg/kg. In a preferred embodiment, the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 4 mg/kg. In another preferred embodiment, the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to 3 mg/kg.
[0088] In some embodiments, the serum concentration of noribogaine is sufficient to inhibit or ameliorate said dependence while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 80 ms. In one embodiment, the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof provides prolongation of the QT
interval of less than 50 ms. In some embodiments, the maintenance dose or therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 30 ms. In a preferred embodiment, the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT
interval of less than

20 ms. In a preferred embodiment, the patient is tested to determine QT
interval before treatment with noribogaine, and if clinician determines that the QT
prolongation would be unacceptable risk, noribogaine therapy will be contraindicated.
[0089] In one aspect, provided herein is a method for treating alcohol dependence in a human patient suffering therefrom, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.
[0090] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of Date Recue/Date Received 2023-11-27 noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day. In another embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides an average serum concentration of about 50 ng/mL to about 200 ng/mL. In another embodiment, the QT
interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT
interval. In another embodiment, the prescreening step comprises ascertaining that noribogaine treatment will not result in a QT interval greater than about 500 ms. In another embodiment, the prescreening step comprises ascertaining that noribogaine treatment will not result in a QT interval greater than about 470 ms. In another embodiment, the prescreening step comprises ascertaining that noribogaine treatment will not result in a QT
interval greater than about 450 ms.
[0091] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0092] In one embodiment, the withdrawal symptoms are due to acute withdrawal.
In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 Date Recue/Date Received 2023-11-27 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day. In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
[0093] In one aspect, provided herein is a method to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is no longer physically dependent on alcohol.
[0094] In one embodiment, the maintenance dosage is less than about 70% of a therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 30 ms. In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 20 ms. In another embodiment, noribogaine or a pharmaceutically acceptable salt and/or solvate thereof is administered.
Drug Addiction [0095] While noribogaine has been disclosed for treatment of substance addiction, its use in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg/kg body weight). Furthermore, human clinical studies demonstrate that the lower dosing of noribogaine has minimal impact on withdrawal symptoms in addicted patients. Thus, the previously disclosed broad range has now been found to be insufficient for human therapy at the lower end of this range.
Date Recue/Date Received 2023-11-27 [0096] The current invention is predicated, in part, on the surprising discovery that treatment with a narrow dosage range of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof; between 1 mg/kg body weight and 4 mg/kg body weight, provides a therapeutic reduction in withdrawal symptoms and/or an increase in time to resumption of drug use in addicted patients. Preferably, the dose range that provide both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in addicted humans is between 1.3 mg per kg body weight and no more than 4 mg per kg body weight and, more preferably between 1.3 mg per kg body weight and no more than 3 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0097] In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in drug addicted humans is about 120 mg. In some embodiments, the dose that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in drug addicted humans is about 2 mg/kg body weight.
[0098] In some embodiments, the patient is administered an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, the initial dose is from 75 mg to 120 mg. In one embodiment, the one or more additional doses are lower than the initial dose.
In one embodiment, the one or more additional doses are from 5 mg to 50 mg. In one embodiment, such a dosing regimen provides an average serum concentration of noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, the one or more additional doses maintain an average serum concentration of 50 ng/mL to 180 ng/mL over a period of time. In one embodiment, the one or more additional doses are administered periodically.
[0099] In some embodiments, the narrow therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate described above unexpectedly do not prolong the QT interval to unacceptable levels in human addicted patients. It is expected that drug-addicted patients will be administered therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof in a clinical setting with cardiac monitoring. In some embodiments, the patient will Date Recue/Date Received 2023-11-27 be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with noribogaine.
[0100] Some aspects of the current invention are further predicated on the discovery that even lower doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, for example approximately 80% or less of the therapeutic dose, may be effective for prevention of relapse of drug use in an addicted patient treated to ameliorate their substance abuse. That is, a lower dose of noribogaine can prevent a patient who is no longer physically addicted to an addictive substance from relapsing to use thereof. Without being bound by theory, it is believed that a patient who is no longer physically addicted to the drug requires less noribogaine to prevent relapse because the drug does not compete with noribogaine for receptor binding, and/or because desensitization of one or more receptors in the brain by the drug is reversed when the patient ceases to take the drug. This lower, maintenance dose of noribogaine results in a QT interval prolongation that does not require clinical cardiac monitoring.
[0101] In some embodiments, the maintenance dose of noribogaine is 5 mg to 100 mg.
In some embodiments, the maintenance dose of noribogaine is about 1.5 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 1 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.9 mg,/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.8 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.7 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.6 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.5 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.4 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.3 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.2 mg/kg body weight. In some embodiments, the maintenance dose of noribogaine is about 0.1 mg/kg body weight.
[0102] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average serum concentration of 50 ng/mL to 400 ng/mL , Date Recue/Date Received 2023-11-27 or any subrange or subvalue there between. In a preferred embodiment, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of 50 ng/mL
to 180 ng/mL.
[0103] In some embodiments, the patient is administered a high (therapeutic) dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdrawal symptoms, and then is administered a lower (maintenance) dose to prevent relapse to drug use. In some embodiments, the patient is administered a therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdrawal symptoms, and then is administered a decreasing (tapered) amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose. In some embodiments, the dose of noribogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
[0104] In some embodiments, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL is administered as a single dose. In some embodiments, the dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL is administered as multiple doses. In an embodiment, the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from 1 mg/kg to 3 mg/kg. In another embodiment, the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from 1 mg/kg to 2.5 mg/kg.
[0105] In some embodiments, the serum concentration is sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 80 ms. In one embodiment, the maintenance Date Recue/Date Received 2023-11-27 dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms.
In some embodiments, the maintenance dose or therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 30 ms. In an embodiment, the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 20 ms.
In one embodiment, the QT prolongation is equivalent to or less than that observed in patients receiving methadone treatment. In a preferred embodiment, the patient is tested to determine QT interval before treatment with noribogaine, and if clinician determines that the QT prolongation would be unacceptable risk, noribogaine therapy will be contraindicated.
[0106] In another aspect, provided herein is a method for treating substance abuse in a human patient addicted thereto, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL
, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0107] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0108] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiments, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after Date Recue/Date Received 2023-11-27 the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0109] In another aspect, provided herein is a a method for treating substance abuse in a human patient addicted thereto, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL
, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval prolongation of less than about 20 ms during said treatment.
[0110] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0111] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose.
[0112] In another aspect, provided herein is a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to drug addiction, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum Date Recue/Date Received 2023-11-27 concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0113] In another embodiment, the withdrawal symptoms are due to acute withdrawal.
In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0114] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose.
[0115] In another aspect, provided herein is a method to prevent relapse of drug abuse in a patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is no longer abusing the drug, wherein the dosage is less than about 70% of the therapeutic dose, and further wherein the prolongation of the QT interval is no greater than about 30 ms.
[0116] In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 50 mg to 100 mg per day.
Pain Date Recue/Date Received 2023-11-27 [0117] In some embodiments, the current invention is predicated on the surprising discovery that treatment with a narrow dosage range of ibogaine between greater than about 0.1 mg/kg body weight and about 8 mg/kg body weight, provides a therapeutic alleviation of pain. Preferably, the dose range that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in humans is between about 0.1 mg per kg body weight and no more than about 3 mg per kg body weight and, more preferably between about 0.7 mg per kg body weight and no more than about 2 mg per kg body weight, or any subrange or subvalue within the aforementioned ranges.
[0118] In some embodiments, the narrow therapeutic doses of ibogaine described above do not prolong the QT interval to unacceptable levels in human patients. In some embodiments, patients are administered therapeutic doses of ibogaine in a clinical setting with cardiac monitoring. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with ibogaine. In one embodiment, a patient who exhibits a QT interval prolongation of less than about 20 ms after treatment with one or more therapeutic doses of ibogaine will not require further clinical monitoring. In one embodiment, the patient is not monitored after administration of ibogaine.
[0119] In some embodiments, the therapeutic dose of ibogaine administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 850 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of ibogaine administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
[0120] In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as a single dose. In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL is administered as multiple doses. In some embodiments, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 8 mg/kg. In one embodiment, the aggregate dose of ibogaine is from about 0.1 mg/kg to about 3 mg/kg. In another embodiment, the aggregate dose of ibogaine is from about 0.7 mg/kg to 1.5 mg/kg.

Date Recue/Date Received 2023-11-27 [0121] In one aspect, provided herein is a method for treating pain in a patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to alleviate and/or inhibit said pain while maintaining a QT interval of less than about 500 ms during said treatment.
[0122] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In one embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0123] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
In another embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 70 mg to 150 mg per day.
[0124] In another aspect, provided herein is a method for treating pain in a patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to alleviate and/or inhibit said pain while maintaining a QT interval prolongation of less than about 20 ms during said treatment.

Date Recue/Date Received 2023-11-27 [0125] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0126] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose.
[0127] In another aspect, provided herein is a method for alleviating pain symptoms in a human patient susceptible to such symptoms, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 500 ms during said treatment.
[0128] In another embodiment, the pain symptoms are due to chronic pain. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and Date Recue/Date Received 2023-11-27 b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0129] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose.
Migraine [0130] The current invention is predicated, in part, on the surprising discovery that treatment with a narrow dosage range of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, of between about 1 mg/kg body weight and about 4 mg/kg body weight, provides a therapeutic alleviation of migraine headaches. Preferably, the dose provides both therapeutic results and an acceptable QT
interval prolongation of less than about 50 milliseconds (ms) in humans.
[0131] This invention is based, in part, on the discovery that noribogaine reduces frequency, severity, and/or length of headaches, and particularly migraine headaches. This invention is further based on the discovery that at very low doses, direct blood stream delivery of noribogaine can treat and/or prevent migraine headaches. Direct blood stream delivery of noribogaine enhances the amount of noribogaine delivered to the brain, because noribogaine so administered does not initially pass through the liver before reaching the brain as it does when ingested. Direct blood stream delivery of noribogaine includes sublingual, buccal, pulmonary and intranasal delivery, where the noribogaine is absorbed directly into the blood stream for delivery into the brain. The rapid delivery of noribogaine into the brain may cause a significant reduction in the symptoms of migraine, typically less than 15 minutes after administration.
[0132] Migraine headaches may contain four phases, although not all phases are experienced in all cases. The first phase is the prodrome phase, wherein the patient experiences irritability, altered mood, depression or euphoria, fatigue, food cravings, Date Recue/Date Received 2023-11-27 muscle stiffness, constipation or diarrhea, and sensitivity to smells and/or noise. The second phase is the aura phase, characterized by visual, sensory, or motor effects. Only a subset of migraines include auras. The third phase is the pain phase; pain is often accompanied by nausea, vomiting, sensitivity to sensory input, fatigue, irritability, vertigo, light-headedness, confusion, blurred vision, nasal stuffiness, diarrhea, frequent urination, pallor, or sweating. The final phase is the postdrome phase, and may include a sore feeling at the site of the migraine, impaired thinking, fatigue, head pain, mood changes, gastrointestinal symptoms, and weakness.
[0133] The cause of migraines is unclear, but migraines can be brought on by triggers, including hormone changes, stress, hunger, fatigue, certain smells, foods, poor air quality, etc. Migraine may also be affected by genetic factors.
[0134] In one aspect, this invention relates to methods of treating or preventing migraines and/or symptoms thereof, comprising administration of a therapeutic amount of noribogaine. As used herein, unless specified otherwise, noribogaine includes noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. In one embodiment, the patient is co-administered a therapeutic amount of an agent known to treat migraines in addition to noribogaine. In a preferred embodiment, the co-treatment does not result in a QT interval prolongation of greater than 50 ms. In one embodiment, both compounds are administered at the same time. In one embodiment, the compounds are administered at different times (e.g., sequentially).
[0135] In one aspect, this invention relates to treating migraines and/or symptoms thereof in a patient in need thereof, comprising administering to the patient by direct blood stream delivery a therapeutically effective amount of noribogaine or derivative. In one aspect, a therapeutically effective amount of noribogaine or derivative is from about 50 ng to about 10 lag per kg of body weight. In some embodiments, the therapeutically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day. In one embodiment, an agent known to treat and/or prevent migraines is also administered.
[0136] In another aspect, this invention provides a method for treating migraines and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a therapeutic amount of noribogaine or a noribogaine derivative or pharmaceutically Date Recue/Date Received 2023-11-27 acceptable salt thereof, wherein the noribogaine or derivative or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, buccal, or intrapulmonary delivery.
[0137] This invention relates to methods of preventing migraines and/or symptoms thereof, comprising administration of a prophylactic amount of noribogaine to prevent or ameliorate migraine and/or symptoms thereof. As used herein, unless specified otherwise, noribogaine includes noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. In one embodiment, an agent known to treat and/or prevent migraines is also administered.
[0138] In one aspect, this invention relates to preventing migraines and/or symptoms thereof in a patient in need thereof, comprising administering to the patient by direct blood stream delivery a prophylactically effective amount of noribogaine. In one aspect, a prophylactically effective amount of noribogaine is from about 1 mg to about 2 mg per kg of body weight. In one aspect, a prophylactically effective amount of noribogaine is from about 50 ng to about 10 lig per kg of body weight. In some embodiments, the prophylactically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day. In some embodiments, the prophylactically effective amount is administered regularly (e.g., every day).
In some embodiments, the prophylactically effective amount is administered prior to, concurrent with, or immediately after potential triggers for migraine. In some embodiments, the prophylactically effective amount is administered when the patient feels the onset of at least one symptom of migraine. In one embodiment, an agent known to treat and/or prevent migraines is also administered.
[0139] In another aspect, this invention provides a method for preventing migraines and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the noribogaine, derivative, or salt thereof is administered by sublingual, intranasal, buccal, or intrapulmonary delivery.
[0140] As will be apparent to the skilled artisan upon reading this disclosure, this invention, in one aspect, provides a method for treating or preventing migraines and/or symptoms thereof in a subject, comprising administering to the patient in need thereof a Date Recue/Date Received 2023-11-27 therapeutically effective amount of noribogaine, a noribogaine derivative, a noribogaine prodrug, or a pharmaceutically acceptable salt of each thereof. In one embodiment, the method further comprises administering at least one agent known to treat or prevent migraines and/or symptoms thereof.
[0141] In another aspect, this invention provides a composition for treating and/or preventing migraines, comprising a therapeutic or prophylactic amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, at least one agent that is known to treat ancUor prevent migraines, and optionally a pharmaceutically acceptable excipient.
[0142] In another aspect, provided herein is a method for treating migraine headache and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a phatmaceutically acceptable salt thereof.
[0143] In one embodiment, the therapeutically effective amount is from about 50 ng to about 10 i.tg per kg body weight per day. In another embodiment, the therapeutically effective amount is from about 1 mg to about 4 mg per kg body weight per day.
In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once a day. In another embodiment, the therapeutically effective amount is administered two or more times per day.
[0144] In another aspect, provided herein is a method for preventing migraine headache and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof.
[0145] In one embodiment, the prophylactically effective amount is from about 50 ng to about 10 lag per kg body weight per day. In another embodiment, the prophylactically effective amount is less than about 90% of the therapeutically effective amount. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, buccal, or intrapulmonary Date Recue/Date Received 2023-11-27 delivery. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered on an as-needed basis as determined by the subject. In another embodiment, the patient's QT interval is not prolonged by more than about 30 ms. In another embodiment, the method further comprises administering at least one agent known to treat and/or prevent migraine and/or symptoms thereof. In another embodiment, the at least one agent is selected from the group consisting of: an analgesic, a triptan, an ergotamine, and dexamethasone.
Reducing Tolerance To Opioid Analgesics [0146] This invention is directed, in part, to the use of noribogaine to modulate tolerance to addictive opioid analgesic agents in a patient who has developed or is at risk of developing a tolerance for the analgesic. In such methods, effective analgesia can be achieved in a patient while resensitizing the patient to the addictive opioid analgesic. The term "resensitizing the patient" is used herein to refer to reducing, relieving, attenuating, and/or reversing tolerance to the analgesic. In one aspect, the resensitized patient obtains therapeutic effect from a lower dose of the opioid analgesic than before resensitization. In one aspect, the resensitized patient obtains improved therapeutic effect from the same dose of the opioid analgesic compared to before resensitization.
[0147] In one embodiment, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered concurrently with the opioid analgesic. In one embodiment, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered after administration of the analgesic, for example one, two, three, four, eight, ten, twelve, 24 hours or more after administration of the analgesic. In one embodiment, one dose of noribogaine is administered.
In one embodiment, two or more doses of noribogaine are administered. In one embodiment, the opioid analgesic is interrupted for a period of time while noribogaine is administered. In one embodiment, a non-opioid analgesic is administered while the opioid analgesic is interrupted. In one embodiment, noribogaine acts as an analgesic. In one embodiment, the opioid analgesic is not interrupted during noribogaine treatment.
[0148] In some embodiments, the unit dose that provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in opioid-tolerant humans is about 120 mg. In some embodiments, the unit dose that provides both therapeutic results Date Recue/Date Received 2023-11-27 and an acceptable QT interval prolongation of less than 50 milliseconds in opioid-tolerant humans is 2 mg/kg body weight.
[0149] In one aspect, provided herein is a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL
said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
[0150] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
In another embodiment, the method further comprises interrupting the dosage of the analgesic. In another embodiment, the method further comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic. In another embodiment, during concurrent administration, the dose of opioid analgesic is reduced. In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0151] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
Date Recue/Date Received 2023-11-27 [0152] In one aspect, provided herein is a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT interval prolongation of less than about 20 ms during said treatment.
[0153] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
In another embodiment, the method further comprising interrupting the dosage of the analgesic. In another embodiment, the method further comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic. In another embodiment, during concurrent administration, the dose of opioid analgesic is reduced. In another embodiment, the method further comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0154] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0155] In another embodiment, the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, Date Recue/Date Received 2023-11-27 buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, and oxymorphone. In another embodiment, the opioid analgesic is morphine.
Depression [0156] There are certain properties of noribogaine that present this compound as a very attractive candidate for the treatment of depression and/or postraumatic stress disorder (PTSD). These include the interaction of noribogaine with a variety of receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opioid receptors (e.g., -opiod receptors). Further, noribogaine elevates brain serotonin levels by blocking synaptic reuptake via the SERT transporter. As such, this invention relates to methods of treating depression and/or PTSD, or symptoms thereof, comprising administering to a patient noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0157] At very low doses, direct blood stream delivery of noribogaine may reduce symptoms of depression and/or PTSD. Such dosing is well below that previously described. Direct blood stream delivery of noribogaine enhances the amount of noribogaine delivered to the brain, because noribogaine does not pass through the liver as it does when ingested. Direct blood stream delivery of noribogaine includes sublingual, pulmonary and intranasal delivery where the noribogaine is absorbed directly into the blood stream and then into the brain. The rapid delivery of noribogaine into the brain, e.g.
less than 15 minutes, may cause a significant reduction in symptoms of depression and/or PTSD.
[0158] In one aspect, this invention relates to treating depression and/or PTSD in a patient in need thereof comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, solvate, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, this invention treats depression. In another embodiment, this invention treats PTSD. In a preferred embodiment, the patient is not addicted to cocaine or an opiate. Unlike PTSD, conventional anxiety disorders are not within the scope of this invention.

Date Recue/Date Received 2023-11-27 [0159] In some embodiments, the therapeutic dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient is sufficient to provide an average serum concentration of 50 ng/mL to 180 ng/mL, or any subrange or subvalue there between. In one embodiment, the dose of noribogaine or phatinaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of 50 ng/mL to 150 ng/mL. In one embodiment, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of 80 ng/mL to 100 ng/mL.
[0160] In some embodiments, the serum concentration is sufficient to inhibit or ameliorate symptoms of depression and/or PTSD while maintaining a QT interval of less than 500 milliseconds (ms) during said treatment. In some embodiments, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms. In some embodiments, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 30 ms. In a preferred embodiment, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 20 ms. In a preferred embodiment, the patient is tested to determine QT interval before treatment with noribogaine, and if clinician determines that the QT prolongation would be an unacceptable risk, noribogaine therapy will be contraindicated.
[0161] In another aspect, this invention provides a method for treating depression and/or PTSD in a patient in need thereof comprising administering to the patient noribogaine or a noribogaine derivative in a sustained release manner such that the concentration of noribogaine, noribogaine derivative, pharmaceutically acceptable salt and/or solvate thereof is maintained at a therapeutically effective amount for period of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or a period of time between any two of these durations.
[0162] In another aspect, provided herein is a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted Date Recue/Date Received 2023-11-27 to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0163] In another aspect, provided herein is a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval prolongation of less than about 20 ms during said treatment.
[0164] In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
[0165] In another embodiment, the method comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.
[0166] In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT
interval. In another embodiment, depression is treated. In another embodiment, posttraumatic stress disorder is treated.

Date Recue/Date Received 2023-11-27 Anxiety [0167] There are certain properties of noribogaine that present this compound as a very attractive candidate for the treatment of anxiety disorders, impulse control disorder, anger/violence-related disorders, or regulation of food intake. These include the interaction of noribogaine with a variety of receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opioid receptors (e.g., -opiod receptors). Further, noribogaine elevates brain serotonin levels by blocking synaptic reuptake via the SERT
transporter. As such, this invention relates to methods of treating anxiety disorders, impulse control disorder, anger/violence-related disorders, or symptoms thereof; or regulation of food intake, comprising administering to a patient noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.
[0168] At very low doses, direct blood stream delivery of noribogaine may reduce symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or provide regulation of food intake. Such dosing is well below that previously described.
Direct blood stream delivery of noribogaine enhances the amount of noribogaine delivered to the brain, because noribogaine does not pass through the liver as it does when ingested.
Direct blood stream delivery of noribogaine includes sublingual, pulmonary and intranasal delivery where the noribogaine is absorbed directly into the blood stream and then into the brain. The rapid delivery of noribogaine into the brain, e.g. less than about 15 minutes, may cause a significant reduction in symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or food cravings.
[0169] In one aspect, this invention relates to treating anxiety disorders, impulse control disorder, anger/violence-related disorders, or regulation of food intake in a patient in need thereof comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, solvate, or pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, this invention treats an anxiety disorder.
In one embodiment, this invention treats OCD. In one embodiment, this invention treats generalized anxiety disorder. In one embodiment, this invention treats social anxiety disorder. In one embodiment, this invention treats panic disorder. In another embodiment, this invention treats impulse control disorder. In another embodiment, this invention treats pathological anger and/or violence. In another embodiment, this invention treats Date Recue/Date Received 2023-11-27 anger/violence-related disorders. In another embodiment, this invention reduces pathological anger in a patient. In another embodiment, this invention reduces violent outbursts in a patient. In another embodiment, this invention regulates food intake. In one embodiment, food consumption is reduced. In one embodiment, food cravings are reduced. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
[0170] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is sufficient to provide an average serum concentration of about 50 ng/mL to about 180 ng/mL, or any subrange or subvalue there between. In a preferred embodiment, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 110 ng/mL. In one embodiment, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of about 50 ng/mL to about 100 ng/mL. In one embodiment, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof administered to the patient provides an average serum concentration of less than about 50 ng/mL.
[0171] In some embodiments, the serum concentration is sufficient to inhibit or ameliorate symptoms of anxiety disorders, impulse control disorder, anger/violence-related disorders, or to regulate food intakewhile maintaining a QT interval of less than about 500 milliseconds (ms) during said treatment. In some embodiments, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof maintains a QT
interval of less than about 450 ms. In some embodiments, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof maintains a QT
interval of less than about 420 ms.
[0172] In some embodiments, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than about 50 ms. In some embodiments, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than about 30 ms.
In a preferred embodiment, the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than about 20 ms.
In a preferred embodiment, the patient is tested to determine QT interval before treatment Date Recue/Date Received 2023-11-27 with noribogaine, and if clinician determines that the QT prolongation would be an unacceptable risk, noribogaine therapy will be contraindicated.
[0173] In another aspect, this invention provides a method for treating anxiety disorders, impulse control disorder, anger/violence-related disorders, or regulating food intakein a patient in need thereof comprising administering to the patient noribogaine or a noribogaine derivative in a sustained release manner such that the concentration of noribogaine, noribogaine derivative, pharmaceutically acceptable salt and/or solvate thereof is maintained at a therapeutically effective amount for period of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or a period of time between any two of these durations.
[0174] In one aspect, provided herein is a method for treating an anxiety-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0175] In one embodiment, the anxiety-related disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social anxiety disorder.
[0176] In one aspect, provided herein is a method for treating an impulse control disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0177] In one embodiment, the impulse control disorder is selected from the group consisting of borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder, attention deficit disorder, schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, Date Recue/Date Received 2023-11-27 kleptomania, sexual compulsion, paraphilia, intemet addiction, trichotillomania, pathological skin picking, and compulsive shopping.
[0178] In one aspect, provided herein is a method for regulating food intake and/or attenuating food craving in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0179] In one aspect, provided herein is a method for treating an anger-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.
[0180] In one embodiment, the method, comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL for a period of time.
[0181] In another embodiment, the initial dose is from about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg.
In another embodiment, the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from about 6 hours to about 24 hours after the previous dose. In another embodiment, the QT
interval is less than about 450 ms. In another embodiment, the method further comprises Date Recue/Date Received 2023-11-27 selecting a patient who is prescreened to evaluate tolerance for prolongation of QT
interval. In another embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.
[0182] Noribogaine induces side effects in some patients. Methods are needed for pre-screening an opioid-addicted patient to determine the patient's tolerance for a therapeutic dose of noribogaine.
[0183] Noribogaine is administered to ameliorate acute and post-acute withdrawal symptoms. In particular, initial testing of noribogaine therapy with methadone addicted patients indicates that a single 120 mg dosing of noribogaine generally provides a meaningful therapeutic response, whereas a single 60 mg dosing of noribogaine generally does not provide a meaningful therapeutic response. It follows that a single 90 mg dose of noribogaine shows some therapy but is sub-therapeutic for commercial purposes.
[0184] Unexpectedly, it was discovered that noribogaine behaves in a linear pattern regarding QT interval prolongation. For example, doubling the dose of noribogaine will result in about a doubling of the QT interval prolongation in the patient. As such, QT
interval and QT interval prolongation data obtained from a sub-therapeutic dose of less than 120 mg of noribogaine, such as about 90 mg, can be used as a predictor of the patient's tolerance for therapeutic noribogaine treatment at the therapeutic dose of 120 mg.
This is possible because the QT interval and QT interval prolongation data obtained from a sub-therapeutic dose of less than 120 mg of noribogaine can be accurately extrapolated for a dose of 120 mg noribogaine without subjecting the patient to a potentially life-threatening side effect at the therapeutic dosage.
[0185] As initially noted above, opioid-addicted patients treated with 120 mg noribogaine exhibit a significantly longer time to resumption of opioid substitution therapy than patients treated with 60 mg. Patients receiving 120 mg noribogaine also exhibit variable QT interval prolongation with an average prolongation of approximately 38 milliseconds (ms). Some patients exhibit QT interval prolongation of greater than 50 ms, or a QT interval of greater than 500 ms. A patient with a QT interval that is greater than 500 ms, or is prolonged more than 50 ms, is at high risk of ventricular tachyarrhythmia and possibly death.

Date Recue/Date Received 2023-11-27 [0186] Provided is a pre-screening method for predicting which patients are eligible for noribogaine therapy based on those who exhibit an unacceptable QT interval prolongation or a QT interval of over 500 milliseconds when treated with noribogaine. This method for predicting either an unacceptable QT interval prolongation of greater than 50 milliseconds or a QT interval of greater than 500 milliseconds can be used as a means of using sub-therapeutic doses (less than 120 mg) of noribogaine to screen out such patients before therapeutic doses (120 mg) of noribogaine therapy are initiated.
Patient Pre-screening [0187] As will be apparent to the skilled artisan upon reading this disclosure, the present invention provides a method for pre-screening an opioid-addicted patient, or another patient in need of treatment or prevention as provided herein, to determine the patient's tolerance for a therapeutic dose of noribogaine.
[0188] In one aspect, provided is a method for screening an opioid-addicted patient, or another patient in need of treatment or prevention as provided herein, to determine the patient's tolerance for a therapeutic dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof, the method comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a sub-therapeutic dose of noribogaine or pharmaceutically acceptable salt thereof; and measuring the patient's post-administration QT interval.
[0189] In some embodiments, the method further comprises one or more of:
determining the difference between pre-administration QT interval and post-administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the second prolongation is the estimated QT interval prolongation expected to be observed in the patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and Date Recue/Date Received 2023-11-27 administering to the patient the therapeutic dose of noribogaine or discontinuing noribogaine treatment, wherein a therapeutic dose is administered if the second prolongation is estimated to be less than about 50 ms.
[0190] In one embodiment, provided is a method for screening an opioid-addicted patient to determine the patient's tolerance for a therapeutic dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof, the method comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a sub-therapeutic dose of noribogaine or pharmaceutically acceptable salt thereof;
measuring the patient's post-administration QT interval;
determining the difference between pre-administration QT interval and post-administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the second prolongation is the estimated QT interval prolongation expected to be observed in the patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and administering to the patient the therapeutic dose of noribogaine or discontinuing noribogaine treatment, wherein a therapeutic dose is administered if the second prolongation is estimated to be less than about 50 ms.
[0191] In one embodiment, a therapeutic dose is administered if the second prolongation is estimated to be less than about 40 ms. In one embodiment, a therapeutic dose is administered if the second prolongation is estimated to be less than about 30 ms. In one embodiment, a therapeutic dose is administered if the second prolongation is estimated to be less than about 20 ms. In one embodiment, a therapeutic dose is administered if the second prolongation is estimated to be less than about 10 ms.
[0192] In one embodiment, the therapeutic dose provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to inhibit or Date Recue/Date Received 2023-11-27 ameliorate opioid addiction while resulting in prolongation of the patient's QT interval of less than a threshold, for example about 50 ms.
[0193] In a preferred embodiment, the therapeutic dose is about 120 mg noribogaine. In another embodiment, the therapeutic dose is between 70-120 mg noribogaine. In another embodiment, the therapeutic dose is between 100-150 mg noribogaine. In another embodiment, the therapeutic dose is more than 150 mg noribogaine. In one embodiment, the therapeutic dose is between 1 mg per kg body weight and 4 mg per kg body weight.
[0194] In one embodiment, the therapeutic dose is administered in one or more dosings, such as one, two, three, four, five or more dosings over one or more days.
[0195] In one embodiment, the sub-therapeutic dose is administered in one or more dosings, such as one, two, three, four, five or more dosings over one or more days.
[0196] In one embodiment, the sub-therapeutic dose of noribogaine may be e.g., 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective dose (e.g., 120 mg) of noribogaine, or any subvalue or subrange there between.
[0197] In one embodiment, the sub-therapeutic dose of noribogaine may be e.g., 110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 5 mg, 2 mg, 1 mg of noribogaine, or any subvalue or subrange there between.
[0198] In one embodiment, where the second prolongation is estimated to be greater than a threshold QT interval prolongation, the patient is administered a sub-therapeutic dose of noribogaine.
[0199] In one embodiment, where the second prolongation is estimated to be greater than a threshold QT interval prolongation, the patient is administered a therapeutic dose of noribogaine in multiple administrations. For example, where the therapeutic dose is 120 mg per day, 60 mg may be given every 12 hours. Without being limited by theory, it is believed that multiple administrations will lower the maximum serum concentration of noribogaine experienced by the patient, thereby reducing QT interval prolongation.
[0200] In one embodiment, where the second prolongation is estimated to be greater than a threshold QT interval prolongation, the patient is administered an initial dose of Date Recue/Date Received 2023-11-27 noribogaine, followed by one or more additional doses. In one embodiment, the initial dose is from 75 mg to 120 mg. In one embodiment, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from mg to 50 mg. In one embodiment, such a dosing regimen provides an average serum concentration of noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, such a dosing regimen provides an average serum concentration of noribogaine of 80 ng/mL to 100 ng/mL. In one embodiment, the one or more additional doses maintain an average serum concentration of 50 ng/mL to 180 ng/mL over a period of time. In one embodiment, the one or more additional doses maintain an average serum concentration of 80 ng/mL to 100 ng/mL over a period of time. In one embodiment, the one or more additional doses are administered periodically, such as every 4 hours, every 6 hours, every 8 hours, every 12 hours, or every 24 hours.
[0201] In one embodiment, the threshold QT interval prolongation is 50 ms. In one embodiment, the threshold QT interval prolongation is 40 ms. In one embodiment, the threshold QT interval prolongation is 30 ms. In one embodiment, the threshold QT interval prolongation is 20 ms. In one embodiment, the threshold QT interval prolongation is 10 ms.
[0202] In one embodiment, the therapeutic amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from 50 ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the therapeutic amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150 ng/mL. In one embodiment, the therapeutic amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from 50 ng/mL to 100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the therapeutic amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from 80 ng/mL to 100 ng/mL The ranges include both extremes as well as any subranges between.
[0203] In one aspect, provided herein is a method for screening an opioid-addicted patient to determine the patient's tolerance for a therapeutic dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof, the method comprising:
measuring the patient's pre-administration QT interval;

Date Recue/Date Received 2023-11-27 administering to the patient a sub-therapeutic dose of noribogaine or pharmaceutically acceptable salt thereof; and measuring the patient's post-administration QT interval.
[0204] In one embodiment, the method further comprises one or more of:
determining the difference between pre-administration QT interval and post-administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the second prolongation is the estimated QT interval prolongation expected to be observed in the patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and administering to the patient the therapeutic dose of noribogaine or discontinuing noribogaine treatment, wherein a therapeutic dose is administered if the second prolongation is estimated to be less than about 50 ms.
[0205] In another embodiment, the therapeutic dose provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to inhibit or ameliorate opioid addiction while resulting in prolongation of the patient's QT interval of less than about 50 ms.
[0206] In another embodiment, the method further comprises:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.

Date Recue/Date Received 2023-11-27 [0207] In another embodiment, the therapeutic dose is administered in one or more dosings. In another embodiment, the sub-therapeutic dose is administered in one or more dosings. In another embodiment, the sub-therapeutic dose is 80% or less than the therapeutic dose. In another embodiment, the sub-therapeutic dose is 70% or less than the therapeutic dose. In another embodiment, the sub-therapeutic dose is between 60 mg and 100 mg. In another embodiment, the sub-therapeutic dose is about 90 mg.
Sustained Treatment [0208] In one aspect, the current invention is predicated on the surprising discovery that treatment with a narrow dosage range of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a therapeutic blood serum concentration in treated patients.
[0209] In some aspects the present invention provides a method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT
interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein said unit dose provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which serum concentration imparts minimal QT interval prolongation; and b) maintaining said serum concentration by periodically administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL during treatment wherein said additional dose or doses are continued as necessary to treat said condition.
[0210] In one embodiment, the therapeutic blood serum concentration is between ng/mL and 180 ng/mL. In a preferred embodiment, the therapeutic serum concentration is 80 ng/mL to 100 ng/mL. In one embodiment, the dose range provides both therapeutic results and an acceptable QT interval prolongation of less than 50 milliseconds in a patient. In one embodiment, an initial unit dose of noribogaine, noribogaine derivative, or Date Recue/Date Received 2023-11-27 pharmaceutically acceptable salt or solvate thereof is administered. In one embodiment, the initial unit dose provides the therapeutic blood serum concentration with minimal QT
interval prolongation. In one embodiment, the QT interval is not prolonged by more than 20 ms.
[0211] In some embodiments, the patient is administered an initial unit dose of noribogaine, noribogaine derivative, or phat tnaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, the initial unit dose is from 50 mg to 120 mg. In one embodiment, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 50 mg.
In one embodiment, such a dosing regimen provides a therapeutic average serum concentration of noribogaine of 50 ng/mL to 180 ng/mL. In one embodiment, the one or more additional doses maintain a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL over a period of time. In one embodiment, the one or more additional doses are administered periodically. In one embodiment, the at least one additional dose is administered between about 6 hours and about 24 hours after administration of the initial unit dose. In one embodiment, the at least one additional dose is administered between about 6 hours and about 24 hours after administration of the previous dose. In one embodiment, one or more doses are administered as a controlled release formulation.
[0212] In one embodiment, the narrow therapeutic doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate described above unexpectedly do not prolong the QT interval to unacceptable levels in human patients. In some embodiments, the patient will be pre-screened to evaluate tolerance for prolongation of QT
interval, e.g., to determine whether the patient has any pre-existing cardiac conditions which would disqualify them from treatment with noribogaine. In some embodiments, the patient undergoes cardiac monitoring during a portion of the treatment. In a preferred embodiment, cardiac monitoring is not required. In one embodiment, the patient is tested to determine QT interval before treatment with noribogaine, and if clinician determines that the QT prolongation would be unacceptable risk, noribogaine therapy will be contraindicated.
[0213] In one aspect, provided herein is a method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically Date Recue/Date Received 2023-11-27 acceptable salt or solvate thereof while maintaining an acceptable QT interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein said unit dose provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which serum concentration imparts an acceptable QT interval in said patient; and b) maintaining said serum concentration by periodically administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the therapeutic average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
wherein said additional dose or doses are continued as necessary to treat said condition, and further wherein said acceptable QT interval is no longer than 500 ms.
102141 In one embodiment, the QT interval is prolonged by less than 50 ms. In another embodiment, the QT interval is prolonged by less than 20 ms. In another embodiment, the initial unit dose is higher than any of the at least one additional dose.
In another embodiment, the initial unit dose and at least one additional dose are incorporated into a single controlled release formulation. In another embodiment, the initial unit dose is administered as subunit doses, which subunit doses are administered serially until the unit dose level is achieved, wherein the aggregate of subunit doses provides the initial unit dose and further provides the therapeutic average serum concentration. In another embodiment, the initial unit dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
102151 In another aspect, provided herein is a method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically Date Recue/Date Received 2023-11-27 acceptable salt or solvate thereof while maintaining an acceptable QT interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein said unit dose provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which serum concentration imparts an acceptable QT interval prolongation in said patient; and b) maintaining said serum concentration by periodically administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the therapeutic average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
wherein said additional dose or doses are continued as necessary to treat said condition, and further wherein said acceptable QT interval prolongation is no longer than 50 ms.
[0216] In one embodiment, the QT interval prolongation is less than 20 ms. In another embodiment, the initial unit dose is higher than any of the at least one additional dose. In another embodiment, the initial unit dose and at least one additional dose are incorporated into a single controlled release formulation. In another embodiment, the initial unit dose is administered as subunit doses, which subunit doses are administered serially until the unit dose level is achieved, wherein the aggregate of subunit doses provides the initial unit dose and further provides the therapeutic average serum concentration. In another embodiment, the initial unit dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg. In another embodiment, the at least one additional dose is administered from 6 hours to 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and further wherein the additional doses are administered from 6 hours to 24 hours after the previous dose. In another embodiment, the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
[0217] In another embodiment, noribogaine or a pharmaceutically acceptable salt and/or solvate thereof is administered.

Date Recue/Date Received 2023-11-27 Formulations [0218] In another aspect, provided herein is a pharmaceutically acceptable formulation comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine is sufficient to provide a serum concentration of about 50 ng/mL to about 180 ng/mL when administered to a patient. In one embodiment, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered in one or more dosings.
In another embodiment, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg.
BRIEF DESCRIPTION OF THE FIGURES
[0219] FIG. 1 represents mean noribogaine concentration-time profiles in healthy patients after single oral dosing with 3, 10, 30 or 60 mg doses. Inset:
Individual concentration-time profiles from 0-12 h after a 10 mg dose.
[0220] FIG. 2 represents mean plasma noribogaine glucuronide concentration-time profiles in healthy patients after single oral 30 or 60 mg doses.
[0221] FIG. 3 illustrates the mean noribogaine concentration-time profile in opioid-addicted patients after a single oral 60 mg (diamonds), 120 mg (squares), or 180 mg (triangles) dose of noribogaine.
[0222] FIG. 4 illustrates hours to resumption of opioid substitution treatment (OST) for each patient given placebo (circles), or a single oral dose of noribogaine (60 mg, squares;
120 mg, triangles; 180 mg, inverted triangles). Center horizontal line represents mean.
Error bars represent standard deviation.
[0223] FIG. 5 illustrates results of noribogaine treatment on final COWS
scores before resumption of OST. Boxes include values representing 25% ¨ 75% quartiles.
Diamonds represent the median, crossbars represent mean. Whiskers represent values within one standard deviation of mid-quartiles. No outliers were present.

Date Recue/Date Received 2023-11-27 [0224] FIG. 6A illustrates of the mean change in total COWS scores over the first 6 hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles). Data is given relative to baseline COWS score.
[0225] FIG. 6B illustrates the mean area under the curve (AUC) over the initial 6 hour period after administration of noribogaine or placebo, based on the COWS score data given in Figure 6A. A negative change in score indicates that withdrawal symptoms subsided over the period.
[0226] FIG. 7A illustrates of the mean change in total 0OWS scores over the first 6 hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles). Data is given relative to baseline 0OWS score.
[0227] FIG. 7B illustrates the mean area under the curve (AUC) over the initial 6 hour period after administration of noribogaine or placebo, based on the 0OWS score data given in Figure 7A. A negative change in score indicates that withdrawal symptoms subsided over the period.
[0228] FIG. 8A illustrates of the mean change in total SOWS scores over the first 6 hours following dosing of noribogaine (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles). Data is given relative to baseline SOWS score.
[0229] FIG. 8B illustrates the mean area under the curve (AUC) over the initial 6 hour period after administration of noribogaine or placebo, based on the SOWS score data given in Figure 8A. A negative change in score indicates that withdrawal symptoms subsided over the period.
[0230] FIG. 9A illustrates the average change in QT interval (AQTc1) for each cohort (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles) over the first 24 hours post administration.
[0231] FIG. 9B illustrates the correlation between serum noribogaine concentration and AQTcl for each patient over time. The equation of the line is given.
Date Recue/Date Received 2023-11-27 [0232] FIG. 10A represents the effects of noribogaine and varenicline in nicotine dependent rats. Data represent mean + standard error of the mean (SEM).
#P<0.10;
***P<0.001 compared to vehicle or saline treatment.
[0233] FIG. 10B represents the effects of noribogaine and varenicline on percentage of inactive lever press during nicotine self-administration. Data represent mean + SEM.
[0234] FIG. 11 represents the effects of noribogaine on general motor activity of zebrafish during nicotine withdrawal. Behavioral endpoints examined include, latency to upper half of tank (panel A), transitions to upper half of tank(panel B), transitions to upper half of tank per minute (panel C), time in upper half of tank (panel D), time in upper half of tank per minute (panel E), average entry duration (panel F), and average entry duration per minute (panel G).
[0235] FIG. 12 represents effects of noribogaine on general motor activity of zebrafish during nicotine withdrawal. Behavioral endpoints examined include, distance moved (panel A), velocity (panel B), rotation angle (panel C), number of rotation events (panel D), change in direction of body/heading (panel E), change in direction of movement per distance moved/meander total (panels F and G).
[0236] FIG. 13 depicts effects of noribogaine on freezing bouts frequency (panel A) and duration of freezing bouts (panels B and C).
[0237] FIG. 14 depicts effects of noribogaine treatment on movement mobility.
Immobile (dark squares) was used to express the frequency of episodes with degree of movement independent of spatial displacement (duration of immobility). Mobile (medium gray squares) reflects overall locomotor activity. Hi-mobile (light gray squares) reflects bouts of accelerated swimming (>60 % of individual average).
[0238] FIG. 15 shows representative traces of control, chronic nicotine, repeated nicotine withdrawal (WD), and WD + 1 mg/L noribogaine treatment (from top to bottom), recorded in the 5 minute novel tank test (NTT) by Ethovision XT8.5 software.
[0239] FIG. 16 shows the effects of noribogaine treatment (at 1-, 5- and 10-mg/L doses) on general motor activity of zebrafish. Behavioral endpoints examined include:
latency to upper half of tank (panel A), transitions to upper half of tank (panel B), transitions to Date Recue/Date Received 2023-11-27 upper half of tank per minute (panel C), time in upper half of tank (panel D), time in upper half of tank per minute (panel E), average entry duration (panel F), and average entry duration per minute (panel G).
[0240] FIG. 17 shows the effects of noribogaine treatment (at 1-, 5- and 10-mg/L doses) on general motor activity of zebrafish. Behavioral endpoints examined include:
distance moved (panel A), velocity (panel B), rotation angle (panel C), number of rotation events (panel D), change in direction of body/heading (panel E), change in direction of movement per distance moved/meander total (panels F and G).
[0241] FIG. 18 depicts effects of noribogaine (at 1-, 5- and 10-mg/L doses) on freezing bouts frequency (panel A) and duration of freezing bouts (panel B).
[0242] FIG. 19 depicts effects of noribogaine treatment on movement mobility, including percentage of events per animal (panel A) and duration (panel B).
"Immobile"
(high frequency "HF" or low frequency "LF") was used to express the frequency of episodes with degree of movement independent of spatial displacement (duration of immobility). Mobile (HF or LF) reflects frequency of episodes of moderate locomotor activity. Hi-mobile (HF and LF) reflects bouts of accelerated velocity (>60 %
of individual average).
[0243] FIG. 20 shows representative traces of control (top row) and noribogaine-treated fish (1, 5 and 10 mg/L, from top to bottom), recorded in the 5 minute novel tank test (NTT) by Ethovision XT8.5 software.
DETAILED DESCRIPTION
[0244] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of this invention will be limited only by the appended claims.
[0245] The detailed description of the invention is divided into various sections only for the reader's convenience and disclosure found in any section may be combined with that Date Recue/Date Received 2023-11-27 in another section. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
[0246] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.
I. Definitions [0247] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.
[0248] The term "about" when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( -) 20%, 10 %, 5 %,1 %, or any subrange or subvalue there between. Preferably, the term "about" when used with regard to a dose amount means that the dose may vary by +1- 20%. For example, "about 2 mg/kg noribogaine"
indicates that a patient may be administered a dose of noribogaine between 1.6 mg/kg and 2.4 mg/kg. In another example, about 120 mg per unit dose of noribogaine indicates that the unit dose may range from 96 mg to 144 mg.
[0249] "Administration" refers to introducing an agent, such as noribogaine, into a patient. Typically, an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used.
The agent, such as noribogaine may be administered by direct blood stream delivery, e.g.
sublingual, buccal, intranasal, or intrapulmonary administration.
[0250] The related terms and phrases "administering" and "administration of', when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient Date Recue/Date Received 2023-11-27 by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.
[0251] "Periodic administration" or "periodically administering" refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of an agent, such as noribogaine one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
[0252] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of' when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of' shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
[0253] As used herein, the term "alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from Ito 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). The term "C, alkyl" refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C3 refers to an alkyl group having 3 carbon atoms.
[0254] "Alkenyl" refers to straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by Date Recue/Date Received 2023-11-27 vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
[0255] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic unsaturation. Examples of such alkynyl groups include acetylenyl (-CECH), and propargyl (-CH2CCH).
[0256] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0257] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, Date Recue/Date Received 2023-11-27 hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.
[0258] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.
[0259] "Alkoxy" refers to the group -0-alkyl wherein alkyl is defined herein.
Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
[0260] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
[0261] "Acyl" refers to the groups H-C(0)-, alkyl-C(0)-, substituted alkyl-C(0)-, alkenyl-C(0)-, substituted alkenyl-C(0)-, alkynyl-C(0)-, substituted alkynyl-C(0)-, cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, cycloalkenyl-C(0)-, substituted cycloalkenyl-C(0)-, aryl-C(0)-, substituted aryl-C(0)-, heteroaryl-C(0)-, substituted Date Recue/Date Received 2023-11-27 heteroaryl-C(0)-, heterocyclic-C(0)-, and substituted heterocyclic-C(0)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CH3C(0)-.
[0262] "Acylamino" refers to the groups -NR38C(0)alkyl, -NR38C(0)substituted alkyl, -NR38C(0)cycloalkyl, -NR38C(0)substituted cycloalkyl, -NeC(0)cycloalkenyl, -NR38C(0)substituted cycloalkenyl, -NR38C(0)alkenyl, -NeC(0)substituted alkenyl, -NR38C(0)alkynyl, -NR38C(0)substituted alkynyl, -NR38C(0)aryl, -NR38C(0)substituted aryl, -NR38C(0)heteroaryl, -NR38C(0)substituted heteroaryl, -NR38C(0)heterocyclic, and -NR38C(0)substituted heterocyclic wherein R38 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0263] "Acyloxy" refers to the groups alkyl-C(0)O-, substituted alkyl-C(0)O-, alkenyl-C(0)O-, substituted alkenyl-C(0)O-, alkynyl-C(0)O-, substituted alkynyl-C(0)O-, aryl-C(0)O-, substituted aryl-C(0)O-, cycloalkyl-C(0)O-, substituted cycloalkyl-C(0)O-, cycloalkenyl-C(0)O-, substituted cycloalkenyl-C(0)O-, heteroaryl-C(0)O-, substituted heteroaryl-C(0)O-, heterocyclic-C(0)O-, and substituted heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0264] "Amino" refers to the group -NH2.
[0265] "Substituted amino" refers to the group -NR39R4 where R39 and R4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted Date Recue/Date Received 2023-11-27 heteroaryl, heterocyclic, substituted heterocyclic, -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cylcoalkyl, -S02-cycloalkenyl, -S02-substituted cylcoalkeny1,-S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, and -S02-substituted heterocyclic and wherein R39 and R4 are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R39 and R4 are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R39 is hydrogen and R4 is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R39 and R4 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R39 or R4 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R39 nor R4 are hydrogen.
102661 "Aminocarbonyl" refers to the group -C(0)NR41R42 where R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
102671 "Aminothiocarbonyl" refers to the group -C(S)NR41R42 where R4' and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where WI and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, Date Recue/Date Received 2023-11-27 alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0268] "Aminocarbonylamino" refers to the group -NR38C(0)NR41R42 where R38 is hydrogen or alkyl and R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R41- and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0269] "Aminothiocarbonylamino" refers to the group -NR38C(S)NR41R42 where R"
is hydrogen or alkyl and R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0270] "Aminocarbonyloxy" refers to the group -O-C(0)NR41R42 where R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted Date Recue/Date Received 2023-11-27 cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0271] "Aminosulfonyl" refers to the group -S02NR41R42 where R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R4' and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0272] "Aminosulfonyloxy" refers to the group -0-S02NR41K'-'42 where R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R41- and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0273] "Aminosulfonylamino" refers to the group -NR38-S02NR41R42 where R38 is hydrogen or alkyl and R41 and R42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R4I and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted Date Recue/Date Received 2023-11-27 cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0274] "Amidino" refers to the group -C(=NR43)NR41R42 where R41, R42, and R43 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R41 and R42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0275] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.
[0276] "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted Date Recue/Date Received 2023-11-27 heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0277] "Aryloxy" refers to the group -0-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
[0278] "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
[0279] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.
[0280] "Substituted arylthio" refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
[0281] "Carbonyl" refers to the divalent group -C(0)- which is equivalent to -C(=0)-.
[0282] "Carboxy" or "carboxyl" refers to -COOH or salts thereof.
[0283] "Carboxyl ester" or "carboxy ester" refers to the groups -C(0)0-alkyl, -C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted cycloalkyl, -C(0)0-cycloalkenyl, -C(0)0-substituted cycloalkenyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0-heterocyclic, and -C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0284] "(Carboxyl ester)amino" refers to the group -NR38-C(0)0-alkyl, -NR38-C(0)0-substituted alkyl, -NR38-C(0)0-alkenyl, -NR38-C(0)0-substituted alkenyl, -NR38-C(0)0-alkynyl, -NR38-C(0)0-substituted alkynyl, -NR38-C(0)0-aryl, -NR38-C(0)0-substituted aryl, -NR38-C(0)0-cycloalkyl, -Nle-C(0)0-substituted cycloalkyl, -NR38-C(0)0-cycloalkenyl, -NR38-C(0)0-substituted Date Recue/Date Received 2023-11-27 cycloalkenyl, -Ne-C(0)0-heteroaryl, -NR38-C(0)0-substituted heteroaryl, -NR38-C(0)0-heterocyclic, and -NR38-C(0)0-substituted heterocyclic wherein R38 is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0285] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl, substituted -0-C(0)0-alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted aryl, -0-C(0)0-cycloalkyl, -0-C(0)0-substituted cycloalkyl, -0-C(0)0-cycloalkenyl, -0-C(0)0-substituted cycloalkenyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0286] "Cyano" refers to the group -CN.
[0287] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and Spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2,]octanyl, norbornyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl.
[0288] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C=C
ring unsaturation and preferably from 1 to 2 sites of >C=C ring unsaturation.

Date Recue/Date Received 2023-11-27 [0289] "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
[0290] "Cycloalkyloxy" refers to -0-cycloalkyl.
[0291] "Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl).
[0292] "Cycloalkylthio" refers to -S-cycloalkyl.
[0293] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).
[0294] "Cycloalkenyloxy" refers to -0-cycloalkenyl.
[0295] "Substituted cycloalkenyloxy" refers to -0-(substituted cycloalkenyl).
[0296] "Cycloalkenylthio" refers to -S-cycloalkenyl.
[0297] "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).
[0298] "Guanidino" refers to the group -NHC(=NH)NH2.
[0299] "Substituted guanidino" refers to -NR44q_NR44)N(R44)2 where each R44 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, Date Recue/Date Received 2023-11-27 aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R44 groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R44 is not hydrogen, and wherein said substituents are as defined herein.
[0300] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
[0301] "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein.
[0302] "Haloalkoxy" refers to alkoxy groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and halo are as defined herein.
[0303] "Haloalkylthio" refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein.
[0304] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0305] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N¨>0), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
[0306] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.
[0307] "Heteroaryloxy" refers to -0-heteroaryl.
[0308] "Substituted heteroaryloxy" refers to the group -0-(substituted heteroaryl).
Date Recue/Date Received 2023-11-27 [0309] "Heteroarylthio" refers to the group -S-heteroaryl.
[0310] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).
[0311] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocycly1"
refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and Spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, and/or sulfonyl moieties.
[0312] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocycly1" refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
[0313] "Heterocyclyloxy" refers to the group -0-heterocycyl.
[0314] "Substituted heterocyclyloxy" refers to the group -0-(substituted heterocycyl).
[0315] "Heterocyclylthio" refers to the group -S-heterocycyl.
[0316] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocycyl).
[0317] Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomotpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.
[0318] "Nitro" refers to the group -NO2.

Date Recue/Date Received 2023-11-27 [0319] "Oxo" refers to the atom (-0) or (-0).
[0320] "Spiro ring systems" refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
[0321] "Sulfonyl" refers to the divalent group -S(0)2-.
[0322] "Substituted sulfonyl" refers to the group -S02-alkyl, -S02-substituted alkyl, -S02-alkenyl, -S02-substituted alkenyl, -S02-cycloalkyl, -S02-substituted cylcoakl, -S02-cycloalkenyl, -S02-substituted cylcoalkenyl, -S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, -S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-S02-, phenyl-S02-, and 4-methylphenyl-S02-. The term "alkylsulfonyl"
refers to -502-alkyl. The term "haloalkylsulfonyl" refers to -502-haloallcyl where haloallcyl is defined herein. The term "(substituted sulfonyl)amino" refers to -NH(substituted sulfonyl), and the term "(substituted sulfonyl)aminocarbonyl" refers to -C(0)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined herein.
[0323] "Sulfonyloxy" refers to the group -0502-alkyl, -0S02-substituted alkyl, -0S02-alkenyl, -0S02-substituted alkenyl, -0S02-cycloalkyl, -0S02-substituted cylcoalkyl, -0502-cycloalkenyl, -0502-substituted cylcoalkeny1,-0S02-aryl, -0S02-substituted aryl, -0S02-heteroaryl, -0S02-substituted heteroaryl, -0S02-heterocyclic, -0502-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0324] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, Date Recue/Date Received 2023-11-27 substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0325] "Thiol" refers to the group -SH.
[0326] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.
[0327] "Thione" refers to the atom (=S).
[0328] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.
[0329] "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
[0330] "Compound" or "compounds" as used herein is meant to include the stereoiosmers and tautomers of the indicated formulas.
[0331] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[0332] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0333] As used herein, the term "phosphate ester" refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.
[0334] As used herein, the term "phosphate ester" refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.
[0335] As used herein, the term "monophosphate" refers to the group ¨P(0)(OH)2.

Date Recue/Date Received 2023-11-27 [0336] As used herein, the term "diphosphate" refers to the group ¨P(0)(OH)-0P(0)(OH)2.
[0337] As used herein, the term "triphosphate" refers to the group ¨P(0)(OH)-(0P(0)(OH))20H.
[0338] As used herein, the term "ester" as it refers to esters of the mono-, di- or triphosphate group means esters of the monophosphate can be represented by the formula ¨P(0)(0R45)2, where each R45 is independently hydrogen, C1-C12 alkyl, C3-Cio cycloalkyl, C6-C14 aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and the like, provided that at least one R45 is not hydrogen. Likewise, exemplary esters of the di-or triphosphate can be represented by the formulas ¨P(0)(0R45)-0P(0)(0R45)2 and -P(0)(0R45)-(0P(0)(0R45))20R45, where R45 is as defined above.
[0339] As used herein, the term "hydrolyzable group" refers to a group that can be hydrolyzed to release the free hydroxy group under hydrolysis conditions.
Examples of hydrolysable group include, but are not limited to those defined for R above.
Preferred hydrolysable groups include carboxyl esters, phosphates and phosphate esters.
The hydrolysis may be done by chemical reactions conditions such as base hydrolysis or acid hydrolysis or may be done in vivo by biological processes, such as those catalyzed by a phosphate hydrolysis enzyme. Nonlimiting examples of hydrolysable group include groups linked with an ester-based linker (-C(0)0- or -0C(0)-), an amide-based linker (-C(0)NR46- or ¨NR46C(0)-), or a phosphate-linker (-P(0)(0R46)-0-, -0-P(S)(0R46)-0-, -0-P(S)(SR46)-0-, -S-P(0)(0R46)-0-, -0-P(0)(0R46)-S-, -S-P(0)(0R46)-S-, -0-P(S)(0R46)-S-, -S-P(S)(0R46)-0-, -0-P(0)(R46)-0-, -0-P(S)(R46)-0-, -S-P(0)(R46)-0-, -S-P(S)(R46)-0-, -S-P(0)(R46)-S-, or -0-P(S)(R46)-S-) where R46 can be hydrogen or alkyl.
[0340] Substituted groups of this invention, as set forth above, do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group can be substituted up to five times.
[0341] "Noribogaine" refers to the compound:

Date Recue/Date Received 2023-11-27 as well as noribogaine derivatives or pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. It should be understood that where "noribogaine" is mentioned herein, one more polymorphs of noribogaine can be utilized and are contemplated. In some embodiments, noribogaine is noribogaine glucuronide.
[0342] Noribogaine can be prepared by demethylation of naturally occurring ibogaine:

which is isolated from Tabernanth iboga, a shrub of West Africa. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by conventional purification.
See, for example, Huffman, et al., J. Org. Chem. 50:1460 (1985), which incorporated herein by reference in its entirety. Noribogaine can be synthesized as described, for example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and 2012/0253037, PCT
Patent Publication No. WO 2013/040471 (includes description of making noribogaine polymorphs), and U.S. Patent App. No. 13/593,454, each of which is incorporated herein by reference in its entirety.
[0343] "Noribogaine derivatives" refer to, without limitation, esters or 0-carbamates of noribogaine, or pharmaceutically acceptable salts and/or solvates of each thereof. Also encompassed within this invention are derivatives of noribogaine that act as prodrug forms of noribogaine. A prodrug is a pharmacological substance administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into an active metabolite. Noribogaine derivatives include, without limitation, those compounds set forth in US Patent Nos. 6,348,456 and 8,362,007; as well as in US Patent Application Serial No. 13/165,626; and US Patent Application Publication Nos.
U52013/0131046; U52013/0165647; U52013/0165425; and U52013/0165414; all of which are incorporated herein by reference. Non-limiting examples of noribogaine Date Recue/Date Received 2023-11-27 derivatives encompassed by this invention are given in more detail in the "Compositions"
section below.
[0344] In some embodiments, the methods of the present disclosure entail the administration of a prodrug of noribogaine that provides the desired maximum serum concentrations and efficacious average noribogaine serum levels. A prodrug of noribogaine refers to a compound that metabolizes, in vivo, to noribogaine. In some embodiments, the prodrug is selected to be readily cleavable either by a cleavable linking arm or by cleavage of the prodrug entity that binds to noribogaine such that noribogaine is generated in vivo. In one preferred embodiment, the prodrug moiety is selected to facilitate binding to the and/or lc receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the i and/or receptors. Examples of prodrugs of noribogaine are provided in United States Patent Application Serial No. 13/165,626, the entire content of which is incorporated herein by reference.
[0345] This invention is not limited to any particular chemical form of noribogaine or noribogaine derivative, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like.
[0346] "Pharmaceutically acceptable composition" refers to a composition that is suitable for administration to a mammal, preferably a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.
[0347] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the Date Recue/Date Received 2023-11-27 molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
[0348] A "pharmaceutically acceptable solvate" or "hydrate" of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
[0349] As used herein the term "solvate" is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of solvent trapped inside. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are certainly not limited to, water, methanol, ethanol, isopropa,nol, butanol, C1-C6 alcohols in general (and optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention. Additionally, various organic and inorganic acids and bases can be added or even used alone as the solvent to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate.
Further, by being left in the atmosphere or recrystallized, the compounds of the present invention may absorb moisture, may include one or more molecules of water in the formed crystal, and thus become a hydrate. Even when such hydrates are formed, they are included in the term "solvate". Solvate also is meant to include such compositions where another compound or complex co-crystallizes with the compound of interest. The term "solvate" as used herein refers to complexes with solvents in which noribogaine is reacted or from which noribogaine is precipitated or crystallized. For example, a complex with water is known as a "hydrate". Solvates of noribogaine are within the scope of the invention. It will be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary based on the solvate used. Thus, all crystalline forms of noribogaine or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.

Date Recue/Date Received 2023-11-27 [0350] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of noribogaine, in the context of treating opioid or opioid-like drug dependency, refers to an amount of noribogaine that attenuates the dependency and/or symptoms of acute withdrawal for at least about 2 hours beyond control (placebo), at least about 5 hours beyond control, and preferably at least about 10 hours beyond control. For example, and without limitation, a therapeutically effective amount of an agent, such as noribogaine, in the context of treating nicotine dependency, refers to an amount of the agent that attenuates the dependency and/or statistically presents little or no risk of relapse to nicotine use.
For example, and without limitation, a therapeutically effective amount of noribogaine, in the context of treating alcohol dependency, refers to an amount of noribogaine that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control.
For example, and without limitation, a therapeutically effective amount of noribogaine, in the context of treating drug dependency, refers to an amount of noribogaine that attenuates the dependency and/or symptoms of acute withdrawal for at least 2 hours beyond control (placebo), at least 5 hours beyond control, and preferably at least 10 hours beyond control.
For example, and without limitation, a therapeutically effective amount of noribogaine, in the context of modulating opioid analgesic tolerance, refers to an amount of noribogaine that resensitizes the patient to the opioid analgesic therapy.

Date Recue/Date Received 2023-11-27 [0351] The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary and intranasal delivery) is used, a lower dose of the compound may be administered. In one aspect, a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 100 i.tg per kg of body weight.
Where other routes of administration are used, a higher dose of the compound may be administered. In one embodiment, the therapeutically effective amount of the compound is from greater than about 1 mg to about 8 mg per kg of body weight per day.
[0352] A "therapeutic level" of a drug is an amount of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that is sufficient to treat a disease or disorder or symptoms of a disease or disorder or to treat, prevent, or attenuate a disease or disorder or symptoms of a disease or disorder but not high enough to pose any significant risk to the patient. Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient. This concentration is referred to as the "serum concentration." Where the serum concentration of noribogaine is mentioned, it is to be understood that the term "noribogaine" encompasses any form of noribogaine, including derivatives thereof.
[0353] A "sub-therapeutic level" of noribogaine or pharmaceutical salt and/or solvate thereof that is less than the therapeutic level described above. For example, the sub-therapeutic level of noribogaine may be e.g., 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount (e.g., 120 mg) of noribogaine, or any subvalue or subrange there between. Sub-therapeutic levels of noribogaine may coincide with "maintenance amounts" of noribogaine which are amounts, less than the therapeutically effective amount, that provide some attenuation and/or prevention of post-acute withdrawal syndrome in a patient. The maintenance amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically addicted to opioid or opioid-like drug.
[0354] As defined herein, a "prophylactically effective amount" of a drug is an amount, typically less than the therapeutically effective amount, that provides attenuation and/or prevention of a disease or disorder or symptoms of a disease or disorder in a patient. For Date Recue/Date Received 2023-11-27 example, the prophylactically effective amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who no longer has a disease or disorder or symptoms of a disease or disorder (e.g., no longer physically addicted to nicotine). For example, a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%
less than a therapeutically effective amount. However, a prophylactically effective amount may be the same as the therapeutically effective amount, for example when a patient who is physically addicted to nicotine is administered noribogaine to attenuate cravings for a period of time when nicotine use is not feasible. The prophylactically effective amount may vary for different a diseases or disorders or symptoms of different diseases or disorders.
[0355] As defined herein, a "maintenance amount" of a drug or an agent is an amount, typically less than the therapeutically effective amount that provides attenuation and/or prevention of syndrome disease or disorder or symptoms of a disease or disorder in a patient. The maintenance amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically manifests a disease or disorder or symptoms of a disease or disorder. For example, a maintenance amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount, or any subvalue or subrange there between.
[0356] "Treatment," "treating," and "treat" are defined as acting upon a disease, disorder, or condition with an agent, such as noribogaine to reduce or ameliorate harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms.
"Treatment," as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e., causing regression of the condition and/or relieving one or more symptoms of the condition.
"Treating" or "treatment of' a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating nicotine addiction; treating, preventing, and/or attenuating cravings for nicotine; and Date Recue/Date Received 2023-11-27 preventing relapse of nicotine use. This includes reducing or eliminating smoking in the patient, and/or reducing or eliminating symptoms of withdrawal, cravings, and the like.
For some purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating substance addiction; treating, preventing, and/or attenuating acute withdrawal symptoms; treating, preventing, and/or attenuating long-term (post-acute) withdrawal symptoms; and preventing relapse of substance use. For purposes of certain aspects of this invention, beneficial or desired clinical results include, but are not limited to: pain relief in all categories and classifications of pain; treating, alleviating and/or preventing acute and/or chronic pain; treating, alleviating and/or preventing cutaneous, somatic, visceral and/or neuropathic pain; and preventing the recurrence of long-term pain.
[0357] As used herein, the term "patient" refers to mammals and includes humans and non-human mammals.
[0358] As used herein, the term "opiate" refers to naturally-occurring alkaloids found in the opium poppy. These include codeine, morphine, oripavine, pseudomorphine, and thebaine. Also included are opium, opium poppy, poppy straw, and extracts and concentrates thereof.
[0359] As used herein, the term "opioid" refers to naturally-occurring opiates and synthetic or semi-synthetic opioids that have psychoactive effects. Non-limiting examples include acetyl-alpha-methylphentanyl, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, benzylmorphine, benzethidine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diethylthiambutene, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyl- thiambutene, dioxaphetyl butyrate, diphenoxylate, difenoxin, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo-alphacetylmethadol, levomethorphan, levorphanol, levophenacylmorphan, levomoramide, Date Recue/Date Received 2023-11-27 lofentanil, loperamide, laudanum, meperidine, meptazinol, metazocine, methadone, 3-methylfentanyl, 3-methylthiofentanyl, metopon, morphine, morpheridine, MPPP (1-methy1-4-pheny1-4-propionoxypiperidine), myrophine, narceine, nicomorphine, noracymethadol, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, para-fluorofentanyl, paregoric, PEPAP (1+2-phenethyl)-4-phenyl-4-acetoxypiperidine), pentazocine, phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, racemoramide, racemethorphan, racemorphan, remifentanil, sufentanil, tapentadol, thebaine, thiofentanyl, tilidine, tramadol, trimeperidine, mixtures of any of the foregoing, salts of any of the foregoing, derivatives of any of the foregoing, and the like. The term opioids also encompasses opioid intermediates, including 4-cyano-2-dimethylamino-4,4-diphenyl butane, 2-methy1-3-morpholino-1,1-diphenylpropane-carboxylic acid, 4-cyano-1-methy1-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and 1-methy1-4-phenylpiperidine-4-carboxylic acid. Many opioids are Schedule I or Schedule II
drugs in the US. Certain preferred examples of opioids include, without limitation, buprenorphine, codeine, heroine, hydrocodone, oxycodone, morphine, thebaine, and their derivatives, which will be well known to the skilled artisan.
[0360] As used herein, the term "opioid-like drug" refers to any illicit drug that binds to one or more opioid receptor and causes opioid-like addiction. Acute and long-term withdrawal symptoms from cessation of use of such drugs may be similar to those from cessation of opioids. Opioid-like drugs include amphetamine, methamphetamine, ketamine, and cocaine.
[0361] As used herein, the term "QT interval" refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart.
Prolongation of the QT interval refers to an increase in the QT interval.
[0362] As used herein, the terms "addiction," "abuse" and "dependence" are used interchangeably to refer to the patient's inability to stop using the opioid or opioid-like drug, nicotine, alcohol, addictive substance, or the like, even when it would be in his/her best interest to stop. The DSMIV-TR criteria for dependency include:

Date Recue/Date Received 2023-11-27 Dependence or significant impairment or distress, as manifested by 3 or more of the following during a 12 month period:
1. Tolerance or markedly increased amounts of the substance to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of substance;
2. Withdrawal symptoms or the use of certain substances to avoid withdrawal symptoms;
3. Use of a substance in larger amounts or over a longer period than was intended;
4. Persistent desire or unsuccessful efforts to cut down or control substance use;
5. Involvement in chronic behavior to obtain the substance, use the substance, or recover from its effects;
6. Reduction or abandonment of social, occupational or recreational activities because of substance use;
7. Use of substances even though there is a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.
103631 As used herein, the term "nicotine addict in remission" refers to any patient who has quit using nicotine for a period of time. As used herein, a nicotine addict in remission includes any person who was previously addicted to nicotine in any form, including but not limited to cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. The period of time since the nicotine addict in remission quit using nicotine may be short, for example one day to a few weeks, or longer-term, for example months or years. Preferably, the patient has quit using nicotine long enough to no longer exhibit physical symptoms of nicotine addiction. The patient may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction.

Date Recue/Date Received 2023-11-27 [0364] As used herein, the terms "addictive substance", "drug", "addictive drug" and the like refer to drugs and other substances whose use results in addiction in at least a subset of individuals who use them. Addictive substances include, without limitation, benzodiazepines (including chlordiazepoxide, clorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, and midazolam), cannabinoids and synthetic cannabinoids, stimulants (including amphetamine, methylphenidate, dexmethylphenidate, dextroamphetamine, mixed amphetamine salts, dextromethamphetamine, lisdexamfetamine, modafinil, adrafinil, armodafinil, caffeine, ephedrine, methylenedioxymethamphetamine, methylenedioxypyrovalerone, mephedrone, phenylpropanolamine, propylhexadrine, pseudoephedrine, and khat), barbiturates (including allobarbital, amobarbital, aprobarbital, alphenal, barbital, brallobarbital, pentobarbital, phenobarbital, and secobarbital), gamma-hydroxybutyrate (GHB), ketamine, opiate, opioid, opioid-like drug, PCP, dextromethorphan (DXM), lysergic acid diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each thereof.
Addictive substances may be illicit drugs, prescription drugs prone to abuse, or other legal drugs prone to abuse.
[0365] Obsessive compulsive disorder (OCD) is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a).
The obsessions or compulsions cause marked distress, are time-consuming, and/or significantly interfere with social or occupational functioning.
[0366] Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort;
(7) nausea or Date Recue/Date Received 2023-11-27 abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself);
(10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
[0367] Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) int' erferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
[0368] Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM-IV, which is incorporated herein by reference (American Psychiatric Association, 1994a).
[0369] Impulse control disorder is a class of psychiatric disorders involving the failure to resist a temptation, urge, or impulse (impulsivity) where such impulse is potentially harmful to the patient and/or others. The American Psychiatric Association's (May 2013) includes impulse control disorders "characterized by problems in emotional and behavioral self-control". These include borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorders, pathological gambling, pyromania, intermittent explosive disorder, kleptomania, sexual compulsion, paraphilia, interne addiction, trichotillomania, Date Recue/Date Received 2023-11-27 pathological skin picking, and compulsive shopping. Impulse control disorder may be related to anxiety disorder and/or OCD.
[0370] Violence and anger, particularly when out of proportion to a stimulus and/or a result of pathological anger, are associated with a number of mental disorders. These include oppositional defiant disorder, attention-deficit/hyperactivity disorder and conduct disorder (in children and adolescents), psychotic disorder, bipolar disorder, antisocial, borderline, paranoid and narcissistic personality disorders, adjustment disorder with disturbance of conduct, and intermittent explosive disorder. Pathological anger and violence account for a significant portion of violent crimes, including many high-profile crimes involving multiple victims. Highly volatile individuals are over-represented in the prison system in the United States.
[0371] As used herein, the term "pain" refers to all categories and classifications of pain, which are summarized below for purposes of illustration. First, cutaneous pain is caused by injury to the skin or superficial tissues. Cutaneous nociceptors terminate just below the skin, and due to the high concentration of nerve endings, produce a well-defined, localized pain of short duration. Example injuries that produce cutaneous pain include paper cuts, minor burns (e.g., first degree burns) and superficial lacerations.
[0372] Second, somatic pain originates from ligaments, tendons, bones, blood vessels, and even nerves themselves, and is detected with somatic nociceptors. The scarcity of nociceptors in these areas produces a sharp, aching, pain of longer duration than cutaneous pain and somewhat less localized. Examples include a sprained ankle or broken bones.
[0373] Third, visceral pain originates from body organs. Visceral nociceptors are located within body organs and internal cavities. Similar to somatic pain, a scarcity of nociceptors in these areas produces a pain usually more aching and of a longer duration than somatic pain. Visceral pain may be more difficult to localize. Injuries to visceral tissue may exhibit "referred" pain, where the sensation is localized to an area completely unrelated to the site of injury. Myocardial ischaemia (i.e., the loss of blood flow to a part of the heart muscle tissue) is an example of referred pain; the sensation can occur in the upper chest as a restricted feeling, or as an ache in the left shoulder, arm, or hand. Another example of referred pain is phantom limb pain. Phantom limb pain is the sensation of pain from a limb that a person no longer has or from which the person no longer receives physical signals.

Date Recue/Date Received 2023-11-27 This phenomena _______________________________________ also known as deafferentation pain is almost universally reported by amputees and quadriplegics.
[0374] Fourth, neuropathic pain (e.g., "neuralgia") can occur as a result of injury or disease to the nerve tissue itself. The injury or disease can disrupt the ability of the sensory nerves to transmit correct information to the thalamus or cortex.
Consequently, the brain interprets painful stimuli even though there is no obvious or documented physiologic cause for the pain.
[0375] Other pain classifications include acute pain and chronic pain. Acute pain is defined as short-term pain or pain with an easily identifiable cause. Acute pain indicates present damage to tissue or disease and may be "fast" and "sharp" followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. Acute pain generally responds well to medications (e.g., morphine).
[0376] Chronic pain may be medically defined as pain that has lasted six months or longer. This constant or intermittent pain has often outlived its purpose because it does not help the body to prevent injury. It is often more difficult to treat than acute pain. Expert care is generally necessary to treat any pain that has become chronic. In addition, stronger medications are typically used for extended periods in an attempt to control the pain. This can lead to drug dependency. For example, opioids are used in some instances for prolonged periods to control chronic pain. Drug tolerance, chemical dependency, and even psychological addiction may occur.
[0377] "Nociceptive pain" refers to pain that is sensed by nociceptors, which are the nerves that sense and respond to parts of the body suffering from a damage.
The nociceptors can signal tissue irritation, impending injury, or actual injury.
When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain. Nociceptive pain is typically well localized, constant, and often has an aching or throbbing quality. A subtype of nociceptive pain includes visceral pain and involves the internal organs. Visceral pain tends to be episodic and poorly localized.
Nociceptive pain may be time limited; when the tissue damage heals, the pain typically resolves.
However, nociceptive pain related to arthritis or cancer may not be time limited.
Nociceptive pain tends to respond to treatment with opiate analgesics, such as, for example, buprenorphin, codeine, hydrocodone, oxycodone, morphine, and the like.

Date Recue/Date Received 2023-11-27 Examples of nociceptive pain include, without limitation, pains from sprains, bone fractures, burns, bumps, bruises, inflammatory pain from an infection or arthritic disorder, pains from obstructions, cancer pain, and myofascial pain related to abnormal muscle stresses.
[0378] "Neuropathic pain" refers to chronic pain, often due to tissue injury.
Neuropathic pain is generally caused by injury or damage to nerve fibers. It may include burning or coldness, "pins and needles" sensations, numbness and/or itching. It may be continuous and/or episodic. Neuropathic pain is difficult to treat, but opioids, including, without limitation, methadone, tramadol, tapentadol, oxycodone, methadone, morphine, levorphanol, and the like. Causes of neuropathic pain include, without limitation, alcoholism; amputation; back, leg, and hip problems; chemotherapy; diabetes;
facial nerve problems; HIV/AIDS; multiple sclerosis; shingles; spine surgery; trigeminal neuralgia;
fibromyalgia; and the like. In some cases, the cause of neuropathic pain may be unclear or unknown.
[0379] "Addictive" refers to a compound that, when administered to a mammal over a period of time, creates dependency in the mammal to that compound. The dependence can be physiological and/or psychological. A therapeutic effect of an addictive compound on a mammal may decrease with prolonged administration of the addictive compound, which is a non-limiting example of a physiological dependence. When administered to a mammal, an addictive compound may also create a craving in the mammal for more of it, which is a non-limiting example of a psychological dependence. Examples of addictive compounds include, without limitation, addictive opioids, and the like.
[0380] "Analgesic" and "analgesic agent" refer to a compound that is capable of inhibiting and/or reducing pain in mammals. Pain may be inhibited and/or reduced in the mammal by the binding of the opioid analgesic agent to the mu receptor. When analgesia is effected through the mu receptor, the analgesic agent is referred to as a mu receptor agonist. Certain analgesic agents are capable of inhibiting nociceptive and/or neuropathic pain including, by way of example, morphine, codeine, hydromorphone, oxycodone, hydrocodone, buprenorphin, and the like.
[0381] The term "tolerance" as used herein refers to the psychological and/or physiologic process wherein the patient adjusts to the frequent presence of a substance Date Recue/Date Received 2023-11-27 such that a higher dose of the substance is required to achieve the same effect. Tolerance may develop at different times for different effects of the same drug (e.g., analgesic effect versus side effects). The mechanisms of tolerance are not entirely understood, but they may include receptor down-regulation or desensitization, inhibitory pathway up-regulation, increased metabolism, and/or changes in receptor processing (e.g., phosphorylation).
103821 The term "dose" refers to a range of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that provides a therapeutic serum level of noribogaine when given to a patient in need thereof. The dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight. The attending clinician will select an appropriate dose from the range based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art.
103831 The term "unit dose" refers to a dose of drug that is given to the patient to provide therapeutic results, independent of the weight of the patient. In such an instance, the unit dose is sold in a standard form (e.g., 20 mg tablet). The unit dose may be administered as a single dose or a series of subdoses. In some embodiments, the unit dose provides a standardized level of drug to the patient, independent of weight of patient.
Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient.
Compositions 103841 As will be apparent to the skilled artisan upon reading this disclosure, this invention provides compositions for treating or preventing diseases or disorders or symptoms of diseases or disorders described herein, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, pharmaceutically acceptable salts and/or solvates of each thereof. This invention further provides compositions for treating, attenuating, or preventing symptoms of diseases or disorders described herein, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, pharmaceutically acceptable salts and/or solvates of each thereof.

Date Recue/Date Received 2023-11-27 [0385] In some embodiments, the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about lmg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 4 mg per kg body weight per day. The ranges include both extremes as well as any subranges there between.
[0386] In one embodiment, the therapeutically effective amount of the compound is from about 1 mg to about 8 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 6 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.3 mg to about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.5 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg to about 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 2 mg to about 3 mg per kg body weight per day.
Date Recue/Date Received 2023-11-27 [0387] In one embodiment, the therapeutically effective amount of the compound is about 8 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 7 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 6 mg/kg body weight per day.
In one embodiment, the therapeutically effective amount of the compound is about 5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day.
In one embodiment, the therapeutically effective amount of the compound is about 2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg/kg body weight per day.
[0388] In one embodiment, the therapeutically effective amount of the compound is about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg per kg body weight per day.
In another embodiment, the therapeutically effective amount of the compound is about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg per kg body weight per day.
[0389] In one aspect, the invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of noribogaine and a pharmaceutically acceptable excipient, wherein the therapeutically or prophylactically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to less than 10 g per kg body weight per day. In some aspects, the therapeutically or prophylactically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 5 g per kg body weight per day.
In some aspects, the therapeutically or prophylactically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 1 jig per kg body weight per day. In some aspects, the composition is formulated for administration Date Recue/Date Received 2023-11-27 once per day. In some aspects, the composition is formulated for administration two or more times per day.
[0390] In some embodiments, the composition is formulated for sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of noribogaine and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to less than 100 g per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 50 lag per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 10 jig per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 1 jig per kg body weight per day. In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day. The ranges include both extremes as well as any subranges there between.
[0391] In another embodiment, the therapeutically effective amount of the compound is from 1.3 mg to 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 1.5 mg to 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 1.7 mg to 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 2 mg to 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 2 mg to 3 mg per kg body weight per day.

Date Recue/Date Received 2023-11-27 COMPOUNDS UTILIZED
[0392] In one embodiment, the noribogaine derivative is represented by Formula I:

or a pharmaceutically acceptable salt and/or solvate thereof, wherein R is hydrogen or a hydrolyzable group such as hydrolyzable esters of from about 1 to 12 carbons.
[0393] Generally, in the above formula, R is hydrogen or a group of the formula:

II
¨C
wherein X is a C1-C12 group, which is unsubstituted or substituted. For example, X may be a linear alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n -decyl, n-undecyl or n-dodecyl, or a branched alkyl group, such as i-propyl or sec-butyl. Also, X may be a phenyl group or benzyl group, either of which may be substituted with lower alkyl groups or lower alkoxy groups. Generally, the lower alkyl and/or alkoxy groups have from 1 to about 6 carbons. For example, the group R
may be acetyl, propionyl or benzoyl. However, these groups are only exemplary.
[0394] Generally, for all groups X, they may either be unsubstituted or substituted with lower alkyl or lower alkoxy groups. For example, substituted X may be o-, m-or p-methyl or methoxy benzyl groups.
[0395] CI-Cu groups include Ci-C12 alkyl, C3-C12 cycloalkyl, C6-C12 aryl, C7-arylalkyl, wherein Cx indicates that the group contains x carbon atoms. Lower alkyl refers to Ci-C4 alkyl and lower alkoxy refers to C1-C4 alkoxy.

Date Recue/Date Received 2023-11-27 [0396] In one embodiment, the noribogaine derivative is represented by Formula II:

L¨ R5 or a pharmaceutically acceptable salt ancUor solvate thereof, wherein is a single or double bond;
R' is halo, OR2, or C1-C12 alkyl optionally substituted with 1 to 5 Rm;
R2 is hydrogen or a hydrolysable group selected from the group consisting of -C(0)1V, -C(0)0Rx and -C(0)N(R)2 where each 12_8 is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 5 le , and each RY is independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with 1 to 5 RI , C6-C14 aryl optionally substituted with 1 to 5 Rm, C3-C10 cycloalkyl optionally substituted with 1 to 5 Rl , C1-C10 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 RI , C1-C10 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 RI , and where each RY, together with the nitrogen atom bound thereto form a C1-C6 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 RR' or a C1-C6 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R16;
R3 is selected from the group consisting of hydrogen, Ci-C 12 alkyl optionally substituted with 1 to 5 le , aryl optionally substituted with 1 to 5 Rm, -C(0)R6, -C(0)NR6R6 and -C(0)0R6;
R4 is selected from the group consisting of hydrogen, -(CH2).0R8, -CR7(OH)R8, -(CH2)õ,CN, -(CH2)6,COR8, -(CH2).0O2R8, -(CH2),X(0)NR7 R8, -(CH2)6,C(0)NR7NR8R8, -(CH2),X(0)NR7NR8C(0)R9, and -(CH2).NR7R8;
m is 0, 1, or 2;

Date Recue/Date Received 2023-11-27 L is a bond or Ci-C12 alkylene;
R5 is selected from the group consisting of hydrogen, Ci-C12 alkyl substituted with 1 to 5 Rim, C1-C12 alkenyl substituted with 1 to 5 R19, -X1-R7, -(X1-Y)õ-X1-R7, -SO2NR7R8, -0-C(0)R9, -C(0)0R8, -C(0)NR7R8, -NR7R8, -NHC(0)R9, and -NR7C(0)R9;
each R6 is independently selected from the group consisting of hydrogen, CI-Cu alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C6-Clo aryl, C1-C6 heteroaryl having 1 to 4 heteroatoms, and C1-C6 heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R19;
X1 is selected from the group consisting of 0 and S;
Y is C1-C4 alkylene or C6-C10 arylene, or a combination thereof;
n is 1, 2, or 3;
R7 and R8 are each independently selected from the group consisting of hydrogen, CI-Cu alkyl optionally substituted with 1 to 5 R19, CI-C6 heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 RIO, C10 cycloalkyl optionally substituted with 1 to 5 R19, C6-Clo aryl optionally substituted with 1 to 5 R19 and C1-C6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R19;
R9 is selected from the group consisting of CI-Cu alkyl optionally substituted with 1 to 5 R19, C1-C6 heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R19, C3-Clo cycloalkyl optionally substituted with 1 to 5 R19, C6-C10 aryl optionally substituted with 1 to 5 R19 and C1-C6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R16;
Rim is selected from the group consisting of CI-C4 alkyl, phenyl, halo, -OR", -CN, -COR11, -CO2R11, -C(0)NHRI 15 -NR"
R", _C(0)NR11Rii, _c(o)Nti-N
HR", -C(0)NR11NHR11, -C(0)NR' 'NR' K _C(0)NFINRUC(0)R11, -C( 0)NHNHC(0)R11, -SO2NR11¨

K11, _C(0)NR11NR11C(C)R11, and -C(0)NR11NHC(0)R11; and R" is independently hydrogen or CI-C12 alkyl;
provided that:
when L is a bond, then R5 is not hydrogen;
10() Date Recue/Date Received 2023-11-27 when ¨ is a double bond, R1 is an ester hydrolyzable group, R3 and R4 are both hydrogen, then -L-R5 is not ethyl;
when ¨ is a double bond, R1 is -OH, halo or C1-C12 alkyl optionally substituted with 1 to 5 R1 , then R4 is hydrogen; and when is a double bond, R1 is OR2, R4 is hydrogen, -L-R5 is ethyl, then R2 is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.
[0397] In one embodiment, the noribogaine derivative is represented by Formula III:

III
or a pharmaceutically acceptable salt and/or solvate thereof, wherein ¨ is a single or double bond;
R12 is halo, -OH, -SH, -NH2, -S(0)2N(Rt7)2, _Rz_c_R19, _Rz_c_R20 or _ Rz_c K
_cHR18¨ 195 where It.' is 0, S or NR17;
L1 is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(0)NR20-alkylene, -C(0)NR20-arylene, -C(NR20)NR20-alkylene or -C(.,4R20)N¨K 20_ arylene, wherein L1 is configured such that -0-L1-R18 is -OC(0)-alkylene-R18, -0C(0)0-arylene-R18, -0C(0)0-alkylene-R18, -OC(0)-arylene-R18, -0C(0)NR20-alkylene-R18, -0C(0)NR20-arylene-R18, -0C(NR20)N- 20_ alkylene-R" or -0C(NR20)NR20-arylene-R18, and wherein the alkylene and arylene are optionally substituted with 1 to 2 R16;
R13 is hydrogen, -S(0)20R20, -S(0)2R20, -C(0)R15, -C(0)NR15R15, -C(0)0R15, C12 alkyl optionally substituted with 1 to 5 R16, C1-C12 alkenyl optionally substituted with 1 to 5 R16, or aryl optionally substituted with 1 to 5 R16;
R14 is hydrogen, halo, -0R17, -CN, CI-Cu alkyl, CI-Cu alkoxy, aryl or aryloxY, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R16;

Date Recue/Date Received 2023-11-27 each R15 is independently selected from the group consisting of hydrogen, C1-alkyl, C2-C12 alkenyl, C2-C12 alkynyl, aryl, heteroaryl, and heterocycle, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R16;
R16 is selected from the group consisting of phenyl, halo, -0R17, -CN, -COR17, _co2R17, _NR17R17, _NR17c(o)R17, _NR17s02K 17, C(0)NR17 R17, -C(0)NR17NR17R17, -SO2NR17R17 and -C(0)NR17NR17C(0)R17;
each R17 is independently hydrogen or C1-C12 alkyl optionally substituted with from 1 to 3 halo;
R18 is hydrogen, -C(0)R20, -C(0)0R20, -C(0)N(R20)2 or -N(R20)C(0)R20;
R19 is hydrogen, -N(R20)2, C(0)N(R20)2, 2, ) _c(NR2o)N(R2o), C(NSO2R20)N(R20, 2, NR26 C (0) N(R20) 2, NR20C(S)N(R20)2, (NR20)N (R20 2, ) NR26C(NSO2R26)1\1(R2 0)2 or tetrazole; and each R2 is independently selected from the group consisting of hydrogen, C1-alkyl and aryl;
provided that:
when - is a double bond and R13 and R14 are hydrogen, then R12 is not hydroxy;
when - is a double bond, R14 is hydrogen, R12 is -0-L1-R18, -0-L1-R19, -0-L1-R20, and L1 is alkylene, then -O-L'-R'8, -O-L'-R'9, -O-L'-R2 are not methoxy;
when - is a double bond, R14 is hydrogen, Rz is 0, L1 is -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(0)NR20-alkylene, or -C(0)NR20-arylene, then none of R18, R19 or R2 are hydrogen.
[0398] In one embodiment, the noribogaine derivative is represented by Formula IV:

or a pharmaceutically acceptable salt and/or solvate thereof, Date Recue/Date Received 2023-11-27 wherein R2' is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of-C(0)R23, -C(0)NR24¨ 25 K and -C(0)0R26, where R23 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R24 and R25 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R26 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R2' is not a saccharide or an oligosaccharide;
L2 is selected from the group consisting of a covalent bond and a cleavable linker group;
R22 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R is not a saccharide or an oligosaccharide;
provided that when L2 is a covalent bond and R22 is hydrogen, then R2' is selected from the group consisting of -C(0)NR24R25 and -C(0)0R26; and further provided that when R2' is hydrogen or -C(0)R23 and L2 is a covalent bond, then R22 is not hydrogen.
[0399] In one embodiment, the noribogaine derivative is represented by Formula V:
,0 V
or a pharmaceutically acceptable salt and/or solvate thereof, wherein:
refers to a single or a double bond provided that when is a single bond, Formula V refers to the corresponding dihydro compound;
R27 is hydrogen or S020R29;
R28 is hydrogen or S020R29;

Date Recue/Date Received 2023-11-27 R29 is hydrogen or C1 - C6 alkyl;
provided that at least one of R27 and R28 is not hydrogen.
[0400] In one embodiment, the noribogaine derivative is represented by Formula VI:
,0 VI
or a pharmaceutically acceptable salt and/or solvate thereof, wherein:
refers to a single or a double bond provided that when is a single bond, Formula VI refers to the corresponding vicinal dihydro compound;
R3 is hydrogen, a monophosphate, a diphosphate or a triphosphate; and R31 is hydrogen, a monophosphate, a diphosphate or a triphosphate;
provided that both R3 and R31 are not hydrogen;
wherein one or more of the monophosphate, diphosphate and triphosphate groups of R3 and R31 are optionally esterified with one or more Ci-C6 alkyl esters.
[0401] Noribogaine as utilized herein, can be replaced by a noribogaine derivative or a salt of noribogaine or the noribogaine derivative or a solvate of each of the foregoing.
[0402] In a preferred embodiment, the compound utilized herein is noribogaine or a salt thereof. In a more preferred embodiment, the compound utilized herein is noribogaine.
III. Methods of the Invention [0403] As will be apparent to the skilled artisan upon reading this disclosure, the present invention provides a method for treating disases treatable by administering noribogaine, as described herein, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.
Nicotine Addiction [0404] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating nicotine addiction in a subject, comprising Date Recue/Date Received 2023-11-27 administering to the patient in need thereof a therapeutically effective amount of noribogaine, a noribogaine derivative, a noribogaine prodrug, or a pharmaceutically acceptable salt of each thereof. This invention further provides a method for treating, attenuating, or preventing nicotine cravings in a subject, comprising administering to the patient in need thereof a therapeutically or prophylactically effective amount of noribogaine, a noribogaine derivative, a noribogaine prodrug, or a pharmaceutically acceptable salt of each thereof.
[0405] In some embodiments, the invention provides for a method for treating nicotine addiction in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
[0406] The subject or patient may be any patient who uses nicotine in any form, including cigarettes, electronic cigarettes or vaporizers ("vaping"), chewing tobacco, cigars, snuff, pipes, hookahs, and the like. In some embodiments, the patient is addicted to nicotine. In some embodiments, the patient is physically addicted to nicotine.
In some embodiments, the patient is psychologically addicted to nicotine.
[0407] In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to less than 10 ps per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 jig per kilogram body weight per day.
In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 jig per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 1 lug to less than 10 jig per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 lug, about 2 lug, about 3 lug, about 3 Date Recue/Date Received 2023-11-27 jig, about 4 pig, about 5 pig, about 6 jig, about 7 jig, about 8 jig, about 9 jig, about 10 jug per kilogram body weight per day. The therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0408] In some embodiments, the therapeutically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered more than two times per day.
[0409] Where the therapeutically effective amount is administered more than one time per day, a portion of the total therapeutically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig noribogaine per kg body weight per day would take 90 pig once a day, 45 lag twice a day, or 30 pig three times a day, etc.
[0410] In some embodiments, the therapeutically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once when needed, e.g., when the patient has a craving for nicotine or anticipates to have a craving for nicotine as described herein.
[0411] In some embodiments, the noribogaine or noribogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
Preventing relapse of nicotine use [0412] In some embodiments, the invention provides for a method for treating, preventing, or attenuating nicotine cravings in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. In some embodiments, the invention provides for a method for preventing recurrence of nicotine addiction in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
[0413] In some situations, a patient who has not ceased nicotine use nonetheless is unable to use nicotine for an extended amount of time. For example, most airplane flights Date Recue/Date Received 2023-11-27 no longer allow smoking, and have banned vaporizers and e-cigarettes, as well.
Other places and situations where nicotine use is not feasible or is difficult include movie theaters, other entertainment venues (including theater, opera, concerts, and the like), and even workplaces, notably hospitals and schools where smoking may not be allowed anywhere on the property. In some embodiments, a prophylactically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered before and/or during a period of time when the patient expects to be unable to use nicotine, wherein the noribogaine, derivative, or salt prevents, interrupts, or attenuates cravings for nicotine. In some embodiments, nicotine cravings are attenuated, interrupted, or prevented for at least 2, 3, 4, 5, 6, 7, 8, 10, 15, or 24 hours.
[0414] In some embodiments, the noribogaine is administered on an as-needed basis by the patient. In some embodiments, the noribogaine may be administered before the nicotine craving occurs. For example, the patient may take a dose of noribogaine in anticipation of cravings, such as before drinking alcohol, before a stressful situation occurs, or when facing another trigger for nicotine use. In some embodiments, the patient takes a dose of noribogaine after the nicotine craving occurs, for example during the craving, in order to reduce or eliminate the craving. In some embodiments, the dose of noribogaine is low enough that a patient can take one dose before a craving occurs, and another later the same day if he/she feels or anticipates another craving.
[0415] In one embodiment, the prophylactically effective amount of the compound is from about 50 ng to less than 10 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 1 jig per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 500 ng to less than 10 mg per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 1 jig to less than 10 jig per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints.

Date Recue/Date Received 2023-11-27 [0416] In some embodiments, the prophylactically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered more than two times per day.
[0417] Where the prophylactically effective amount of noribogaine is administered more than one time per day, a portion of the total prophylactically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig noribogaine per kg body weight per day would take 90 jig once a day, 45 jig twice a day, or 30 lug three times a day, etc.
[0418] In some embodiments, the noribogaine or noribogaine derivative is administered sublingually, intrapulmonary, or intranasally. These routes of administration are discussed in further detail in the subsection titled "Dosage and Routes of Administration."
Opioid or Opioid-Like Drug Addiction [0419] In one aspect, this invention relates to treatment of acute withdrawal from an opioid or opioid-like drug in an addicted patient comprising administration of a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.
[0420] In one aspect, this invention relates to a method for treating opioid or opioid-like drug abuse in an addicted patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0421] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 80 ng/mL to about 100 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient Date Recue/Date Received 2023-11-27 to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
104221 In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT interval is not prolonged more than about 20 ms. In one embodiment, the QT
interval is not prolonged more than about 10 ms.In one embodiment, prolongation of the QT interval is equivalent to or less than the prolongation observed for methadone-treated patients.
104231 In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid or opioid-like drug addiction, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 60 ng/mL to about 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
[0424] In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 100 ng/mL, or about Date Recue/Date Received 2023-11-27 60 ng/mL to about 100 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 80 ng/mL to about 150 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 80 ng/mL to about 100 ng/mL.
The ranges include both extremes as well as any subranges between.
[0425] In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1000 ng*hr/mL and about 6000 ng*hr/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng*hr/mL and about 5800 ng*hr/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng*hr/mL and about 5500 ng*hr/mL. The ranges include both extremes as well as any subranges between.
[0426] In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 40 ng/mL and about 250 ng/mL. In a preferred embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and about 200 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 100 ng/mL and about 180 ng/mL.
[0427] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1 mg/kg to about 4 mg/kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, Date Recue/Date Received 2023-11-27 noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
[0428] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 4 mg/kg body weight per day.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.9 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.8 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.7 mg/kg body weight per day.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.6 mg/kg body weight per day.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about Date Recue/Date Received 2023-11-27 1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.1 mg/kg body weight per day.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1 mg/kg body weight per day.
[0429] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 70 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 75 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 90 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 100 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 110 mg and about 130 mg.
[0430] In another embodiment, there is provided a unit dose of noribogaine, noribogaine derivative, or salt or solvate thereof which is about 120 mg per dose. It being understood that the term "unit dose" means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.
[0431] In some embodiments, the patient is administered an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. In one embodiment, such a dosing regimen provides an average serum concentration of noribogaine of about 50 ng/mL to about 180 ng/mL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL over a period of time.

Date Recue/Date Received 2023-11-27 [0432] In some embodiments, the initial dose of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 60 mg to about 120 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.
[0433] In some embodiments, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 50 mg. In one embodiment, the one or more additional doses may or may not comprise the same amount of noribogaine, noribogaine derivative, or salt or solvate thereof. In one embodiment, at least one additional dose is about 5 mg. In one embodiment, at least one additional dose is about 10 mg. In one embodiment, at least one additional dose is about 15 mg.
In one embodiment, at least one additional dose is about 20 mg. In one embodiment, at least one additional dose is about 25 mg. In one embodiment, at least one additional dose is about 30 mg. In one embodiment, at least one additional dose is about 35 mg. In one embodiment, at least one additional dose is about 40 mg. In one embodiment, at least one additional dose is about 45 mg. In one embodiment, at least one additional dose is about 50 mg.
[0434] In one embodiment, the one or more additional doses are administered periodically. In one embodiment, the one or more additional doses are administered every 4 hours. In one embodiment, the one or more additional doses are administered every 6 hours. In one embodiment, the one or more additional doses are administered every 8 hours. In one embodiment, the one or more additional doses are administered every 10 hours. In one embodiment, the one or more additional doses are administered every 12 hours. In one embodiment, the one or more additional doses are administered every 18 hours. In one embodiment, the one or more additional doses are administered every 24 hours. In one embodiment, the one or more additional doses are administered every 36 hours. In one embodiment, the one or more additional doses are administered every 48 hours.

Date Recue/Date Received 2023-11-27 [0435] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or salt or solvate thereof is a tapered dosing over a period of time, during which the patient is detoxified, for example, without suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering will allow the full therapeutic effect of noribogaine with less prolongation of the QT interval.
Tapering involves administration of one or more subsequently lower doses of noribogaine over time. For example, in some embodiments, the first tapered dose is 50% to 95%
of the first or original dose. In some embodiments, the second tapered dose is 40% to 90%
of the first or original dose. In some embodiments, the third tapered dose is 30% to 85% of the first or original dose. In some embodiments, the fourth tapered dose is 20% to 80% of the first or original dose. In some embodiments, the fifth tapered dose is 10% to 75% of the first or original dose.
[0436] In some embodiments, the first tapered dose is given after the first dose of noribogaine. In some embodiments, the first tapered dose is given after the second, third, or a subsequent dose of noribogaine. The first tapered dose may be administered at any time after the previous dose of noribogaine. The first tapered dose can be given once, for example, followed by subsequent further tapered doses, or it can be given multiple times with or without subsequent, further tapered doses (e.g., second, third, fourth, etc. tapered doses), which likewise can be given once or over multiple administrations, for example. In some embodiments, the first tapered dose is administered about one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of noribogaine. Similarly, second, third, fourth, etc. tapered doses, if given, can be given about one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of noribogaine.
[0437] In some embodiments, one tapered dose is given to achieve the desired lower therapeutic dose. In some embodiments, two tapered doses are given to achieve the desired lower therapeutic dose. In some embodiments, three tapered doses are given to achieve the desired lower therapeutic dose. In some embodiments, four or more tapered doses are given to achieve the desired lower therapeutic dose. Determination of the tapered doses, number of tapered doses, and the like can be readily made a qualified clinician.

Date Recue/Date Received 2023-11-27 [0438] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0439] Noribogaine, noribogaine derivative, or a pharmaceutically acceptable solvate or salt thereof, suitable for administration in accordance with the methods provide herein, can be suitable for a variety of delivery modes including, without limitation, oral,transdermal, sublingual, buccal, intrapulmonary or intranasal delivery. Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used.
Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions.
Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A.
Oslo editor, Easton Pa. 1980).
[0440] In a preferred embodiment, noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the noribogaine is provided as noribogaine HCl, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
[0441] The patient may suffer from addiction to any opioid or opiate or opioid-like drug.
In a preferred embodiment, the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, oxycodone, hydrocodone, and methamphetamine. In one embodiment, the opioid or opioid-like drug is heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one embodiment, the opioid or opioid-like drug is morphine.

Date Recue/Date Received 2023-11-27 [0442] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from opioids or opioid-like drug in an addicted patient with a maintenance amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.
[0443] In some aspects, this invention relates to a method to prevent relapse of opioid or opioid-like drug abuse in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of noribogaine.
[0444] In some embodiments, the patient undergoes long-term (e.g., one year or longer) treatment with maintenance doses of noribogaine, noribogaine derivative, or salt or solvate thereof. In some embodiments, the patient is treated for acute withdrawal with therapeutic doses of noribogaine as described above, and then the amount of noribogaine is reduced to maintenance levels after acute withdrawal symptoms would be expected to have subsided.
Acute withdrawal symptoms generally are the most pronounced in the first 48 to 72 hours after cessation of the drug of addiction, although acute withdrawal may last as long as a week or more.
[0445] In some embodiments, the patient is administered a high (therapeutic) dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to opioid or opioid-like drug use. In some embodiments, the patient is administered a therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof over time until the maintenance dose is reached.
[0446] In some embodiments, the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is 70% of the therapeutic dose. In some embodiments, the maintenance dose is 60% of the therapeutic dose. In some embodiments, the maintenance dose is 50% of the therapeutic dose. In some embodiments, the maintenance dose is 40% of the therapeutic dose. In some embodiments, the maintenance dose is 30% of the therapeutic dose. In some embodiments, the maintenance Date Recue/Date Received 2023-11-27 dose is 20% of the therapeutic dose. In some embodiments, the maintenance dose is 10%
of the therapeutic dose.
[0447] In some embodiments, the maintenance average serum level of noribogaine is about 70% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 60% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 50% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 40% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 30% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 20% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 10% of the therapeutic average serum level of noribogaine.
[0448] In some embodiments, the maintenance Cmax of noribogaine is about 70%
of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about 60% of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmaxof noribogaine is about 50% of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about 40%
of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about 30% of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about 20% of the therapeutic Cmax of noribogaine. In some embodiments, the maintenance Cmax of noribogaine is about 10%
of the therapeutic Cmax of noribogaine.
[0449] In some embodiments, the maintenance AUC/24 h of noribogaine is about 70%
of the therapeutic AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of noribogaine is about 60% of the therapeutic AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of noribogaine is about 50% of the therapeutic AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of noribogaine is about 40% of the therapeutic AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of noribogaine is about 30% of the therapeutic Date Recue/Date Received 2023-11-27 AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of noribogaine is about 20% of the therapeutic AUC/24 h of noribogaine. In some embodiments, the maintenance AUC/24 h of noribogaine is about 10% of the therapeutic Cma AUC/24 h of noribogaine.
[0450] In one embodiment, the therapeutic dose is tapered over time until the desired maintenance dose is reached. For example, in some embodiments, the first tapered dose is 50% to 95% of the therapeutic dose. In some embodiments, the second tapered dose is 40% to 90% of the therapeutic dose. In some embodiments, the third tapered dose is 30%
to 85% of the therapeutic dose. In some embodiments, the fourth tapered dose is 20% to 80% of the therapeutic dose. In some embodiments, the fifth tapered dose is 10% to 75%
of the therapeutic dose. In some embodiments, one tapered dose is given to achieve the maintenance dose. In some embodiments, two tapered doses are given to achieve the maintenance dose. In some embodiments, three tapered doses are given to achieve the maintenance dose. In some embodiments, four or more tapered doses are given to achieve the maintenance dose. Determination of the tapered doses, number of tapered doses, and the like can be readily made a qualified clinician.
[0451] In one embodiment, the QT interval is not prolonged more than about 30 ms. In a preferred embodiment, the QT interval is not prolonged more than about 20 ms.
In one embodiment, the QT interval is not prolonged more than about 10 ms.
[0452] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 10 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 20 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 30 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 40 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 50 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 60 mg and about 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, Date Recue/Date Received 2023-11-27 noribogaine derivative, or salt or solvate thereof is between about 60 mg and about 90 mg.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 60 mg and about 80 mg.
In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 60 mg and about 70 mg.
[0453] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0454] Noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, suitable for administration in accordance with the methods provide herein, can be suitable for a variety of delivery modes including, without limitation, oral,transdermal, sublingual, buccal, intrapulmonary or intranasal delivery.
Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used.
Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions.
Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A.
Oslo editor, Easton Pa. 1980).
[0455] In a preferred embodiment, noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the noribogaine is provided as noribogaine HO, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.

Date Recue/Date Received 2023-11-27 [0456] The patient may suffer from addiction to any opioid or opiate, or opioid-like drug. In a preferred embodiment, the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, hydrocodone, oxycodone, and methamphetamine. In one embodiment, the opioid or opioid-like drug is heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one embodiment, the opioid or opioid-like drug is morphine.
Alcohol Dependence [0457] In one aspect, this invention relates to treatment of acute withdrawal from alcohol in an alcohol dependent patient comprising administration of a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0458] In one aspect, this invention relates to a method for treating alcohol abuse in an alcohol-dependent patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL,said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.
[0459] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 60 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.

Date Recue/Date Received 2023-11-27 [0460] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to alcohol dependence, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
[0461] In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In a preferred embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/rnL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 200 ng/mL, or about 60 ng/mL to about 200 ng/mL. In one embodiment, the average serum concentration of noribogaine is from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0462] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof is from greater than about 1 mg/kg to about 8 mg/kg body weight per day. The aggregate dosage is the Date Recue/Date Received 2023-11-27 combined dosage, for example the total amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 7 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 6 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 5 mg/kg body weight. In a preferred embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 2 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
[0463] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 8 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 6 mg/kg body weight per day. In one embodiment, the dosage or Date Recue/Date Received 2023-11-27 aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 1.7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 1.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 1 mg/kg body weight per day.
[0464] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from alcohol dependence, and/or symptoms of withdrawal, in an addicted patient by administering a maintenance amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0465] In some aspects, this invention relates to a method to prevent relapse of alcohol abuse and/or use in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0466] In some embodiments, the patient undergoes long-term (e.g., one month, three months, six months, one year or longer) treatment with maintenance doses of noribogaine, noribogaine derivative, or salt and/or solvate thereof. In some embodiments, the patient is treated for acute withdrawal with therapeutic doses of noribogaine as described above, and then the amount of noribogaine is reduced to maintenance levels after acute withdrawal symptoms would be expected to have subsided. Acute withdrawal symptoms generally are Date Recue/Date Received 2023-11-27 the most pronounced in the first week after cessation of alcohol use, although acute withdrawal may last as long as six weeks or more.
[0467] In some embodiments, the patient is administered a high (therapeutic) dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a lower (maintenance) dose to prevent relapse to drug use. In some embodiments, the patient is administered a therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof for a period of time to ameliorate the most significant withdraw symptoms, and then is administered a decreasing (tapered) amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof over time until the maintenance dose is reached.
Drug Addiction [0468] In one aspect, this invention relates to treatment of acute withdrawal from an addictive substance in an addicted patient comprising administration of a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0469] In one aspect, this invention relates to a method for treating substance abuse in an addicted patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT
interval of less than about 500 ms during said treatment.
[0470] In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 80 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.

Date Recue/Date Received 2023-11-27 Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
104711 In one aspect, this invention relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to substance addiction, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt ancUor solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal.
104721 In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150 ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 150 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL. The ranges include both extremes as well as any subranges between.
104731 The patient may suffer from addiction to any addictive drug or substance. In a preferred embodiment, the drug is selected from the group consisting of benzodiazepines, cannabinoids and synthetic cannabinoids, stimulants, barbiturates, gamma-hydroxybutyrate (GHB), ketamine, PCP, dextromethorphan (DXM), lysergic acid diethylamide (LSD), mescaline, anabolic steroids, and derivatives of each thereof.

Date Recue/Date Received 2023-11-27 [0474] In one aspect, this invention relates to treatment or attenuation of post-acute withdrawal from an addictive substance, and/or symptoms of withdrawal, in an addicted patient with a maintenance amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0475] In some aspects, this invention relates to a method to prevent relapse of drug abuse in an addicted patient treated to ameliorate said abuse, said method comprising periodically administering to said patient a maintenance dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
Pain [0476] As will be apparent to the skilled artisan upon reading this disclosure, the present invention provides a method for treating pain in a patient by alleviating and/or inhibiting pain in said patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0477] In one aspect, this invention relates to treatment of pain in a patient suffering from pain comprising administration of a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.
[0478] In one aspect, this invention relates to a method for treating pain in a patient suffering from pain, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 20 ng/mL to 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said pain while maintaining a QT
interval of less than about 500 ms during said treatment. In one embodiment, the concentration is sufficient to inhibit or ameliorate said pain while maintaining a QT interval prolongation of less than about 20 ms during said treatment.
[0479] In one aspect, this invention relates to a method for attenuating pain in a human patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 20 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to Date Recue/Date Received 2023-11-27 attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0480] In one aspect, this invention relates to a method for attenuating pain in a human patient susceptible to such symptoms, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0481] In one aspect, this invention relates to a method for attenuating pain in a human patient susceptible to such symptoms, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 80 ng/mL to 100 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0482] In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 180 ng/mL, or 20 ng/mL to 180 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 20 ng/mL to 150 ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to Date Recue/Date Received 2023-11-27 100 ng/mL, or 20 ng,/mL to 100 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL.The ranges include both extremes as well as any subranges between.
[0483] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt andJor solvate thereof is from 0.1 mg/kg to 4 mg/kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg to 1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.3 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1.1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg to 1 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.7 mg to 1.5 mg per kg body weight per day. The ranges include both extremes as well as any subranges there between.
[0484] In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.5 mg/kg body weight per day.

Date Recue/Date Received 2023-11-27 In one embodiment, the therapeutically effective amount of the compound is about 1.4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.3 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.2 mg/kg body weight per day.
In one embodiment, the therapeutically effective amount of the compound is about 1.1 mg,/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.9 mg/kg body weight per day.
In one embodiment, the therapeutically effective amount of the compound is about 0.8 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.7 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.6 mg/kg body weight per day.
In one embodiment, the therapeutically effective amount of the compound is about 0.5 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.3 mg/kg body weight per day.
In one embodiment, the therapeutically effective amount of the compound is about 0.2 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.1 mg/kg body weight per day.
[0485] In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 60 mg and 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 70 mg and 150 mg.
In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 80 mg and 140 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 90 mg and 140 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 90 mg and 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 100 mg and 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 110 mg and 130 mg.
[0486] In another embodiment, there is provided a unit dose of noribogaine or salt or solvate thereof which is about 120 mg per dose. It being understood that the term "unit Date Recue/Date Received 2023-11-27 dose" means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.
[0487] In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 10 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 50 mg and 100 mg.
In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 60 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 60 mg and 90 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 60 mg and 80 mg. In one embodiment, the dosage or aggregate dosage of noribogaine or salt or solvate thereof is between 60 mg and 70 mg.
Treating Migraine [0488] In some embodiments, the invention provides for a method for treating migraines and/or symptoms thereof in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof. In one embodiment, the method further comprises administering at least one agent known to treat or prevent migraines and/or symptoms thereof. In a preferred embodiment, treatment with noribogaine and/or the agent does not result in a QT interval prolongation of more than about 50 ms. Where noribogaine is discussed throughout the specification, it is to be understood that such an agent may optionally be administered in conjunction with (e.g., before, after, or concurrently with) noribogaine or derivative.
[0489] The subject or patient may be any patient who exhibits migraine ancUor symptoms thereof. In a preferred embodiment, the patient is subject to recurrent migraines.
In one embodiment, the patient has chronic migraine. Chronic migraine is characterized by headaches (tension and/or migraine) on more than 15 days per month for at least 3 months, with migraine (without aura) on at least 8 days per month (or successful treatment of expected symptoms).
[0490] In one aspect, this invention relates to a method for treating migraine and/or symptoms thereof in a patient, comprising administering to the patient a dosage of Date Recue/Date Received 2023-11-27 noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to treat said migraine and/or symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
[0491] In some embodiments, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to treat the patient while maintaining a QT
interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 420 ms during treatment.
[0492] In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT interval is not prolonged more than about 20 ms. In one embodiment, the QT
interval is not prolonged more than about 10 ms.
[0493] In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1000 ng=hr/mL and about 6000 ng=hr/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng=hr/mL and about 5800 ng-hr/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 1200 ng=hr/mL and about 5500 ng=hr/mL. The ranges include both extremes as well as any subranges between.
[0494] In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 40 ng/mL and about 250 ng/mL. In a preferred embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and about 200 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or Date Recue/Date Received 2023-11-27 pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 100 ng/mL and about 180 ng/mL.
[0495] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1 mg/kg to about 4 mg/kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
[0496] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 70 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 75 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 90 mg and about 140 mg. In one embodiment, the dosage or aggregate Date Recue/Date Received 2023-11-27 dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 100 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 110 mg and about 130 mg.
[0497] In some embodiments, the therapeutically effective amount of the compound is from about 50 ng to about 10 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 jig per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 g per kilogram body weight per day.
In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 jig per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 1 jig to less than 10 g per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 g, about 2 g, about 3 g, about 3 g, about 4 g, about 5 jug, about 6 jig, about 7 jig, about 8 g, about 9 jig, or about 10 g per kilogram body weight per day. The therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0498] In some embodiments, the therapeutically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered more than two times per day.
[0499] Where the therapeutically effective amount is administered more than one time per day, a portion of the total therapeutically effective amount is administered at each Date Recue/Date Received 2023-11-27 time. For example, an 90 kg patient taking 1 pig noribogaine per kg body weight per day would take 90 g once a day, 45 jig twice a day, or 30 jig three times a day, etc.
[0500] In some embodiments, the therapeutically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered when needed, e.g., when the patient has a migraine or symptoms thereof or anticipates having a migraine (e.g., anticipates or experiences a trigger, has symptoms or predrome phase, etc).
[0501] In some embodiments, noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered to a patient periodically, such as once, twice, three times, four times or five times daily. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation.
Determination of dosage and frequency suitable for the present technology can be readily made by a qualified clinician.
[0502] In some embodiments, the noribogaine or noribogaine derivative is administered sublingually, intrapulmonary, buccally, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
Preventing Migraine [0503] In some embodiments, the invention provides for a method for preventing or attenuating migraine and/or symptoms thereof in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
In some embodiments, the invention provides for a method for preventing or attenuating migraine and/or symptoms thereof in a subject, comprising administering to the patient in need thereof a prophylactically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof in conjunction with an agent known to prevent migraines and/or symptoms thereof. Where noribogaine is discussed throughout the specification, it is to be understood that such an agent may optionally be administered Date Recue/Date Received 2023-11-27 in conjunction with (e.g., before, after, concurrently or substantially concurrently with) noribogaine or derivative.
[0504] In some embodiments, the noribogaine is administered on an as-needed basis by the patient. In some embodiments, the noribogaine may be administered before the migraine and/or symptoms thereof occurs. For example, the patient may take a dose of noribogaine in anticipation of symptoms (e.g., after, concurrent with, or in anticipation of a migraine trigger; when one or more predrome symptoms are experienced; etc).
In some embodiments, the prophylactically effective amount of noribogaine may be administered on a regularly scheduled basis (e.g., daily, every other day, weekly, etc.) to prevent migraine.
[0505] In one embodiment, the prophylactically effective amount of the compound is up to about 90% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 80% of the therapeutic amount.
In one embodiment, the prophylactically effective amount of the compound is up to about 70%
of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 60% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 50% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 40% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 30% of the therapeutic amount.
In one embodiment, the prophylactically effective amount of the compound is up to about 20%
of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 10% of the therapeutic amount.
[0506] In one embodiment, the prophylactically effective amount of the compound is from about 50 ng to less than 10 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 jig per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 1 lag per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 500 ng to less than 10 jig per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the Date Recue/Date Received 2023-11-27 compound is from about 1 jig to less than 10 jig per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints.
[0507] In one embodiment, the QT interval is not prolonged more than about 30 ms. In a preferred embodiment, the QT interval is not prolonged more than about 20 ms.
In one embodiment, the QT interval is not prolonged more than about 10 ms.
[0508] In some embodiments, the prophylactically effective amount of noribogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered more than two times per day.
[0509] Where the prophylactically effective amount of noribogaine is administered more than one time per day, a portion of the total prophylactically effective amount is administered at each time. For example, an 90 kg patient taking 1 jig noribogaine per kg body weight per day would take 90 jig once a day, 45 jig twice a day, or 30 jig three times a day, etc.
[0510] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0511] In some embodiments, the noribogaine or noribogaine derivative is administered orally, sublingually, intrapulmonary, buccally, or intranasally. These routes of administration are discussed in further detail below in the subsection titled "Dosage and Routes of Administration."
[0512] In some embodiments, the maintenance average serum level of noribogaine is about 10% to about 80% of the therapeutic average serum level of noribogaine.
In some embodiments, the maintenance average serum level of noribogaine is about 70%
of the Date Recue/Date Received 2023-11-27 therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 60% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 50% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 40% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 30% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 20% of the therapeutic average serum level of noribogaine. In some embodiments, the maintenance average serum level of noribogaine is about 10% of the therapeutic average serum level of noribogaine.
Reducing Analgesics Tolerance [0513] In one aspect of this invention, patient is being treated with an addictive opioid analgesic to relieve the patient's pain. The pain may be of any type and from any source.
In one embodiment, the patient is treated for acute pain. In one embodiment, the patient is treated for chronic pain. In one embodiment, the patient is treated for nociceptive pain. In one embodiment, the patient is treated for neuropathic pain. In some embodiments, the pain is caused by surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, central pain syndrome, tissue damage, physical injury, and the like. In some embodiments, the source of the pain is unknown or unclear.
[0514] In one aspect, this invention relates to a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient resensitize the patient to the opioid as an analgesic while maintaining a QT interval of less than about 500 ms during said treatment.
[0515] In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150 ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to Date Recue/Date Received 2023-11-27 100 ng/mL, or 60 ng,/mL to 100 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0516] In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 10 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 20 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 30 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 40 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 50 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 60 mg and 100 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 60 mg and 90 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 60 mg and 80 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between 60 mg and 70 mg.
[0517] The patient may be receiving any addictive opioid analgesic for the treatment of pain. In a preferred embodiment, the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, heroin, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, oxymorphone, and derivatives of each thereof.
Depression [0518] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating depression and/or PTSD in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.

Date Recue/Date Received 2023-11-27 Noribogaine derivatives include, but are not limited to, the compounds described in the "Compositions of the Invention" section above.
[0519] The following description of depressive disorders and PTSD is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of this invention. The definitions of depressive disorders and PTSD given below are those listed in American Psychiatric Association, 1994a or American Psychiatric Association, 1987. Additional information regarding these disorders can be found in this reference, as well as other references cited below, all of which are hereby incorporated herein by reference.
[0520] In some embodiments, it is contemplated that the compounds of this invention will be effective in treating depression in patients who have been diagnosed as having depression based upon the administration of any of the following tests:
Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in improving certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
[0521] This invention provides, in certain embodiments, a method of treating a patient suffering from major depressive disorder, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein effective to treat the subject's major depressive disorder.
[0522] The invention also provides a method of treating a patient suffering from dysthymic disorder, bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
[0523] It is contemplated that the compounds utilized herein can be effective in treating PTSD in patients who have been diagnosed as having PTSD based upon the administration Date Recue/Date Received 2023-11-27 of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated Impact of Event Scale (IES). It is further contemplated that the compounds described herein will be effective in inducing improvements in the scores of the CAPS, TES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds described herein will be effective in preventing relapse of PTSD.
[0524] This invention provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's post-traumatic stress disorder.
[0525] Another aspect of the current invention provides a method for treating depression and/or PTSD in a patient in need thereof, which method comprises administering noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof to the patient, wherein the amount of the noribogaine or a noribogaine derivative is sufficient to treat depression and/or PTSD in the patient.
[0526] In a preferred embodiment, the invention provides a method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides average noribogaine serum levels of between 50 to 800 ng/ml.
In some embodiments, the average noribogaine serum level provided by the dosage is less than about 50 ng/mL. In one embodiment, the therapeutically effective amount is between 0.5 mg to 4 mg per kg of body weight. In one embodiment, the therapeutically effective amount is between 50 ng to less than 100 jig per kg of body weight. In one embodiment, depression is treated. In one embodiment, posttraumatic stress disorder is treated. In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
[0527] In some embodiments, the composition is administered via sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides administering a pharmaceutical composition comprising a pharmaceutically effective amount of noribogaine and a pharmaceutically acceptable excipient, wherein the therapeutically Date Recue/Date Received 2023-11-27 effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to less than 100 pig per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 50 pig per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 10 pig per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 1 pig per kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is administered two or more times per day. In some embodiments, the composition is administered less than once a day, for example once every two days, once every three days, once every four days, once a week, etc.
[0528] In some embodiments, the composition is administered via oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In one embodiment, the dosage or aggregate dosage of compound is from 0.5 mg to 4 mg per kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of noribogaine or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of compound is from 1 mg to 4 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 1 mg to 3 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is from 1 mg to 2 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is from 1.5 mg to 3 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is from 1.7 mg to 3 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is from 2 mg to 4 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is from 2 mg to 3 mg per kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 2 mg per kg body weight per day.
[0529] In one embodiment, the dosage or aggregate dosage of compound is about mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of Date Recue/Date Received 2023-11-27 compound is about 3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 1.7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 1.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is about 1 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of compound is less than about 1 mg/kg body weight per day.
[0530] In certain preferred embodiments of this invention, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered in an amount that provides an average serum concentration of noribogaine from 50 ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150 ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0531] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with noribogaine, noribogaine derivative, or salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made by a qualified clinician.
[0532] In one aspect, this invention relates to a method for attenuating symptoms of depression and/or PTSD in a human patient, comprising administering to the patient a dosage of noribogaine or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient Date Recue/Date Received 2023-11-27 to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0533] In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In a preferred embodiment, the QT interval is not prolonged more than about 20 ms. In one embodiment, the QT interval is not prolonged more than about 10 ms.
[0534] Noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
Anxiety etc.
[0535] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides a method for treating anxiety disorder, impulse control disorder, anger/violence-related disorders, or regulating food intake in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. In a preferred embodiment, the patient is not addicted to cocaine or an opiate.
Noribogaine derivatives include, but are not limited to, the compounds described in the "Compositions of the Invention" section above.

Date Recue/Date Received 2023-11-27 [0536] The following description of anxiety disorders and impulse control disorders is provided for the purpose of facilitating an understanding of the utility of the compounds and compositions of this invention. Disorders associated with violence ancUor anger are included in these descriptions.The definitions of anxiety disorders and impulse control disorders given below are those listed in American Psychiatric Association, 2013, American Psychiatric Association, 1994a, or American Psychiatric Association, 1987.
Additional information regarding these disorders can be found in this reference, as well as other references cited below, all of which are hereby incorporated herein by reference.
[0537] Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating these disorders in patients who have been diagnosed as having such disorders.
[0538] This invention provides for a method of treating a patient suffering from anxiety which comprises administering to the patient an amount of any of the compounds described herein effective to treat the subject's anxiety.
[0539] It is contemplated that the compounds described herein will be effective in treating obsessions and compulsions in patients who have been diagnosed as having obsessive compulsive disorder based upon administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (for adults), National Institute of Mental Health Global OCD
Scale (NIMH GOCS), CGI-Severity of Illness scale. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds described herein will be effective in preventing relapse of obsessive compulsive disorder.
[0540] This invention provides a method of treating obsessions and compulsions in a patient with obsessive compulsive disorder, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein effective to treat the subject's obsessions and compulsions.

Date Recue/Date Received 2023-11-27 [0541] It is contemplated that the compounds described herein will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of the factors measured in these evaluations, such as a reduction in frequency or elimination of panic attacks, an improvement in the CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds described herein will be effective in preventing relapse of panic disorder.
[0542] This invention provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's panic disorder.
[0543] It is contemplated that the compounds described herein can be effective in treating social anxiety disorder in patients who have been diagnosed as having social anxiety disorder based upon the administration of any of the following tests:
the Liebowitz Social Anxiety Scale (LSAS), the CGI-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V
Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II
(ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile, the World Health Organization Quality of Life-100 (WHOQOL-100), or other tests as described in Bobes, 1998, which is incorporated herein by reference. It is further contemplated that the compounds described herein will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds described herein will be effective in preventing relapse of social anxiety disorder.
[0544] This invention provides a method of treating social anxiety disorder in a patient which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's social anxiety disorder.

Date Recue/Date Received 2023-11-27 [0545] It is contemplated that the compounds utilized herein can be effective in treating generalized anxiety disorder in patients who have been diagnosed as having this disorder based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds described herein will be effective in preventing relapse of general anxiety disorder.
[0546] The invention provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the patient an amount of any of the compounds described herein effective to treat the subject's generalized anxiety disorder.
105471 Impulse control disorders include pathological gambling (PG), kleptomania, trichotillomania (TTM), intermittent explosive disorder (TED), and pyromania.
Impulse control disorders may also include pathological skin picking (PSP), compulsive sexual behavior (CSB), compulsive buying (CB), conduct disorder, antisocial personality disorder, oppositional defiant disorder, borderline personality disorder, attention deficit/hyperactivity disorder (ADHD, which includes attention deficit disorder, ADD), schizophrenia, mood disorders, paraphilia, and interne addiction. Symptoms of impulse control disorders include: repetitive participation in behavior despite adverse consequences, diminished control over the behavior, an urge/impulse to engage in the behavior, and feelings of pleasure while participating in the behavior.
[0548] It is contemplated that the compounds utilized herein can be effective in treating impulse control disorders in patients who have at least one impulse control disorder based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of the impulse control disorder.
[0549] It is contemplated that the compounds utilized herein can be effective in treating ADHD or ADD in patients who have the disorder, based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized Date Recue/Date Received 2023-11-27 herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of ADD or ADHD.
[0550] It is contemplated that the compounds utilized herein can be effective in treating schizophrenia in patients who have the disorder, based upon the diagnostic criteria described in DSM-IV or DSM-5. Schizophrenia is characterized by delusions, hallucinations, disorganized speech and behavior, and other symptoms that cause social or occupational dysfunction. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder. It is also contemplated that the compounds described herein will be effective in preventing relapse of schizophrenia.
[0551] It is contemplated that the compounds described herein will be effective in treating non-suicidal self injury disorder in patients who have been diagnosed with this disorder based on the patient's exhibition of symptoms including deliberate tissue injury without suicidal intent (e.g., cutting, burning, self-poisoning, or self-mutilation). It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of self injury. It is also contemplated that the compounds described herein will be effective in preventing relapse of non-suicidal self injury disorder.
[0552] This invention provides a method of treating non-suicidal self injury disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's non-suicidal self injury disorder.
[0553] It is contemplated that the compounds described herein will be effective in treating Miinchausen syndrome in patients who have been diagnosed with this disorder based on the patient's propensity for feigning disease, illness, or psychological trauma to draw attention, sympathy, or reassurance to themselves. Symptoms may include frequent hospitalizations, knowledge of several illnesses, frequent requests for medication (e.g., pain killers), willingness to undergo extensive surgery, few to no visitors during hospitalizations, and exaggerated or fabricated stories about multiple medical problems. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination Date Recue/Date Received 2023-11-27 of one or more symptoms. It is also contemplated that the compounds described herein will be effective in preventing relapse of Miinchausen syndrome. Miinchausen syndrome also includes Miinchausen syndrome by proxy, in which a caregiver exaggerates, fabricates, or induces illness in someone in his/her care.
[0554] This invention provides a method of treating Miinchausen syndrome in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's Miinchausen syndrome.
[0555] It is contemplated that the compounds described herein will be effective in treating disruptive mood dysregulation disorder in patients who have been diagnosed with this disorder on the basis of severe and recurrent temper outbursts, grossly out of proportion to the stimulus or situation, as well as a persistent irritable/angry mood most of the time. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as a reduction in frequency or elimination of tember outbursts and/or an improvement in mood. It is also contemplated that the compounds described herein will be effective in preventing relapse of disruptive mood dysregulation disorder disorder.
[0556] This invention provides a method of treating disruptive mood dysregulation disorder in a subject, which comprises administering to the patient a therapeutically effective amount of any of the compounds utilized herein to treat the subject's disruptive mood dysregulation disorder.
[0557] It is contemplated that the compounds utilized herein can be effective in reducing the frequency, intensity, and duration of anger and/or violence in individuals prone to one or both. Although anger and violence disorders other than those associated with other disorders (e.g., as described above) are not outlined in DSM IV or DSM 5, many health professionals recognize that such disorders are associated with significant dysfunction.
Anger management training and other psychosocial treatments are often used in an effort to treat these individuals.
[0558] It is contemplated that the compounds utilized herein can be effective in regulating food intake and/or reducing food cravings in patients in need thereof. In some embodiments, the patient is overweight. In some embodiments, the patient is obese. In Date Recue/Date Received 2023-11-27 some embodiments, the patient exhibits comorbidities associated with overweight/obesity, for example coronary heart disease, high blood pressure, stroke, type 2 diabetes, abnormal levels of blood fats, metabolic syndrome, cancer, osteoarthritis, sleep apnea, reproductive issues, and/or gallstones.
[0559] In a preferred embodiment, the invention provides a method for treating anxiety disorders, impulse control disorders, OCD, and/or anger/violence-related disorders, or regulating food intake and/or food cravings, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides average noribogaine serum levels of between about 50 to about ng/ml. In some embodiments, the average noribogaine serum level provided by the dosage is less than about 50 ng/mL. In one embodiment, the therapeutically effective amount is between about 1 mg to about 4 mg per kg of body weight. In one embodiment, the therapeutically effective amount is between about 50 ng to about 100 p.g per kg of body weight. In one embodiment, an anxiety disorder is treated. In one embodiment, OCD is treated. In one embodiment, an impulse control disorder is treated. On one embodiment, an anger-related disorder is treated. in one embodiment, a violence-related disorder is treated. In one embodiment, symptoms of anger are reduced or eliminated. In one embodiment, violent outbursts are reduced or eliminated. In one embodiment, food intake is regulated. In one embodiment, food cravings are attenuated. In one embodiment, the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
Dosage and Routes of Administration [0560] In some embodiments, the composition is administered via sublingual, intranasal, or intrapulmonary delivery. In one aspect, the invention provides administering a pharmaceutical composition comprising a pharmaceutically effective amount of noribogaine and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 100 ps per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate Date Recue/Date Received 2023-11-27 amount of noribogaine of about 50 ng to about 50 jig per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 10 jig per kg body weight per day. In some aspects, the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 1 Jig per kg body weight per day. In some aspects, the composition is administered once per day.
In some aspects, the composition is administered two or more times per day. In some embodiments, the composition is administered less than once a day, for example once every two days, once every three days, once every four days, once a week, etc.
[0561] In some embodiments, the composition is administered via oral, buccal, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery.
[0562] In one embodiment, the dosage or aggregate dosage of compound is from about 1 mg to about 4 mg per kg body weight per day. The aggregate dosage is the combined dosage, for example the total amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day.
[0563] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with noribogaine, noribogaine derivative, or salt and/or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made by a qualified clinician.
[0564] In another embodiment, there is provided a unit dose of noribogaine, noribogaine derivative, or salt or solvate thereof which is about 50 mg to about 200 mg per dose. In one embodiment, the unit dose is about 50 to about 120 mg per dose.
In one embodiment, the unit dose is about 120 mg per dose. It being understood that the term "unit dose" means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.

Date Recue/Date Received 2023-11-27 [0565] In one aspect, this invention relates to a method for attenuating symptoms of anxiety disorder, impulse control disorder, or an anger and/or violence-related disorder in a human patient, comprising administering to the patient a dosage of noribogaine or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to attenuate said symptoms while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0566] In one aspect, this invention relates to a method for attenuating food cravings in a human patient, comprising administering to the patient a dosage of noribogaine or pharmaceutically acceptable salt ancUor solvate thereof that provides an average serum concentration of about 50 ng/mL to about 400 ng/mL, said concentration being sufficient to attenuate said cravings while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 470 ms during treatment.
Preferably, the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said cravings while maintaining a QT
interval of less than about 420 ms during treatment.
[0567] In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In a preferred embodiment, the QT interval is not prolonged more than about 20 ms. In one embodiment, the QT interval is not prolonged more than about 10 ms.
[0568] Noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, Date Recue/Date Received 2023-11-27 lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
Sustained Treatment [0569] As will be apparent to the skilled artisan upon reading this disclosure, one aspect of the present invention provides a method for treating a condition in a patient, such condition being treatable by noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, the method comprising administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that an average therapeutic serum concentration is achieved by the initial unit dose and maintained by the at least one additional dose.
[0570] In one aspect, this invention relates to a method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof while maintaining an acceptable QT interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein said unit dose provides a therapeutic average serum concentration of 50 ng/mL to 180 ng,/mL
which serum concentration imparts minimal QT interval prolongation; and b) maintaining said serum concentration by periodically administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL during treatment Date Recue/Date Received 2023-11-27 wherein said additional dose or doses are continued as necessary to treat said condition.
[0571] In one aspect, the serum concentration provides a maximum QT interval of less than about 500 ms during said treatment. In some embodiments, the serum concentration provides a maximum QT interval of less than about 470 ms during treatment.
Preferably, the serum concentration provides a maximum QT interval of less than about 450 ms during treatment. In one embodiment, the serum concentration provides a maximum QT
interval of less than about 420 ms during treatment.
[0572] In one embodiment, the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT interval is not prolonged more than about 20 ms. In one embodiment, the QT
interval is not prolonged more than about 10 ms.
[0573] In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 180 ng/mL, or 60 ng/mL to 180 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 150 ng/mL, or 60 ng/mL to 150 ng/mL.
In one embodiment, the average serum concentration of noribogaine is from 50 ng/mL to 100 ng/mL, or 60 ng/mL to 100 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 150 ng/mL. In one embodiment, the average serum concentration of noribogaine is from 80 ng/mL to 100 ng/mL. In some aspects of the invention, a lower serum concentration may be therapeutic for a given condition. In one embodiment, the therapeutic serum concentration is between 1 ng/mL
and 10 ng/mL. By way of non-limiting example, the therapeutic serum concentration for treatment of nicotine addiction is believed to be lower than that for addiction to opioids.
The ranges above include both extremes as well as any subranges between.
[0574] In some embodiments, the initial unit dose of noribogaine, noribogaine derivative, or salt or solvate thereof is from 50 mg to 120 mg. In one embodiment, the initial dose is about 50 mg. In one embodiment, the initial dose is about 55 mg. In one embodiment, the initial dose is about 60 mg. In one embodiment, the initial dose is about 65 mg. In one embodiment, the initial dose is about 70 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial Date Recue/Date Received 2023-11-27 dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.
[0575] In some embodiments, the initial unit dose of noribogaine, noribogaine derivative, or salt or solvate thereof is administered as subdoses, such that the aggregate dose achieves the unit dose. In some embodiments, the initial unit dose is administered as subunit doses, which subunit doses are administered serially until the unit dose level is achieved, wherein the aggregate of subunit doses provides the initial unit dose and further provides the therapeutic average serum concentration. In some embodiments, the aggregate dose provides a therapeutic serum concentration of 80 ng/mL to 150 ng/mL. In some embodiments, the subdoses are administered every 15 minutes to 6 hours until the unit dose is achieved. In some embodiments, the subdoses are administered every 15 minutes, every 30 minutes, every 1 hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, or every 6 hours until the unit dose is achieved. The ranges above include both extremes as well as any subranges between.
[0576] In some embodiments, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 75 mg. In one embodiment, the one or more additional doses may or may not comprise the same amount of noribogaine, noribogaine derivative, or salt or solvate thereof. In one embodiment, at least one additional dose is about 5 mg. In one embodiment, at least one additional dose is about 10 mg. In one embodiment, at least one additional dose is about 15 mg.
In one embodiment, at least one additional dose is about 20 mg. In one embodiment, at least one additional dose is about 25 mg. In one embodiment, at least one additional dose is about 30 mg. In one embodiment, at least one additional dose is about 35 mg. In one embodiment, at least one additional dose is about 40 mg. In one embodiment, at least one additional dose is about 45 mg. In one embodiment, at least one additional dose is about 50 mg. In one embodiment, at least one additional dose is about 55 mg. In one embodiment, at least one additional dose is about 60 mg. In one embodiment, at least one additional dose is about 65 mg. In one embodiment, at least one additional dose is about Date Recue/Date Received 2023-11-27 70 mg. In one embodiment, at least one additional dose is about 75 mg. The ranges above include both extremes as well as any subranges between.
[0577] In one embodiment, the one or more additional doses are administered periodically. In one embodiment, the one or more additional doses are administered every 4 hours to every 48 hours. In a preferred embodiment, the one or more additional doses are administered every 6 hours to every 24 hours. In one embodiment, the one or more additional doses are administered every 4 hours. In one embodiment, the one or more additional doses are administered every 6 hours. In one embodiment, the one or more additional doses are administered every 8 hours. In one embodiment, the one or more additional doses are administered every 10 hours. In one embodiment, the one or more additional doses are administered every 12 hours. In one embodiment, the one or more additional doses are administered every 18 hours. In one embodiment, the one or more additional doses are administered every 24 hours. In one embodiment, the one or more additional doses are administered every 36 hours. In one embodiment, the one or more additional doses are administered every 48 hours. The ranges above include both extremes as well as any subranges between.[0578] In some embodiments, the therapeutic dose of noribogaine, noribogaine derivative, or salt or solvate thereof is a tapered dosing over a period of time, during which the patient is detoxified, for example, without suffering significant acute withdrawal symptoms. Without being bound by theory, it is believed that tapering will allow the full therapeutic effect of noribogaine with less prolongation of the QT interval. Tapering involves administration of one or more subsequently lower doses of noribogaine over time. For example, in some embodiments, the first tapered dose is 50%
to 95% of the initial or at least one additional dose. In some embodiments, the second tapered dose is 40% to 90% of the initial or at least one additional dose. In some embodiments, the third tapered dose is 30% to 85% of the initial or at least one additional dose. In some embodiments, the fourth tapered dose is 20% to 80% of the initial or at least one additional dose. In some embodiments, the fifth tapered dose is 10% to 75%
of the initial or at least one additional dose.
[0579] In some embodiments, the first tapered dose is given after the first dose of noribogaine. In some embodiments, the first tapered dose is given after the second, third, or a subsequent dose of noribogaine. The first tapered dose may be administered at any time after the previous dose of noribogaine. The first tapered dose can be given once, for Date Recue/Date Received 2023-11-27 example, followed by subsequent further tapered doses, or it can be given multiple times with or without subsequent, further tapered doses (e.g., second, third, fourth, etc. tapered doses), which likewise can be given once or over multiple administrations, for example. In some embodiments, the first tapered dose is administered one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of noribogaine.
Similarly, second, third, fourth, etc. tapered doses, if given, can be given one hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous dose of noribogaine.
[0580] In some embodiments, the dose is tapered starting 12 to 96 hours after the initial dose. In some embodiments, the dose is tapered starting 12 hours after the initial dose. In some embodiments, the dose is tapered starting 18 hours after the initial dose. In some embodiments, the dose is tapered starting 24 hours after the initial dose. In some embodiments, the dose is tapered starting 30 hours after the initial dose. In some embodiments, the dose is tapered starting 36 hours after the initial dose. In some embodiments, the dose is tapered starting 42 hours after the initial dose. In some embodiments, the dose is tapered starting 48 hours after the initial dose. In some embodiments, the dose is tapered starting 54 hours after the initial dose. In some embodiments, the dose is tapered starting 60 hours after the initial dose. In some embodiments, the dose is tapered starting 66 hours after the initial dose. In some embodiments, the dose is tapered starting 72 hours after the initial dose. In some embodiments, the dose is tapered starting 78 hours after the initial dose. In some embodiments, the dose is tapered starting 84 hours after the initial dose. In some embodiments, the dose is tapered starting 90 hours after the initial dose. In some embodiments, the dose is tapered starting 96 hours after the initial dose.

Date Recue/Date Received 2023-11-27 [0581] In some embodiments, at least one additional dose is administered 4 hours to 24 hours after the initial unit dose. In some embodiments, the additional doses are administered 4 hours to 24 hours after the previous dose. In some embodiments, the doses are administered every 4 hours to 24 hours. In some embodiments, the doses are administered as needed. The dosage and frequency of the administration depends on the route of administration, dosage, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0582] In some embodiments, the doses are administered at varying time points.
That is, each dose need not be administered at the same interval as the previous dose.
In some embodiments, the additional doses are administered more frequently at the beginning of treatment, and less frequently after a certain period of time. For example and without limitation, withdrawal symptoms are the most severe in the first 72 hours after the last dose of the drug of addiction. Noribogaine, noribogaine derivative, or a pharmaceutically acceptable solvate or salt thereof may be administered, for example, every 4 hours to 12 hours for the first 72 hours, and less frequently (e.g., 12 hours to 24 hours) thereafter.
[0583] In some embodiments, the noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered for an indefinite period of time (e.g., for several months or several years, up to the lifetime of the patient).
[0584] In some embodiments, the patient undergoes long-term (e.g., one year or longer) treatment with maintenance doses of noribogaine, noribogaine derivative, or salt or solvate thereof. In some embodiments, the patient is first treated for acute symptoms of the condition with therapeutic doses of noribogaine as described above, and then the amount of noribogaine is reduced to maintenance levels, for example after acute symptoms would be expected to have subsided. This is particularly relevant to treating drug addiction, as acute withdrawal symptoms generally are the most pronounced in the first 48 to 72 hours after cessation of the drug of addiction, although acute withdrawal may last as long as a week or more.

Date Recue/Date Received 2023-11-27 Patient Pre-screening and Monitoring [0585] Pre-screening of patients before treatment with noribogaine and/or monitoring of patients during noribogaine, noribogaine derivative, or pharmaceutically acceptable said and/or solvate thereof treatment may be required to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than about 500 ms can be considered dangerous for individual patients. Pre-screening and/or monitoring may be necessary at high levels of noribogaine treatment.
[0586] In a preferred embodiment, a patient receiving a therapeutic dose of noribogaine is monitored in a clinical setting. Monitoring may be necessary to ensure the QT interval is not prolonged to an unacceptable degree. A "clinical setting" refers to an inpatient setting (e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient setting with frequent, regular monitoring (e.g., outpatient clinic that is visited daily to receive dose and monitoring). Monitoring includes monitoring of QT interval. Methods for monitoring of QT interval are well-known in the art, for example by ECG.
[0587] In one embodiment, a patient receiving a maintenance dose of noribogaine is not monitored in a clinical setting. In one embodiment, a patient receiving a maintenance dose of noribogaine is monitored periodically, for example daily, weekly, monthly, or occasionally.
[0588] In one aspect, this invention relates to a method for treating, preventing, or attenuating a disease or disorder or symptoms of a disease or disorder described herein who is prescreened to evaluate the patient's expected tolerance for prolongation of QT
interval, administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse or symptoms while maintaining a QT
interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 420 ms during treatment.

Date Recue/Date Received 2023-11-27 [0589] In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 450 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT
interval over about 420 ms. In one embodiment, prescreening comprises determining the patient's pre-treatment QT interval.
[0590] As it relates to pre-screening or pre-selection of patients, patients may be selected based on any criteria as determined by the skilled clinician. Such criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like. The following are examples of selection criteria for disallowing noribogaine treatment or restricting dose of noribogaine administered to the patient: high QT interval before treatment (e.g., such that there is a risk of the patient's QT interval exceeding about 500 ms during treatment);
congenital long QT syndrome; bradycardia; hypokalemia or hypomagnesemia;
recent acute myocardial infarction; uncompensated heart failure; and taking other drugs that increase QT interval. In some embodiments, the methods can include selecting and/or administering/providing noribogaine to a patient that lacks one more of such criteria.
[0591] In one embodiment, this invention relates to pre-screening a patient to determine if the patient is at risk for prolongation of the QT interval beyond a safe level. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is not administered noribogaine. In one embodiment, a patient at risk for prolongation of the QT
interval beyond a safe level is administered noribogaine at a limited dosage.
[0592] In one embodiment, this invention relates to monitoring a patient who is administered a therapeutic dose of noribogaine. In one embodiment, the dose of noribogaine is reduced if the patient has serious adverse side effects. In one embodiment, the noribogaine treatment is discontinued if the patient has serious adverse side effects. In one embodiment, the adverse side effect is a QT interval that is prolonged beyond a safe Date Recue/Date Received 2023-11-27 level. The determination of a safe level of prolongation is within the skill of a qualified clinician.
[0593] In one aspect, this invention relates to a method for treating an anxiety disorder, an impulse control disorder, or an anger/violence-related disorder, and/or treating or attenuating the symptoms thereof in a patient, comprising selecting a patient exhibiting symptoms of an anxiety disorder, impulse control disorder, or anger/violence-related disorder who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL, said concentration being sufficient to inhibit or ameliorate said disorder or symptoms while maintaining a QT
interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to attenuate said symptoms while maintaining a QT
interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
[0594] In one aspect, this invention relates to a method for regulating food intake, and/or treating or attenuating food cravings, in a patient, comprising selecting an overweight or obese patient who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said disorder or symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
Kit of Parts [0595] One aspect of this invention is directed to a kit of parts for the treatment a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the kit comprises a composition comprising noribogaine, noribogaine derivative, or salt or solvate thereof and Date Recue/Date Received 2023-11-27 a means for administering the composition to a patient in need thereof. The means for administration to a patient can include, for example, any one or combination of a pharmaceutically acceptable formulation comprising noribogaine, or a noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof (e.g., a pill, transdermal patch, injectable, and the like, without limitation) and optionally a means for dispensing and/or administering the formulation (e.g., a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, an inhaler comprising the composition, etc, without limitation). In one embodiment, the kit of parts further comprises instructions for dosing and/or administration of the composition.
[0596] In some aspects, the invention is directed to a kit of parts for administration of noribogaine, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of noribogaine and further wherein each delivery vehicle is identified by the amount of noribogaine provided therein; and optionally further comprising a dosing treatment schedule in a readable medium. In some embodiments, the dosing treatment schedule includes the amount of noribogaine required to achieve each average serum level is provided. In some embodiments, the kit of parts includes a dosing treatment schedule that provides an attending clinician the ability to select a dosing regimen of noribogaine based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In some embodiments, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight (or mass) and sex of the patient. In an embodiment, the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit. In an embodiment, the storage medium can include electronic, optical, or other data storage, such as a non-volatile memory, for example, to store a digitally-encoded machine-readable representation of such information.
[0597] The term "delivery vehicle" as used herein refers to any formulation that can be used for administration of noribogaine to a patient. Non-limiting, exemplary delivery vehicles include caplets, pills, capsules, tablets, powder, liquid, or any other form by which the drug can be administered. Delivery vehicles may be intended for administration by oral, inhaled, injected, or any other means.

Date Recue/Date Received 2023-11-27 [0598] The term "readable medium" as used herein refers to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human-readable formats include pamphlets, inserts, or other written forms. Non-limiting examples of machine-readable formats include any mechanism that provides (i.e., stores and/or transmits) information in a form readable by a machine (e.g., a computer, tablet, and/or smartphone). For example, a machine-readable medium includes read-only memory (ROM); random access memory (RAM); magnetic disk storage media; optical storage media; and flash memory devices. In one embodiment, the machine-readable medium is a CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one embodiment, the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode.
[0599] In some aspects, the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of noribogaine and optionally other drug information. In some embodiments, the software may be interactive, such that the attending clinician or other medical professional can enter patient information. In a non-limiting example, the medical professional may enter the weight and sex of the patient to be treated, and the software program provides a recommended dosing regimen based on the information entered. The amount and timing of noribogaine recommended to be delivered will be within the dosages that result in the serum concentrations as provided herein.
[0600] In some embodiments, the kit of parts comprises multiple delivery vehicles in a variety of dosing options. For example, the kit of parts may comprise pills or tablets in multiple dosages, such as 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and/or 5 mg of noribogaine per pill. Each pill is labeled such that the medical professional and/or patient can easily distinguish different dosages. Labeling may be based on printing or embossing on the pill, shape of the pill, color of pill, the location of the pill in a separate, labeled compartment within the kit, and/or any other distinguishing features of the pill. In some embodiments, all of the delivery vehicles within a kit are intended for one patient. In some embodiments, the delivery vehicles within a kit are intended for multiple patients.
[0601] One aspect of this invention is directed to a kit of parts for the treatment, prevention, or attenuation of a disease or disorder or symptoms of a disease or disorder Date Recue/Date Received 2023-11-27 described herein, wherein the kit comprises a unit dose form of noribogaine, noribogaine derivative, or salt or solvate thereof. The unit dose form provides a patient with an average serum level of noribogaine of from about 50 ng/mL to about 180 ng/mL or about ng/mL to about 180 ng/mL. The unit dose form provides a patient with an average serum level of noribogaine of from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the unit dose form provides a patient with an average serum level of noribogaine of from about 50 ng/mL to about 400 ng/mL
or about 60 ng/mL to about 400 ng/mL. In one embodiment, the unit dose form provides a patient with an average serum level of noribogaine of from 80 ng/mL to 100 ng/mL.
[0602] In some embodiments, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 20 mg to 120 mg.
In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 30 mg.
In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg.
In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg.
In one embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg.
In one embodiment, the unit dose is 100 mg. In one embodiment, the unit dose is 110 mg. In one embodiment, the unit dose is 120 mg.
[0603] In some embodiments, the unit dose form comprises one or multiple dosages to be administered periodically, such as once, twice, three times, four times or five times daily with noribogaine or its prodrug. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.
[0604] In some embodiments, the initial unit dose and one or more additional doses of noribogaine, noribogaine derivative, or salt or solvate thereof are provided as one or multiple dosages to be administered periodically, such as once, twice, three times, four times or five times daily with noribogaine or its prodrug. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a Date Recue/Date Received 2023-11-27 week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.
106051 In one aspect, provided herein is a kit of parts comprising two or more doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the two or more doses comprise an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that is sufficient to maintain a serum concentration of 50 ng/mL to 180 ng/mL when administered to a patient.
106061 In one embodiment, one dose comprises an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, said initial dose being sufficient to achieve a therapeutic serum concentration when administered to a patient; and at least one additional dose, said additional dose sufficient to maintain a therapeutic serum concentration when administered to a patient, wherein the therapeutic serum concentration is between 50 ng/mL and 180 ng/mL In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg.
106071 These dose ranges may be achieved by transdermal, oral, or parenteral administration of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof in unit dose form. Such unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form. In certain embodiments, the noribogaine is provided as noribogaine HO, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HCl is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients. In some embodiments, noribogaine is provided in saline for intravenous administration.

Date Recue/Date Received 2023-11-27 Formulations [0608] This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 180 ng/mL
when administered to a patient. In a preferred embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of about 80 ng/mL to about 100 ng/mL when administered to a patient. In one embodiment, the amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 10 n per kg body weight per day.
[0609] In some embodiments, the unit dose of noribogaine is administered in one or more dosings.[0610] This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine is sufficient to provide andJor maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL when administered to a patient. In a preferred embodiment, the amount of noribogaine is sufficient to provide andJor maintain an average serum concentration of 80 ng/mL to 100 ng/mLwhen administered to a patient.
[0611] In some embodiments, the unit dose of noribogaine is administered in one or more dosings.
[0612] In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from 50 ng/mL to 180 ng/mL, or 60 ng/mL to ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from 50 ng/mL to 150 ng/mL, or 60 ng/mL to ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from Date Recue/Date Received 2023-11-27 about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 80 ng/mL to about 100 ng/mL.The ranges include both extremes as well as any subranges between.
[0613] In some embodiments, the initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 50 mg to about 120 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is about 65 mg. In one embodiment, the unit dose is about 70 mg.
In one embodiment, the unit dose is about 75 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 85 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 95 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is 105 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 115 mg. In one embodiment, the unit dose is about 120 mg.
[0614] In some embodiments, the at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 5 mg to 75 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the unit dose is mg. In one embodiment, the unit dose is 15 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 35 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 45 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 65 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 75 mg.
[0615] In some embodiments, the formulation comprises a delivery vehicle, as described above. In one embodiment, the delivery vehicle comprises 5 mg to 120 mg noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

Date Recue/Date Received 2023-11-27 [0616] In some embodiments, the formulation is a controlled release formulation. The term "controlled release formulation" includes sustained release and time-release formulations. Controlled release formulations are well-known in the art. These include excipients that allow for sustained, periodic, pulse, or delayed release of the drug.
Controlled release formulations include, without limitation, embedding of the drug into a matrix; enteric coatings; micro-encapsulation; gels and hydrogels; implants;
transdermal patches; and any other formulation that allows for controlled release of a drug.
[0617] In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 180 ng/mL, or about 60 ng/mL to about 180 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 150 ng/mL, or about 60 ng/mL to about 150 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 120 ng/mL, or about 60 ng/mL to about 120 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about ng/mL to about 100 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 80 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0618] In some embodiments, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg.
In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit dose is about 30 mg. In one embodiment, the unit dose is about 40 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 120 mg.
[0619] This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof, wherein the amount of noribogaine is sufficient to Date Recue/Date Received 2023-11-27 provide an average serum concentration of about 50 ng/mL to about 850 ng/mL
when administered to a patient. In a preferred embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of about 50 ng/mL to about 400 ng/mLwhen administered to a patient.
[0620] In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 800 ng/mL or about 60 ng/mL to about 800 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 700 ng/mL or about 60 ng/mL to about 700 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 600 ng/mL, or about 60 ng/mL to about 600 ng/mL. In a preferred embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 500 ng/mL, or about 60 ng/mL to about 500 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 400 ng/mL, or about 60 ng/mL to about 400 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 300 ng/mL, or about 60 ng/mL to about 300 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 200 ng/mL, or about ng/mL to about 200 ng/mL. In one embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of noribogaine from about 50 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
[0621] In some embodiments, the formulation is designed for periodic administration, such as once, twice, three times, four times or five times daily with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation.
Determination of Date Recue/Date Received 2023-11-27 dosage and frequency suitable for the present technology can be readily made a qualified clinician.
[0622] In some embodiments, the formulation designed for administration in accordance with the methods provide herein can be suitable for a variety of delivery modes including, without limitation, oral,transdermal, sublingual, buccal, intrapulmonary or intranasal delivery. Formulations suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All formulations may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
[0623] In a preferred embodiment, the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form.
In certain embodiments, the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
[0624] Noribogaine or a noribogaine derivative can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing noribogaine may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, etc.
[0625] The compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal Date Recue/Date Received 2023-11-27 administration. The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve.
Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler.
[0626] The compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets. Sublingual tablets are designed to dissolve very rapidly. The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol.
[0627] It has been discovered that noribogaine has a bitter taste to at least some patients.
Accordingly, compositions for oral use (including sublingual, inhaled, and other oral formulations) may be formulated to utilize taste-masking technologies. A
number of ways to mask the taste of bitter drugs are known in the art, including addition of sugars, flavors, sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes;
granulation;
microencapsulation; numbing of taste buds; multiple emulsion; modification of viscosity;
prodrug or salt formation; inclusion or molecular complexes; ion exchange resins; and solid dispersion. Any method of masking the bitterness of the compound of the invention may be used.
EXAMPLES
[0628] The following Examples are intended to further illustrate certain embodiments of the disclosure and are not intended to limit its scope.

Date Recue/Date Received 2023-11-27 Example 1. Pharmacokinetics and pharmaco dynamics of noribogaine in humans [0629] Thirty-six healthy, drug-free male volunteers, aged between 18-55 years, were enrolled in and completed the study. This was an ascending single-dose, placebo-controlled, randomized double blind, parallel group study. Mean (SD) age was 22.0 (3.3) years, mean (SD) height was 1.82 (0.08) m, and mean (SD) weight was 78.0 (9.2) kg.
Twenty-six subjects were Caucasian, 3 were Asian, 1 Maori, 1 Pacific Islander, and 5 Other. The protocol for this study was approved by the Lower South Regional Ethics Committee (LRS/12/06/015), and the study was registered with the Australian New Zealand Clinical Trial Registry (ACTRN12612000821897). All subjects provided signed informed consent prior to enrolment, and were assessed as suitable to participate based on review of medical history, physical examination, safety laboratory tests, vital signs and ECG.
[0630] Within each dose level, 6 participants were randomized to receive noribogaine and 3 to receive placebo, based on a computer-generated random code. Dosing began with the lowest noribogaine dose, and subsequent cohorts received the next highest dose after the safety, tolerability, and blinded pharmacokinetics of the completed cohort were reviewed and dose-escalation approved by an independent Data Safety Monitoring Board.
Blinded study drug was administered as a capsule with 240 ml of water after an overnight fast of at least 10 hours. Participants did not receive any food until at least 5 hours post-dose. Participants were confined to the study site from 12 hours prior to drug administration, until 72 hours post-dose, and there were subsequent outpatient assessments until 216 hours post-dose.
[0631] Blood was obtained for pharmacokinetic assessments pre-dose and then at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 18, 24, 30, 36, 48, 60, 72, 96, 120, 168 and 216 hours post-dose. Samples were centrifuged and plasma stored at -70 C until analyzed. Block 24 hour urine collections were obtained following study drug administration for the 30 and 60 mg cohorts. Aliquots were frozen at -20 C until analyzed.
[0632] Pulse oximetry and capnography data were collected continuously using a GE
Carescape B650 monitoring system from 2 hours prior to dosing and until six hours after dosing, and thereafter at 12, 24, 48 and 72 hours post-dosing. Additional oximetry data Date Recue/Date Received 2023-11-27 were collected at 120, 168 and 216 hours. Pupillary miosis was assessed by pupillometry.
Dark-adapted pupil diameter was measured in triplicate using a Neuroptics PLR-pupillometer under standardized light intensity (<5 lux) pre-dose, and at 2, 4, 6, 12, 24, 48, 72, 96, 120, 168 and 216 hours post-dosing.
[0633] Plasma noribogaine concentrations were determined in the 3 mg and 10 mg dose groups using a validated, sensitive LCMSMS method. Sample preparation involved double extraction of basified plasma samples with tert-butyl methyl ether, drying the samples under a stream of nitrogen and reconstitution of sample with acetonitrile:B.P.
water (5:95, v/v) containing 0.1% (v/v) formic acid. The compounds were separated by a 150 x 2.0 mm Luna 5[1m C18 column and detected with a triple ¨ quadruple API
4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d4 was used as the internal standard. The precursor-production transition values for noribogaine were m/z 297.6 -> 122.3, and for the internal standard noribogaine-d4 m/z 301.1 -> 122.2. Analyst software was used for data acquisition and processing. The ratio of the peak area of noribogaine to the internal standard noribogaine-d4 was used for calibration and measurement of the unknown concentration of noribogaine. The lower limit of quantification (LLOQ) was 0.025 ng/ml noribogaine. The calibration curve was between 0.025 and 25.600 ng/ml noribogaine.
Mobile phase A was acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid, and mobile phase B was acetonitrile:B.P. water (95:5, v/v) containing 0.1%
(v/v) formic acid. Total run time was 6 minutes. Binary flow: Initial concentration was 8%
mobile phase B; hold at 8% mobile phase B for 0.5 minutes and linear rise to 90%
mobile phase B
over 1.5 minutes; hold at 90% mobile phase B for 1 minute and then drop back to 8%
mobile phase B over 0.01 minute. Equilibrate system for 3 minutes. Total run time was 6 minutes. Within- and between-day assay precision was <9%, and within- and between-day assay accuracy was < 9%.
[0634] Plasma noribogaine concentrations were determined in the 30 mg and 60 mg dose groups using a validated, sensitive LCMSMS method. Sample preparation involved deproteinization of plasma samples with acetonitrile and dilution of sample with 0.1%
(v/v) formic acid. The compounds were separated by a 150 x 2.0 mm Luna 5[tm column and detected with a triple ¨ quadruple API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring.
Noribogaine-d4 Date Recue/Date Received 2023-11-27 was used as the internal standard. The precursor-product ion transition values for noribogaine were m/z 297.6 -> 122.3, and for the internal standard noribogaine-d4 m/z 301.1 -> 122.2. Analyst software was used for data acquisition and processing. The ratio of the peak area of noribogaine to the internal standard noribogaine-d4 was used for calibration and measurement of the unknown concentration of noribogaine. The LLOQ
was 0.50 ng/ml noribogaine. The calibration curve was between 0.50 and 256.00 ng/ml noribogaine. Mobile phase was the same as method A, and binary flow was also the same as method A. The within- and between-day assay precision was <9%, and the within- and between-day assay accuracy was < 9%.
[0635] Plasma noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method. Sample preparation involved deproteinization of plasma samples with acetonitrile, drying the samples under a stream of nitrogen and reconstitution of sample with acetonitrile: B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid. The compounds were separated by a 150 x 2.0 mm Luna 5mm C18 column and detected with a triple ¨ quadruple API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d4 was used as the internal standard. The precursor-product ion transition values for noribogaine glucuronide were m/z 472.8 -> 297.3, and for the internal standard noribogaine-d4 m/z 301.1 -> 122.2. Analyse software was used for data acquisition and processing. The ratio of the peak area of noribogaine glucuronide to the internal standard noribogaine-d4 was used for calibration and measurement of the unknown concentration of noribogaine glucuronide. The LLOQ was 0.050 ng/ml noribogaine glucuronide. The calibration curve was between 0.050 and 6.400 ng/ml noribogaine glucuronide. Mobile phases was the same as method A. Binary flow:
Initial concentration was 6% mobile phase B; hold at 6% mobile phase B for 0.5 minutes and linear rise to 90% mobile phase B over 2 minutes; hold at 90% mobile phase B
for 1 minute and then drop back to 6% mobile phase B over 0.01 minute. Equilibrate system for 3.5 minutes. Total run time was 7 minutes. The within- and between-day assay precision was < 11%, and the within- and between-day assay accuracy was < 10%.
[0636] Urine noribogaine and noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method.
Sample preparation involved deproteinization of urine samples with acetonitrile and Date Recue/Date Received 2023-11-27 dilution of the sample with 0.1% (v/v) formic acid. The compounds were separated by a 150 x 2.0 mm Luna 5[tm C18 column and detected with a triple ¨ quadruple API
4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogaine-d4 was used as the internal standard. The precursor-production transition values for noribogaine were m/z 297.6 -> 122.3, noribogaine glucuronide m/z 472.8 -> 297.3, and for the internal standard noribogaine-d4 m/z 301.1 ->
122.2. Analyst software was used for data acquisition and processing. The ratios of the peak area of noribogaine and noribogaine glucuronide to the internal standard noribogaine-d4 were used for calibration and measurement of the unknown concentration of noribogaine and its glucuronide. Assay LLOQ was 20.0 ng/ml for noribogaine and 2.0 ng/ml for noribogaine glucuronide. The calibration curve was between 20.0 and 5120.0 ng/ml noribogaine, and 2.0 and 512.0 ng/ml noribogaine glucuronide. Mobile phases were as described in method A, and binary flow as in method C. The within- and between-day assay precision was < 13%, and within- and between-day assay accuracy was <
12%.
[0637] Noribogaine and noribogaine glucuronide concentrations above the limit of quantification were used to calculate pharmacokinetic parameters using model-independent methods. The maximum plasma concentration (Cmax) and time to maximum plasma concentration (Tmax) were the observed values. Plasma concentration data in the post-distribution phase of the plasma concentration-time plot were fitted using linear regression to the formula ln C = in Co ¨ t.Kel, where Co was the zero-time intercept of the extrapolated terminal phase and Kel was the terminal elimination rate constant. The half-life (t1/2) was determined using the formula t112= 0.693/Kel. The area under the concentration-time curve (AUC) from time zero to the last determined concentration-time point (tf) in the post distribution phase was calculated using the trapezoidal rule. The area under the curve from the last concentration-time point in the post distribution phase (Ctf) to time infinity was calculated from AUCt,õ= Ctf/Kel. The concentration used for Ctf was the last determined value above the LLOQ at the time point. The total AUC0_,, was obtained by adding AUCtf and AUCt_.. Noribogaine apparent clearance (CL/F) was determined using the formula CL/F = Dose/AUC0_00 x 1000, and apparent volume of distribution (Vd/F) was determined using the formula Vd/F = (CL/F)/Kel. Total urine noribogaine was the sum of both analytes.

Date Recue/Date Received 2023-11-27 [0638] Summary statistics (means, standard deviations, and coefficients of variation) were determined for each dose group for safety laboratory test data, ECG and pharmacokinetic parameters, and pharmacodynamic variables. Categorical variables were analysed using counts and percentages. Dose-proportionality of AUC and Cmax was assessed using linear regression. The effect of dose on pharmacodynamic parameter values over time was assessed using two-factor analysis of variance (ANOVA). Pairwise comparisons (with Tukey-Kramer adjustment) between each dose group to the placebo were conducted at each time point using the least squares estimates obtained from the ANOVA, using SAS Proc Mixed (SAS ver 6.0).
Results 106391 Pharrnacokinetics: Mean plasma concentration-time plots of noribogaine are shown in Figure 1, and mean pharmacokinetic parameters are shown in Table 1.
Table 1 ' '' mg ___________________ 0,509111-1 ,r &atm, (mean (mean (mean (mean (SD) ;
74.2 (13.1) 254.5 (78.9) 700.4 (223.3) 1962.2 (726.5) (ng.hr/m1) AUC0_216== ID 72.2 (13.2) 251.4 (78.5) 677.6 (221.1) 1935.4 (725.4) Cmax ,g====
(n,g/m1) 52(14) 145(21) 559(148) 1160(225) ;;;;;;,,,!;;
Tmax (hr) 1.9 (0.6) 2.9 (1.8) 1.8 (0.6) 2.4 (0.6) tii2(hr) 40.9 (8.7) 49.2 (11.5) 27.6 (7.0)) 29.1 (9.3) .Vd/F. 2485.1 (801.5) 3085.8 (1197.0) 1850.8 (707.9) 1416.8 (670.1) CL/F :(L/h) 41.4 (7.0) 42.3 (12.0) 46.9 (16.4) 34.0 (11.4) Nbribbgaine glucuronide AUC0,., .....
25.8 (9.3) 67.1 (21.9) (ng.hr/r.p1) .
AU CO-2 I 6 25.7 (9.1) 65.0 (21.5) (ng.ht/M1):
(.'.rnax ..... . ;41i1 1.8 (0.6) 4.1 (1.2) (*ml,) TmaX (hr) ..... - 3.0 (0.6) 3.8 (1.2) (hr): - 20.6 (4.9) 23.1 (3.0) [0640] Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing. Fluctuations in individual distribution-phase concentration-time profiles may suggest the possibility of enterohepatic recirculation (see highlighted individual 4-8 Date Recue/Date Received 2023-11-27 hour profiles in Figure 1, insert). Both Cmax and AUC increased linearly with dose (Table 1, upper panel). Mean half-life estimates of 28-50 hours were observed across dose groups for noribogaine. Volume of distribution was extensive (1417-3086 L
across dose groups).
[0641] Mean plasma noribogaine glucuronide concentration-time plots for the 30 mg and 60 mg dose group are shown in Figure 2, and mean pharmacokinetic parameters are shown in Table 1, lower panel. Noribogaine glucuronide was detected in all subjects by 0.75 hours, with peak concentrations occurring 3-4 hours after noribogaine dosing. Mean half-life of 21-23 hours was estimated for plasma noribogaine glucuronide. The proportion of noribogaine glucuronide Cmax and AUC relative to noribogaine was 3-4% for both dose groups. Total urine noribogaine elimination was 1.16 mg and 0.82 mg for the 30 mg and 60 mg dose groups respectively, representing 3.9% and 1.4% of the doses administered.
[0642] The subject mean serum levels over time of noribogaine free base from a single dose of 3 mg noribogaine free base under fasting conditions were plotted. The mean Cmax of 5.2 ng/ml was observed 1.9 hours after administration, while the mean AUC/24 hr of 3.1 ng/ml was obtained.
[0643] The subject mean serum levels over time of noribogaine free base from a single dose of 10 mg noribogaine free base under fasting conditions were plotted. The mean C. of 14.5 ng/ml was observed 2.9 hours after administration, while the mean hr of 10.6 ng/ml was obtained.
[0644] The subject mean serum levels over time of noribogaine free base from a single dose of 30 mg noribogaine free base under fasting conditions were plotted. The mean C. of 55.9 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 of 29.2 ng/ml was obtained.
[0645] The subject mean serum levels over time of noribogaine free base from a single dose of 60 mg noribogaine free base under fasting conditions were plotted. The mean C. of 116 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 ng/ml of 61 was obtained.

Date Recue/Date Received 2023-11-27 [0646] The subject mean serum levels over time of noribogaine free base for all 4 cohorts were plotted. The extrapolated dosage of noribogaine free base required to provide a C. ranging from about 5.2 ng/ml to about 1980 ng/ml and an AUC/24 hr of about 3.1 ng/ml to about 1100 ng/ml was determined.
[0647] Pharmacodynamics: There was no evidence of pupillary constriction in subjects dosed with noribogaine. No between-dose group differences in pupil diameter were detected over time. After adjusting for baseline differences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p>0.9).
[0648] Noribogaine treatment showed no analgesic effect in the cold pressor test.
Analgesic effect was assessed based on duration of hand immersion in ice water and on visual analog scale (VAS) pain scores upon hand removal from the water bath.
For duration of hand immersion, after adjusting for baseline differences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p>0.9). Similarly, for VAS pain scores, after adjusting for baseline differences, comparison of each dose group with placebo by ANOVA showed no statistically significant differences (p=0.17).
Example 2. Safety and tolerability of noribogaine in healthy humans [0649] Safety and tolerability of noribogaine were tested in the group of volunteers from Example 1. Cold pressor testing was conducted in 1 C water according to the method of Mitchell et al. (J Pain 5:233-237, 2004) pre-dose, 6, 24, 48, 72 and 216 hours post-dosing.
Safety evaluations included clinical monitoring, recording of adverse events (AEs), safety laboratory tests, vital signs, ECG telemetry from -2h to 6h after dosing, and 12-lead electrocardiograms (ECGs) up to 216 hours post-dosing.
Results [0650] A total of thirteen adverse events were reported by seven participants (Table 2).
Six adverse events were reported by three participants in the placebo group, five adverse events were reported by two subjects in the 3 mg dose group, and one adverse event was reported by single subjects in the 10 mg and 30 mg dose groups, respectively.
The most common adverse events were headache (four reports) and epistaxis (two reports). All adverse events were of mild-moderate intensity, and all resolved prior to study completion. There were no changes in vital signs or safety laboratory tests of note. In Date Recue/Date Received 2023-11-27 particular, there were no changes in oximetry or capnography, or changes in respiratory rate. There were no QTcF values >500 msec at any time. One subject dosed with 10 mg noribogaine had a single increase in QTcF of >60 msec at 24 hours post-dosing.
Table 2 Dose Mild Moderate 'c (ng) HO m Placebo Blepharitis Epistaxis Bruising :
HO I Dry Skin 111 1111 111 Eye pain, nonspecific : Infection at cannula site . Back pain Headache Dizziness . .
Epistaxis =
Headache Headache 30 Headache 09 ..
Example 3. Safety, tolerability, and efficacy of noribogaine in opioid-addicted humans [0651] This example is to illustrate that noribogaine can be administered at a therapeutic dosing while maintaining an acceptable QT interval. While the therapy employed is directed to opioid-dependent participants in a randomized, placebo-controlled, double-blind trial, the results show that a therapeutic window can be established for noribogaine.
[0652] The efficacy of noribogaine in humans was evaluated in opioid-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients had been receiving methadone treatment as the opioid substitution therapy, but were transferred to morphine treatment prior to noribogaine administration. This was done to avoid negative noribogaine-methadone interactions that are not observed between noribogaine and morphine. See U.S. Application Serial Nos. 14/214,157, filed March 14, 2014 and 14/346,655, filed March 21, 2014, which are incorporated herein by reference in their entireties.
[0653] Three cohorts of nine (9) subjects (6 administered noribogaine and 3 administered placebo in each cohort) were evaluated for tolerability, pharmacokinetics, and efficacy. Cohort 1 received a single dose of 60 mg noribogaine or placebo.
Cohort 2 Date Recue/Date Received 2023-11-27 received a single dose of 120 mg noribogaine or placebo. Cohort 3 received a single dose of 180 mg noribogainc or placebo. Treatment was administered 2 hours after last morphine dose and the time to resumption of morphine (opioid substitution treatment, OST) was determined. Few adverse effects of noribogaine were observed in any of the participants, including no hallucinatory effects. Table 3 shows the reported adverse events for each treatment that were not attributable to withdrawal from opioids.
Headaches were frequent in the placebo and 60 mg noribogaine treatment groups, but were attenuated in the 120 mg and 180 mg dose groups.
Table 3: Treatment Emergent Adverse Events Summary +-Sym00t 0,g0n Cos* Pinet10 00 nx: ;20 mg 168:, rpg Pre001:0.1 Teem (64) lYssmbre of SaJjouts Stopvetimj, nni AEsi MI 177,6%; : 16.6 (323%) 20:0 t100.016) : 2:4 ((6.7%) Ear sod ktabyrktif; Disonfixl 0 0 2.2 (33.3%) 0 '7056060 0 0 (.2(3%) 0 Er, thscolsrs 2:(222%1 3:3 .,50Ø%) . 6:0 (M%) 1/4,1)s.;a) tolmfmerli 2ZaZ214) 21(33.3%) 60(8.3.S%) 5:4(042%) ray 610 0 1:1 06.7%) 0 0 (1.*2(0320.4402,13124,0140t 3.2Z2%) 2:2 (13 2%) 72(33..%J
42(333%
. Naom1 14412414) 0 3;2 (2.13%) Orli PAck.at 0 0 IA (10,1%) '11 -4:10,1%6 Vo.11:10%i 0 0 21 f16.7V 1:1600.:7%) 1::66r0p:00 ti (11.14) 0 1:i (1V.P.,4) 0 C..42;40,441 :LI MAIO 2:2(333%) 0 0 6µ,1,4),* 0;4010f0:0 a+,1I Adrnoiamdeo $go Covtison6 02 (33.3%) 0 2:2 (22324) 1:1 (16.7%) Cathole, S:so Re4thei Reac.tices 0 0 0 1=1 {10 2%) 1:::sfttce 3606010 22 (222%) 0 2.2 (322%) ... 0 , 61660041 1:1 (11.11,c) 0 0 0 fokaio.s ono infwelomns 11 (11.1%) 0 1.-1 ((61%) . .. .
22 i33.3).) C06,0:66 0 0 1:0 (6.r%) 1:1-(111:2%) tjtimary 7:00 031066.,) 0 0 0 I!) 0 0.7M
Cattwer 360 000.2ion 1:1 (11.414) 0 0 -- 0 Date Reeue/Date Received 2023-11-27 Sobsens ow am MDIDIDD SD mg 120 DID 180 Dv pfecr;03-rtrz% 0,0.01 0440 cwiel 1.4.0) MtmoskIskaetal end Connezttan Maw 131suraters I:1 MI%) 21 (111116) ilat% RIN, 1:1 (11.1%) 21 (10.111.) 0 I:1 2103%) i..1010 riwoimico .0 0 D 1:1 (14.116) .......................... .... ....
............
Novot=D8y.:4049 Matto 7:t tsti.0%) .. 7A t00.7%) 8'4 .:5"ti,i114 $.12 ;03 394 Heviac3,5: SWAIM %WOW% ItiNVON ORMIE
Ftywae00caSta 0 1:1. ilD.71S) 0 Pseistiawstaiyais 0 0 11 (10.?%) 0 itimot 0 0 tri mg") 0 80001010000 1:1 (11.1%} 0 0 0 Psyeattrib Odstralvat I:1 01.1%1 1:1 (15.?%) a a DISP:Mit,C3 k400d 0 11 00.1%) 0 r Eaphotta Mood I:I 131.1%) a 0 0 R=apstatory, 700)000: am/ is/0000m MN:stem a 0 41 (33,3%) e ii. 21 (le ?IQ 0 or' tp40,,,,n000: Men 0 0 1:1 (WV a Fthittorptioaa 0 0 11 (Iar%) 0 Sien atm admien mem Pam Otarient 0 a rt (18.7%) i a a.* En:zowlfaa a 0 II MU%) ' 0 Vadn Irstabort 0 a 11 (WM a : ____________________________________________________________________ ..
om: y=00gx astv: swam ,tem Z3:2:3$7 PMWS,44 TtMtRU Wfi MiSkV)3Rd by tk\li=WrditV ko,4K.Utit:4 ttt eVemt}XeztV $S 5p*Iiplc Ra141 0i20$
1.x$14:=: 1.= 0000P:a 0 7 000FAls 0$ ID* WO? p0p4Dliart, [0654] Figure 3 indicates the average serum noribogaine concentration over time after administration of noribogaine for each cohort (60 mg, diamonds; 120 mg, squares; or 180 mg, triangles). Further results are detailed in U.S. Provisional Patent Application No.
62/023,100 , filed July 10, 2014, and titled "METHODS FOR ACUTE AND LONG-TERM TREATMENT OF DRUG ADDICTION," which is incorporated herein by reference in its entirety.
Results [0655] Pharrnacokinetic results for each cohort are given in Table 4. Maximum serum concentration of noribogaine (Cmax) increased in a dose-dependent manner. Time to Cmax (Tmax) was similar in all three cohorts. Mean half-life of serum noribogaine was similar to that observed in healthy patients.

Date RecueiDate Received 2023-11-27 Table 4: Pharmacokinetic results from the Patients in Phase I B Study Cohort 1 ...................................... Cohort .... ...... ............ . . .
Data (mean SD) Data (mean SD) Data PK parameter ..... ................ ......... . .
.........
troil . [range] ....
81.64 23.77 172.79 30.73 267.88 46.92 Cmax (ng/ml) [41.29¨ 113.21] [138.84 ¨ 229.55] [204.85 ¨338.21]
359 092 299 1.23 ...... ......................................... 44I*180: HHHHHHHHHHHH:
-----------------------[3 -.00 8.00]
- - , --------- . . - .
-----AUC(0.4) 2018.01 613.91 3226.38 1544.26 6523.28 2909.80 (ng.hr/m1) [1094.46¨ 2533.44] [1559.37 ¨5638.98] [3716.69 ¨ 10353.12]

::tniolirimo,:,,:,,:,,i,m,,:::-:[1:1-22:a9-..---:4..2.4$:tkilINIltt$9,-$A4;--4.$161t$2F(374.$4a1 -1228f/911M
29.32 7.28 30.45 9.14 23.94 5.54 Half-life (hrs) [18.26 ¨ 37.33] [21.85 ¨48.33] [19.32 ¨ 34.90]

.................. . . . . . . . . . .
CUF 32 ...... 14 12.38 44.68 21.40 31.47 13.12 [23.51 ¨ 53.46] [20.80 ¨75.20] [14.66 ¨48.20]
[0656] Figure 4 indicates the time to resumption of morphine (OST) for patients treated with placebo (circles), 60 mg noribogaine (squares), 120 mg noribogaine (triangles), and 180 mg noribogaine (inverted triangles). Patients receiving a single 120 mg dose of noribogaine exhibited an average time to resumption of opioids of greater than 20 hours.
Patients receiving a single 180 mg dose of noribogaine exhibited an average time to resumption of opioids similar to that of placebo. This demonstrates that increasing the dose of noribogaine to 180 mg results in a shorter time to resumption of OST
than observed in patients receiving 120 mg noribogaine. Time to resumption of OST
after treatment with 180 mg was still longer than untreated patients (7 hours, not shown) or those administered 60 mg noribogaine.

Date Rectw/Date Received 2023-11-27 [0657] Patients were evaluated based on the Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), and Objective Opiate Withdrawal Scale (00WS) scoring systems over the period of time between administration of noribogaine (or placebo) until resumption of OST. These scales are outlined in Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, World Health Organization, Geneva (2009), Annex 10, which is incorporated herein by reference in its entirety. The scales measure the intensity of withdrawal symptoms, based on clinical, subjective, and objective indicia.
[0658] Figure 5 shows the COWS scores at time of resumption of OST for each cohort.
Box includes values representing 25% - 75% quartiles. Diamond = median;
crossbar in box = mean; whiskers = values within standard deviation of mid-quartiles. No outliers present. The highly variable COWS scores across and within each cohort indicates that patients were resuming opiates without relation to the intensity of withdrawal. This was also reflected in SOWS and 0OWS scores at the time of resumption of OST.
[0659] Figure 6A shows the mean change in total COWS scores over the first six hours following dosing and prior to resumption of OST. Figure 6B shows the mean AUC(0-6 hours) of the COWS total score change from baseline. Figure 7A shows the mean change in total 0OWS scores over the first six hours following dosing and prior to resumption of OST. Figure 7B shows the mean AUC(0-6 hours) of the 0OWS total score change from baseline. Figure 8A shows the mean change in total SOWS scores over the first six hours following dosing and prior to resumption of OST. Figure 8B shows the mean AUC(0-6 hours) of the SOWS total score change from baseline. These data indicate that withdrawal symptoms get worse over time after cessation of OST, and that patients administered placebo experience generally worse withdrawal symptoms over that period.
Patients who received 120 mg noribogaine generally experienced fewer withdrawal symptoms than the other patients, regardless of the scale used. Patients administered placebo generally experienced more withdrawal symptoms than patients who were administered noribogaine.
[0660] Patients' QT intervals were evaluated at regular time points throughout the study.
Figure 9A shows the average change in QT interval (AQTcl, i.e., QT interval prolongation) over the first 24 hours post noribogaine (or placebo) administration. Figure Date Recue/Date Received 2023-11-27 9B shows the estimated correlation between noribogaine concentration and change in QT
interval. There is a dose-dependent increase in QT interval prolongation that is correlated with the serum concentration of noribogaine.
[0661] Based on above data, it is believed that the therapeutic window for a single bolus dose of noribogaine is bound at the lower end by 50 mg and at the upper end by less than 180 mg. In particular, the therapeutic serum concentration in vivo appears to be between about 50 ng/mL and about 180 ng/mL.
**1 think this can be removed now bc updated results and are covered in the "other"
example 3 above.Example 4. Multiple dosing of noribogaine in humans [0662] The efficacy of multiple dosing of noribogaine in humans is evaluated in opioid-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients are receiving methadone treatment as the opioid substitution therapy, but are transferred to morphine treatment prior to noribogaine administration.
[0663] Patients are treated with an initial unit dose of noribogaine of 80 mg, followed by 15 mg to 20 mg of noribogaine every 6 hours to 12 hours, as indicated in Table 5.
Table 5 Flour 0 6 12 18 24 30 36 42 48 54 60 66 72 84 96 108 120 132 144 156 Dose (mg) [0664] Patients are treated with an initial unit dose of noribogaine of 80 mg, which is administered as subdoses of 40 mg followed by 20 mg at 2 hours and 4 hours after the first dose. The initial unit dose is followed by 15 mg to 20 mg of noribogaine every 6 hours to 12 hours, as indicated in Table 6.

Date Recue/Date Received 2023-11-27 Table 6 Hour 0 2 4 6 12 18 24 30 36 42 48 54 60 66 72 84 96 108 120 132 Dose (mg) Example 5. Efficacy of noribogaine to modulate opioid tolerance in humans [0665] A female patient, age 59, undergoing opioid analgesic therapy for chronic back pain, is treated with noribogaine hydrochloride at a dose of about 2 mg/kg concurrently with the opioid. The amount of opioid required to treat her back pain to the same level as before noribogaine treatment is determined after noribogaine treatment.
Example 6. Effect of noribogaine on nicotine dependence in Sprague-Dawley rats Animals [0666] Fourteen young adult, male Sprague-Dawley rats (300-325 g) from Harlan were used in this study. The rats underwent catheter surgery and training of nicotine self-administration.
[0667] Upon arrival, the rats were assigned a unique identification numbers (tail marks).
Animals were housed 2-3 per cage in suspended polycarbonate rat cages with filter paper covering mesh shelf and were acclimated for up to 7 days. All rats were examined, handled, and weighed prior to initiation of the study to assure adequate health and suitability. During the course of the study, 12/12 light/dark cycles were maintained. The room temperature was 20-23 C with a relative humidity maintained 30-70%. Water was provided ad libitum for the duration of the study. Following surgery (in 14 nicotine training rats), all rats were single housed and remained single housed throughout the duration of the study.
Test compounds [0668] Noribogaine (12.5, 25 and 50 mg/kg, converted to free base doses with a correction factor 1.12) was dissolved in 35% of the total required volume of 0.5% Tween 80 in 5% Dextrose. Suspension was stirred for at least 30 minutes. 1.5%
methylcellulose was added to make up 65% of the total volume and the suspension was stirred again for at Date Recue/Date Received 2023-11-27 least 30 minutes. As a result, 12.5mg/kg and 25mg/kg doses were clear solutions and 50mg/kg was a slightly cloudy suspension.
[0669] The mix of 0.5% Tween 80 in 5% Dextrose (35% of total volume) and 1.5%
methylcellulose solution (65% of total volume) was used as compound vehicle treatment.
[0670] Vehicle and noribogaine were administered orally 2 hours prior to test at a dose volume of 5 ml/kg.
[0671] Varenicline (1.7 mg/kg) was dissolved in saline (0.9% NaC1) and administered intraperitoneal 30 minutes prior to test. Dose volume of varenicline was 1 ml/kg. The formulation of varenicline (1.7 mg/kg) was a clear solution.
Nicotine self-administration test [0672] Apparatus: Intravenous drug self-administration and tests took place in experimental chambers within sound-attenuating cubicles equipped with an exhaust fan (Med Associates, VT). Each chamber contained two response levers situated on one wall of the chamber. A stimulus light was located above each lever and a house light is located at the top of opposite wall. An infusion pump mounted above each chamber delivered drug solution via Tygon tubing connected to a single channel fluid swivel, which was mounted on a balance arm above the operant chamber. The output of the liquid swivel was attached to the external terminus of the intravenous catheter.
[0673] Food Training and Surgery: Prior to intravenous catheterization, animals were trained to lever press for food. After acquiring the lever-press response rats were prepared with intravenous catheters. One week later, rats were allowed to self-administer nicotine solution (0.03 mg in 0.1m1 over a 0.8 second period under a fix-ratio 3 (FR3)) by pressing the previously food-paired lever in return for delivery of the drug solution.
In present study, 4 weeks of operant training was needed to obtain stable nicotine infusion (defined as no less than 6 infusions and less than 20% variation in the mean number of reinforcers earned in 1-hour training over 3 consecutive days).
[0674] Self-administration Procedures: Animals were first trained to respond for nicotine (0.03 mg/kg/infusion) under a FR3, time-out 20 seconds schedule of reinforcement. After the completion of training and the establishment of stable baselines, the effects of Date Recue/Date Received 2023-11-27 noribogaine were assessed. Noribogaine or the reference compound varenicline (a nicotinic acetylcholine receptor partial agonist) were only administered when the animals exhibited responding at baseline levels (i.e. no less than 6 infusions and less than 20%
variation in the mean number of reinforcers earned in 1-hour training over last three consecutive non-drug test days). Compound testing was performed on Wednesdays and Fridays, assuming baseline levels of self-administration behavior on Tuesdays and Thursdays.
Study Design and Data Analysis [0675] A within-subject design in which each rat received all treatments was applied with a Latin square test schedule. The six treatments which were blind to the experimenter were:
1. Saline 2. Varenicline 1.7mg/kg 3. Vehicle (35% of 0.5% Tween-80 in 5% Dextrose and 65% of 1.5%
methylcellulose) 4. Noribogaine 12.5 mg/kg 5. Noribogaine 25 mg/kg 6. Noribogaine 50 mg/kg [0676] The data of nicotine infusions obtained during test sessions were analyzed via repeated measure ANOVA followed by Fisher LSD post hoc comparisons where appropriate. Percentage of inactive lever presses were also analyzed with repeated measure ANOVA for non-specific behavioral effects. An effect is considered significant if P<0.05. Data are represented as the mean and standard error to the mean (s.e.m.).
Statistical outliers falling beyond mean +/- (2 x standard deviation) are removed from the analysis. With this criterion, 0-2 outliers were eliminated in different measures.
Results [0677] The effects of noribogaine and varenicline on nicotine infusion are shown in Figure 10A. Repeated measure ANOVA found a significant main effect of treatment [F(5,58)= 29.708, P<0.001]. Post hoc comparisons indicated that varenicline and noribogaine at both 25 and 50 mg/kg significantly depressed nicotine infusion (Ps<0.001).

Date Recue/Date Received 2023-11-27 A trend of depression of nicotine infusions was also found at 12.5 mg/kg dose (P<0.10).
Data represent mean + s.e.m.
[0678] The effects of noribogaine and varenicline on inactive lever press during nicotine self-administration are shown in Figure 10B. Repeated measure ANOVA found no significant main effect of treatment. [F(5,54)=0.356, P>0.05]. These results suggest that the effects of the test compounds on lever-pressing for nicotine infusion was not compromised by nonspecific inactive lever pressing.
Example 7: Effect of low dose of noribogaine on smoking cessation in humans 106791 A female habitual smoker intranasally absorbed a nanogram amount of noribogaine hydrochloride. During a period of several hours, any craving to smoke stopped and only resumed afterwards. The patient was unaware during that period of any nicotine or smoking cravings.
Example 8: Effect of noribogaine on withdrawal from alcohol in humans [0680] Six patients are orally administered a single dose of 2 mg/kg noribogaine, and three patients receive placebo in a randomized, placebo-controlled, double-blind trial. All patients are dependent on alcohol. Treatment is administered at least 2 hours after last alcohol use. Patients receiving noribogaine exhibit fewer and/or less severe symptoms of alcohol withdrawal compared to those receiving placebo, as determined by self-evaluation (e.g., questionnaires) and clinical observation.
Example 9: Efficacy of Noribogaine in Treating Substance Dependency [0681] The efficacy of noribogaine is evaluated in substance-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients are administered 60 mg or 120 mg of the compound and QT interval is measured.
Example 10: Effect of noribogaine on treatment of pain in humans [0682] A female patient, age 57, with chronic back pain, is treated with noribogaine hydrochloride at a dose of about 2 mg/kg. Her pain is attenuated, as determined by self-evaluation and clinical evaluation.
Example 11: Effect of noribogaine on chronic migraine in humans Date Recue/Date Received 2023-11-27 [0683] A female patient, age 25, with recurrent migraine headaches not attributable to withdrawal from opioids, is treated with noribogaine hydrochloride at a dose of about 1.5 mg/kg. During a period of several hours, her migraine symptoms are attenuated, as determined by self-evaluation and clinical evaluation.
Example 12. Forced Swim Test (FST) With Rats [0684] Animals: Male Sprague-Dawley rats (Taconic Farms, N.Y.) are used in all experiments. Rats are housed 5 per cage and maintained on a 12:12-h light-dark cycle.
Rats are handled for 1 minute each day for 4 days prior to behavioral testing.
[0685] Drug Administration: Animals are randomly assigned to receive a single intraperitoneal administration of vehicle (2.5% Et0H/2.5% Tween-80), imipramine (positive control; 60 mg/kg), or Test Compound 60 minutes before the start of the 5 minute test period. All injections are given using 1 cc tuberculin syringe with 26 3/8 gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, N.J.). The volume of injection is 1 ml/kg.
[0686] Experimental Design: The procedure used in this study employs a water depth of 31 cm. The greater depth in this test prevents the rats from supporting themselves by touching the bottom of the cylinder with their feet. Swim sessions are conducted by placing rats in individual plexiglass cylinders (46 cm tall and 20 cm diameter) containing 23-25 C water. Swim tests are conducted always between 9:00 and 17:00 hours and included an initial 15-minute conditioning test followed 24 hours later by a 5-minute test.
Drug treatments are administered 60 minutes before the 5-minute test period.
Following all swim sessions, rats are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes and returned to their home cages. All test sessions are videotaped using a color video camera and recorded for scoring later.
[0687] Behavioral Scoring: The rat's behavior is rated at 5 second intervals during the 5 minute test by a single individual, who is blind to the treatment condition.
Scored behaviors are: 1. Immobility--rat remains floating in the water without struggling and is only making those movements necessary to keep its head above water; 2.
Climbing--rat is making active movements with its forepaws in and out of the water, usually directed against the walls; 3. Swimming--rat is making active swimming motions, more than Date Recue/Date Received 2023-11-27 necessary to merely maintain its head above water, e.g. moving around in the cylinder; and 4. Diving--entire body of the rat is submerged.
[0688] Data Analysis: The forced swim test data (immobility, swimming, climbing, diving) are subjected to a randomized, one-way AND VA and post hoc tests conducted using the Newman-Keuls test. The data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).
Example 13. Forced Swim Test (FST) With Mice [0689] Animals: DBA/2 mice (Taconic Farms, N.Y.) are used in all experiments.
Animals are housed 5 per cage in a controlled environment under a 12:12 hour light:dark cycle. Animals are handled 1 min each day for 4 days prior to the experiment.
This procedure includes a mock gavage with a 1.5 inch feeding tube.
[0690] Drug Administration: Animals are randomly assigned to receive a single administration of vehicle (5% Et0H/5% Tween-80), Test Compound, or imipramine (60 mg/kg) by oral gavage 1 hour before the swim test.
[0691] Experimental Design: The procedure for the forced swim test in the mouse is similar to that described above for the rat, with the following modifications.
The cylinder used for the test is a 1 liter beaker (10.5 cm diameter and 15 cm height) filled to 800 ml (10 cm depth) with 23 25 C. water. Only one 5-minute swim test is conducted for each mouse, between 13:00 and 17:00 hours. Drug treatments are administered 30-60 minutes before the 5-minute test period. Following all swim sessions, mice are removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes.
All test sessions are videotaped using a Sony color video camera and recorder for scoring later.
[0692] Behavioral Scoring: The behavior during minutes 2-5 of the test is played back on a TV monitor and scored by the investigator. The total time spent immobile (animal floating with only minimal movements to remain afloat) and mobile (swimming and movements beyond those required to remain afloat) are recorded.
[0693] Data Analysis: The forced swim test data (time exhibiting immobility, mobility;
seconds) are subjected to a randomized, one-way AND VA and post hoc tests conducted Date Recue/Date Received 2023-11-27 using the Newman-Keuls test. The data are analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, Calif.).
Example 14: Single dose toxicity in rats [0694] The objective of this study was to determine the toxicity and toxicokinetic profile of noribogaine HC1 following a single oral (gavage) administration in the Sprague-Dawley rat. A single dose of 100, 300 and 800 mg/kg (achieved with doses of 400 mg/kg 3 h +/-30 min apart because of the limitations of maximum dose formulation concentration). Five male rats/group were used. Mortality occurred in all male rats in the 800 mg/kg group, approximately 2-3 h after administration of the second dose of 400 mg/kg.
Hypoactivity, vocalization, chewing movements, changes in respiration/posture, salivation, stimuli sensitivity, tremors, twitches and penile erection occurred prior to death.
Hypoactivity, vocalization, salivation, stimuli sensitivity, loss of limb function and lying on the cage floor occurred on the day of treatment and persisted until Day 2 in 3/5 rats given 300 mg/kg. The low dose rats treated at 100 mg/kg did not show any treatment related signs.
The no observed adverse effect level (NOAEL) was determined to be 100 mg/kg.
Example 15: Single dose toxicity in dogs [0695] In an acute oral toxicity/TK study in dogs, no mortality occurred at doses of 5 (n=2) or 10 (n=2) mg/kg. Convulsions and other CNS-related clinical signs, including twitches, salivation, vocalization, incoordination and hypoactivity, occurred at a dose of mg/kg, beginning 20 minutes after dosing and persisting until 3h 40m post-dose. The 5 mg/kg dose was considered the NOAEL, as only transient reduction in food consumption in one dog occurred at that dose.
Example 16: Single dose toxicity in Cynomolgus Monkeys [0696] The objective of the study was to determine the toxicity and toxicokinetic profile of noribogaine following oral (gavage) administration to the cynomolgus monkey. Each dose was followed by a 7 day washout period. Dosing was staggered by 45 minutes. On study day 15, one animal was administered 80 mg/kg and the other animal was administered 160 mg/kg. The test article was administered as follows in Table 7:

Date Recue/Date Received 2023-11-27 Table7. Toxicity and Toxicokinetic Study in Cynomolgus monkeys Treatment on Study Day Dose Level (mg/kg) Number of Animals 1 20 2 males 8 40 2 males 15 80 and 160 2 males [0697] Parameters monitored on the study included: mortality, clinical signs and body weights. Blood samples were collected for TK evaluation. No mortality or treatment related clinical signs were noted for doses up to and including 160 mg/kg, The single dose maximum tolerated dose (MTD) was determined to be greater than 160 mg/kg based on the parameters monitored during the study.
Example 17: Fourteen day repeat dose toxicity and toxicokinetics in rats [0698] This study was conducted to evaluate the toxicity profile of noribogaine-HCl following oral (gavage) administration to the rat for 14 days following Table 8 below:
Table 8. Toxicity and Toxicokinetic Study in Rats Group Dose Level = Dose: m Toxicology Animali'''Toxiciikineticisl (mg/kg/day Concentration Main Recovery Animals = :11 (Mg/mL) Mal Femal Mal Femal Male Female ;,=0 .
= =
e e eii]]i]]: ;.]:0 ===== = =]=]=]= :
I
Control 0 0 10 10 5 5 3 3 Low 25 5 10 10 6 6 Dose Mid Dose 50 10 10 10 6 6 High 100 20 10 10 5 5 6 6 Dose [0699] Male and female Sprague-Dawley rats, 10/sex/group, were administered 0, 25, 50 or 100 mg/kg notibogaine HC1 daily by single oral gavage for 14 days. An additional 5 rats/sex/group in the 0 (control) and 100 mg/kg groups were retained for a 28 day recovery period during which no drug was administered. Six rats/sex/group (3 rats/sex controls) Date Recue/Date Received 2023-11-27 were similarly dosed and sampled on study days 1 and 14 for analysis of noribogaine-HCl concentrations in the blood. Rats were observed for mortality, clinical signs, body weight, food consumption, ophthalmology (pre-dose, during week 2, and at the end of recovery), hematology, coagulation, clinical chemistry, urinalysis, gross necropsy, organ weights and histopathology (full tissue panel, plus immunocytochemistry of 5 sections of the brain and spinal cord by staining for GFAP and Calbindin). There were no test article-related effects on mortality (none occurred), clinical signs, ophthalmoscopy, hematology, coagulation parameters, clinical chemistry, urinalysis, gross necropsy or histopathology.
Food consumption and body weight were slightly reduced (food consumption: -4.7% in males and females; body weight: -5.5% in males and -2.6% in females) in the high dose (100 mg/kg) groups. Minor increases in liver weight in the mid- and high dose groups were not correlated with histopathologic changes and are considered incidental. No treatment-related differences in the brain were seen in sections stained for GFAP or Calbindin.
[0700] The NOAEL dose in this study was interpreted to be 100 mg/kg, the highest dose tested in the study.
Example 18: Fourteen day repeat dose toxicity and toxicokinetics in dogs [0701] The objective of this study was to determine the toxicity profile of noribogaine HCl given following oral (gavage) administration to dogs for 14 days according to the following Table 9 below:
Table 19. Toxicity and Toxicokinetic Study in Dogs Group Dose Level r = :::;::1777377 Dose I oxicology Animals :
Concentration Main Recovery Designation (mg/kg/day) (mg/mL) Male Female Male Female Control 0 0 4 4 4 4 Low Dose 0.5 0.1 4 4 Mid Dose 1.0 0.2 4 4 High Dose 5.0 1.0 4 4 4 4 [0702] Noribogaine HC1 was administered to groups of 4 male and 4 female dogs by single oral gavage daily for 14 days at doses of 0, 0.5, 1.0 and 5.0 mg/kg/day. An additional group of 4 male and 4 female dogs received either the vehicle control or 5.0 mg/kg/day for 14 days and were held for an additional 28 days after cessation of dosing to assess recovery from any potential drug-induced changes. The study was conducted under Date Recue/Date Received 2023-11-27 GLP guidelines and included comprehensive examinations of clinical signs, body weight, clinical pathology parameters, ophthalmologic examinations, ECG recordings and analyses of plasma for bioanalytical measurement of drug levels at appropriate intervals during the study. At the termination of the dosing phase and at the termination of the recovery phase, all dogs were subjected to a complete post-mortem examination including gross examination of major organs and histologic examination of an extensive list of tissues. Additional sections of brain were obtained from cerebrum, cerebellus, brain stem and spinal cord and examined histologically to evaluate potential effects on brain histopathology. In addition, these sections were examined with immunohistochemical stains for GFAP for evidence of gliosis and Calbindin for a more comprehensive examination of cerebellar Purkinje cells. No evidence of adverse effect was observed in any dog from any treatment group during the dosing or recovery phase in clinical observations, body weights, clinical pathological parameters, ophthalmologic examinations, ECG recordings, or gross lesions at necropsy. The results of the plasma drug level measurements at Day 1 and Day 14 of the study are shown in the Table below.
Noribogaine-HC1 maximum plasma concentrations (C.) were reached between 0.5 and 0.9 hours post-dosing, following which plasma concentrations gradually decreased over a period of up to 24 hours, except in the male dogs and female dogs of Group 4, for which significant levels of noribogaine were still detected at 24 h post-dosing on both Days 1 and 14.
[0703] The only target tissue identified in this study was the lacrimal gland of dogs receiving 5 mg/kg/day. The lacrimal gland changes were characterized by slight to moderate atrophy and degeneration of the acinar cells accompanied by slight to moderate accumulation of brown/yellow pigment and infiltration of mononuclear cells.
There was an associated mononuclear infiltration in the draining mandibular lymph nodes of affected dogs in this dose group. Despite the appearance of isolated ocular abnormalities in several dogs in this high dose group on ophthalmologic examination, there was no clear association between these ocular signs and the appearance of the lacrimal gland changes suggesting that these morphologic changes did not result in sufficient functional abnormality of the gland to produce physical changes in exterior structures of the eye.
There was no clear evidence of local irritation associated with drug treatment in these high dose dogs. No evidence of drug-induced effect was observed in any other tissue including Date Recue/Date Received 2023-11-27 the extensive sections of brain evaluated with conventional histopathology or with immunohistochemistry. Examination of the animals in the recovery group showed clear evidence of regeneration of this lacrimal gland change. While slight atrophy was still evident in the acinar cells of the gland after 28 days off drug, no evidence of continuing and ongoing degeneration or cellular infiltration was observed. The NOAEL in this study was 1 mg/kg/day based on the lacrimal gland changes at 5 mg/kg/day. The results are summarized in Tables 10 and 11.
Table 10. Mean plasma toxicokinetic parameters for noribogaine in male dogs on days 1 and 14 Gr 2 - 0.5 mg/kg ' Gr 1.0 mg/kg Cr 4 - 5.0 mg/kg1 'Parameters T112(h) 1.3 r 1.3 1.2 1.8 4.7 6.5 Tina, (h) 0.7 0.7 0.9 0.8 0.6 0.9 Cmax (ng/ml) 28.8 29.4 58.6 67.6 693 716 AITCI)-iust (heng/m1) 46.6 53.2 102.5 172.3 3515.0 6403.3 A LTC4}-24h (hr*ng/m1) 59.7 64.5 119.8 210.4 3515.0 6403.3 õ õ
AUCO
(heng/m1) 67.8 68.2 120.8 195.7 3630.5 6961.4 Table 11. Mean plasma toxicokinetic parameters for noribogaine in female dogs on days 1 and 14 .; .
Cr - 0.5 mg/kg Gr 3 - 1.0 mg/kg Cr 4 - 5.0 mg/kg Parameters Tit(hr) 1.0 1.1 1.4 1.6 4.3 5.7 Tmax(hr) 0.5 1.0 0.8 0.5 0.6 0.6 CillaN (ng/m11) 25.3 29.8 68.5 74.1 691 683 AUCti-inst (heng/m1) 31.5 35.4 148.9 169.0 3367.9 5951.2 AUC4)-241, (hr*ng/m1) 40.4 55.0 176.2 203.7 3367.9 5951.2 (hr*ng/m1) 44.9 45.7 165.3 197.0 3425.7 6283.2 Example 19. Effect of noribogaine on depression in humans [0704] A male patient, age 55, suffering from depression unrelated to the use of any illicit substance, is treated with noribogaine hydrochloride at a dose of about 1 mg/kg/day for a period of four weeks. During the treatment period, his depression change in symptoms and/or changes in one or more of the following tests: HDRS, Hamilton depressed mood item, and CGI-Severity of Illness are determined.

Date Recue/Date Received 2023-11-27 Example 20. Social Interaction Test (SIT) [0705] Animals: Male albino Sprague-Dawley rats (Taconic Farms, N.Y.) are housed in pairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with free access to food and water.
[0706] Rats are allowed to acclimate to the animal care facility for 5 days and are housed singly for 5 days prior to testing. Animals are handled for 5 minutes per day.
On the test day, weight matched pairs of rats ( 5%), unfamiliar to each other, are given identical treatments and returned to their home cages. Animals are randomly divided into treatment groups, with 5 pairs per group, and are given one of the following i.p.
treatments: Test Compound (1, 2 or 4 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg). Dosing is done 1 hour prior to testing. Rats are subsequently placed in a white perspex test box or arena (54x37x26 cm), whose floor is divided up into 24 equal squares, for 15 minutes. An air conditioner is used to generate background noise and to keep the room at approximately 74 F. All sessions are videotaped using a JVC camcorder (model GR-SZ1, Elmwood Park, N.J.) with either TDK (HG ultimate brand) or Sony 30 minute videocassettes. All sessions are conducted between 13:00 and 16:30 hours.
Active social interaction, defined as grooming, sniffing, biting, boxing, wrestling, following and crawling over or under, is scored using a stopwatch (Sportsline model no. 226, 1/100 sec.
discriminability). The number of episodes of rearing (animal completely raises up its body on its hind limbs), grooming (licking, biting, scratching of body), and face ishing (i.e.
hands are moved repeatedly over face), and number of squares crossed are scored. Passive social interaction (animals are lying beside or on top of each other) is not scored. All behaviors are assessed later by an observer who is blind as to the treatment of each pair.
At the end of each test, the box is thoroughly wiped with moistened paper towels.
[0707] Data Analysis: The social interaction data (time interacting, rearing and squares crossed) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Student-Newman-Keuls test. The data are subjected to a test of normality (Shapiro-Wilk test). The data are analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, Md., 1997).

Date Recue/Date Received 2023-11-27 Example 21: Effect of noribogaine on food consumption [0708] The effects of noribogaine and varenicline on food consumption in food maintained responding rats are shown in Figure 10A. Repeated measure ANOVA
found a significant main effect of treatment [F(5,33)=16.905, P<0.001]. Post hoc comparisons indicated that compared to vehicle treatment, noribogaine (25 and 50 mg/kg) significantly decreased food consumption (P<0.05 and P<0.001, respectively). Noribogaine (12.5 mg/kg) and varenicline (1.7 mg/kg) had no significant effect on this measure.
[0709] The effects of noribogaine and varenicline on inactive lever response in food maintained responding rats are shown in Figure 10B. Repeated measure ANOVA
found a significant main effect of treatment [F(5,31)¨ 7.583, P<0.001]. This main effect is solely contributed by high dose noribogaine (50 mg/kg), as shown in post hoc comparisons (P<0.001 compared to vehicle treatment.) This result suggests that for high frequency lever-pressing in food test the high dose of noribogaine (50 mg/kg) may cause some behavioral disturbance.
[0710] At 12.5 mg/kg, noribogaine showed no effect on food consumption. At 25 mg/kg, noribogaine decreased food intake by 10% (P<0.05). At 50 mg/kg, noribogaine decreased food intake by 25% (P<0.001). In general, the inactive lever responding percentage was very low during food consumption test under all treatments.
Example 22: Single dose toxicity in rats [0711] The objective of this study was to determine the toxicity and toxicokinetic profile of noribogaine HC1 following a single oral (gavage) administration in the Sprague-Dawley rat. A single dose of 100, 300 and 800 mg/kg (achieved with doses of 400 mg/kg 3 h +/-30 min apart because of the limitations of maximum dose formulation concentration). Five male rats/group were used. Mortality occurred in all male rats in the 800 mg/kg group, approximately 2-3 h after administration of the second dose of 400 mg/kg.
Hypoactivity, vocalization, chewing movements, changes in respiration/posture, salivation, stimuli sensitivity, tremors, twitches and penile erection occurred prior to death.
Hypoactivity, vocalization, salivation, stimuli sensitivity, loss of limb function and lying on the cage floor occurred on the day of treatment and persisted until Day 2 in 3/5 rats given 300 mg/kg. The low dose rats treated at 100 mg/kg did not show any treatment related signs.
The NOAEL was determined to be 100 mg/kg.

Date Recue/Date Received 2023-11-27 Example 23. Effect of noribogaine on anxiety disorder in humans [0712] A male patient, age 45, suffering from generalized anxiety disorder unrelated to the use of any illicit substance, is treated with noribogaine hydrochloride at a dose of about 1 mg/kg/day for a period of four weeks. His generalized anxiety level is determined by the patient's self-reporting of attenuation of at least one of the following symptoms:
restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.
Example 24. Effect of noribogaine on nicotine withdrawal in zebrafish expressed by anxiety-related endpoints Animals [0713] A total of 60 adult wild type short-fin zebrafish (-50:50 male:female ratio) were used in this study. Fish were housed in groups of 20-30 fish per 40-L
tank.
Tanks were filled with filtered water and maintained at 25 C. Illumination (1000-1100 lx) was provided by ceiling-mounted fluorescent lights on a 12-h cycle (on: 6.00 h, off: 18.00 h) according to the standards of zebrafish care. All fish used in this study were experimentally naive and fed Tetramin Tropical Flakes (Tetra USA, Blacksburg, VA) twice a day. Following behavioral testing, the animals were euthanized in 500 mg/L Tricaine (Sigma¨Aldrich, St. Louis, MO) buffered to pH = 7Ø Animal experimentation in this study fully adhered to national and institutional guidelines and regulations.
Test compounds [0714] A 1 mg/L dose of noribogaine (DMX1) was chosen based on pilot experiments and literature reports on effective doses other similar compounds.
A pilot experiment revealed sub-maximal efficacy of noribogaine at 1 mg/L, a dose that did not promote any locomotors effects susceptible to be confounded with efficacy endpoints of interest in other protocols. A standard 20-mM pre-treatment time was chosen based on experience with a wide range of other neuroactive compounds and the results of pilot studies. This exposure time was also sufficient for provoking physiological (e.g., cortisol and c-fos) responses of zebrafish to multiple drugs. Drug exposure in this study was performed by submerging individual zebrafish in a 1-L

Date Recue/Date Received 2023-11-27 plastic beaker for 20 mm prior to the testing. The solution was regularly changed after each exposure, to ensure that each fish is exposed to a consistent concentration of noribogaine. Control fish were exposed to noribogaine-free water for the same treatment time, as described above.
Tests and Procedures [0715] Apparatus: Behavioral testing was performed between 11:00 and 15:00 h using tanks with water adjusted to the holding room temperature (25 C). The study used the novel tank test (NTT) protocol. NTT represents one of the most commonly used neurophenotyping tests for adult zebrafish. To avoid the test battery or handling effects, each assay was performed once, on a separate individual naïve fish each time.
Prior to testing, fish were pre-exposed individually in a 1-L plastic beaker for 20 mm to either drug- treated or drug-free water. During testing, zebrafish behavior was recorded by two trained observers blind to the treatments, who manually scored different behavioral endpoints (inter- and intra-rater reliability in all experiments >0.85) with subsequent automated analysis of generated traces by Ethovision XT8.5 software (Noldus IT, Wageningen, Netherlands). The NTT, used to assess zebrafish anxiety and locomotion, was a 1.5-L trapezoidal tank (15 cm height x 28 cm top x 23 cm bottom x 7 cm width; Aquatic Habitats, Apopka, FL) maximally filled with water and divided into two equal virtual horizontal portions by a line marking the outside walls. Fish were individually pre-exposed to water (water control), chronic nicotine (1 mg/L), repeated withdrawal from chronic nicotine (WD), and repeated withdrawal plus noribogaine (1 mg/L) for 20 min and tested in the standard 5-mM NTT.
[0716] Behavioral analyses: Zebrafish behavior was recorded by trained observers, scoring the latency to reach the top half of the tank(s), time spent in top(s), number of transitions to top, as well as the number and duration(s) of freezing bouts.
Freezing was defined as a total absence of movement, except for the gills and eyes, for >2 s.
Trials were also recorded to a computer using a USB webcam (2.0-megapixel, Gigaware, UK) and subsequently analyzed by Ethovision XT8.5, assessing distance traveled (m), velocity (m/s), and meandering endpoints. During manual observation, videos were recorded in MPEG1 format with the maximum sample rate 30 fps for each trial by auto-focusing 2.0 MP USB webcams, placed 25 cm in front of the Date Recue/Date Received 2023-11-27 tanks, and attached to laptop computers. Recorded videos were analyzed with Ethovision XT8.5 software. All environments were calibrated for each arena and the calibration axes were placed to designate the origin (0,0) at the center of each tank. The exported traces were independently evaluated on a consensus basis by two trained observers blinded to the treatments, to illustrate the spatial pattern of zebrafish swimming.
[0717] Study Design and Data Analysis: The study exposed adult zebrafish individually (15 animals per group) to water control, chronic nicotine, repeated nicotine withdrawal, and nicotine withdrawal + 1 mg/L noribogaine acutely (for min) by water immersion, following testing in NTT for 5 min, prior to euthanizing the fish. Raw data from manual and automatic endpoints were analyzed using GraphPad Prism to generate graphics and descriptive statistics, for manual and computer-generated endpoints. D'Agostino & Pearson omnibus normality K2 test was performed on data groups. When control group passed normality test, data groups were analyzed by the Bennett's test or Boniferroni all paired-wise comparisons test (ANOVA). When data were not following Gaussian distribution or were non-suitable for previously described statistical approach, sub-grouping and/or ranking was performed, data were treated in a differential manner to allow sub-groups and/or categorical comparison. The accepted value for significance was P<0.05 and higher significance was indicated where it applied. For illustration purposes, data analyzed by parametric statistics were represented as mean SEM, while non-parametric data were represented as scattered points or categorical sub-grouping.
Results [0718] The effects of noribogaine on zebrafish behavior are shown in Figure 11, panels A-G, and Figure 12, panels A-G. Zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups showed increased latency to top(s), while zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-DMX1) group showed a statistically significant decrease. Figure 11, panel A. Zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups also showed decreased transitions to top, while zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-DMX1) group showed a statistically significant increase. Figure 11, panel B. In addition, zebrafish in the chronic Date Recue/Date Received 2023-11-27 nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups exhibited normal habituation patterns, while zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-DMX1) group reached values equivalent to the control group at 5 minutes. Figure 11, panel C.
Statistically significant increases in the duration of time spent in the top(s) portion of the tank was exhibited by zebrafish in the withdrawal + 1 mg/L noribogaine (Nic WD-DMX1) group as compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups. Figure 11, panel D. Furthermore, zebrafish in the withdrawal + 1 mg/L
noribogaine (Nic WD-DMX1) group exhibited statistically significant increases in the duration of time spent in and average entry duration in the top(s) portion of the tank as compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups. Figure 11, panels E and F. Fish treated with noribogaine spent an average of more time in each of their travels to the top, suggesting a likely anxiolytic-like effect of noribogaine. Fish treated with noribogaine also exhibited an increased average entry duration as compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups. Figure 11, panel G.
[0719] Total distance traveled in the tank was measured and zebrafish in the nictotine withdrawal group exhibited an increased anxiety-like response which was corrected by treatment with noribogaine (Figure 12, panel A). Average velocity of zebrafish was also corrected by noribogaine treatment (Figure 12, panel B). There was no difference observed in the absolute change in direction of zebrafish in any of the test group (Figure 12, panel C). In addition, zebrafish receiving noribogaine treatment exhibited a slight increase in turning rotation rate over both chronic nicotine and nicotine withdrawal groups (Figure 12, panel D). On the other hand, no change was seen in the relative change in direction between any of the groups or absolute change in direction of movement per distance moved (Figure 12, panels E and F). Reduced absolute change in direction of movement per distance moved observed in the nicotine withdrawal group was corrected by treatment with noribogaine. (Figure 12, panel G). These results suggest anxiolytic-like anti-withdrawal effects of noribogaine treatment.
[0720] Anxiety/fear responses were also tested by recording freezing bout frequency and freezing duration. Figure 13. More freezing bouts and longer freezing duration indicate elevated anxiety and/or fear. Noribogaine treatment (Nic WD + Cpd 1 mg/L) re-Date Recue/Date Received 2023-11-27 established the high bouts due to nicotine withdrawal toward control levels (panel A) and duration of freezing (panels B and C).
[0721] Effect of noribogaine treatment on movement mobility was also detected.
Figure 14. The labele "immobile" was used to express the frequency of episodes with dress of movement independent of spatial displacement (duration of immobility). The label "mobile" reflects overall locomotor activity. The label "Hi-mobile" reflects bouts of accelerated swimming (>60 % of individual average). A strong decrease in immobile, mobile, and high mobile events was observed in nicotine withdrawal zebrafish, while noribogaine-treated zebrafish exhibited an increase in high-mobility number of events.
(Figure 14, panel A). In addition, nicotine withdrawal specifically decreased mobility of fish and increased immobility. Chronic nicotine treated fish showed a moderate increase of mobility and moderate decrease in immobility durations, while noribogaine-treated fish showed control-equivalent values for mobility and immobilitiy endpoints and displayed a slight increase of high-mobile activity. (Figure 14, panel B).
Discussion [0722] Analyses of manual NTT endpoints indicate statistically significant anxiolytic-like effects of noribogaine at 1 mg/L, as assessed by shorter latency to enter the top from control and longer time spent by noribogaine-treated fish in the more aversive top (vs. more 'protective' bottom) compartment of the test (Figure 11, panels A and D). The number of transitions from top to bottom (top entries) also differed at 1 mg/L noribogaine in nicotine withdrawal fish, suggesting general activation of exploration as this dose. (Figure 11, panel B). Freezing bouts' frequency and duration were increased in chronic nicotine and especially nicotine withdrawal fish. Noribogaine at 1 mg/L reversed that effect in nicotine withdrawal fish and re-established levels to that of the control fish group. (Figure 13) All fish showed normal habituation responses, as assessed by the per-minute distribution of swimming activity in all manual parameters, generally confirming the lack of behavioral anomalies in the applied testing conditions, which were standard and consistent with other published NTT studies. Analyses of computer-generated NTT endpoints reveal a consistent pattern of unaltered motor activity (assessed by distance traveled and velocity measures) at 1 mg/L noribogaine, but reduced activity in WD group.
(Figure Date Recue/Date Received 2023-11-27 12, panels A and B). Heading (movement directionality index) and mean meandering (straightness index) were similar in all groups. (Figure 12, panels E and F).
[0723] Erratic movements in this study were automatically measured using the frequency of high-mobility episodes. These endpoints are generally characteristic of higher anxiety states, but may be seen when reaching characteristic states of altered perception (e.g., hallucinogenic drugs). In this experiment there was no changes seen for chronic nicotine and nicotine withdrawal treatment. (Figure 14). An increase of hi-mobility duration and frequency (by a factor of ¨2) was observed in the noribogaine-treated fish in the nicotine withdrawal state. Noriobgaine did not evoke circling behavior (note unaltered turn angle as well), which would have been common for anti-glutaminergic drugs given acutely. Movement mobility (mobility frequency) and mobility duration, whose endpoints were reflecting general locomotor activity and anxiogenic treatments, showed significant effects of chronic nicotine, nicotine withdrawal and noribogaine treatment. (Figure 14). Hypo-locomotive effects of nicotine withdrawal were observed (as seen in both in duration and frequency of mobility endpoints, as well as in distance moved and velocity endpoints).
(Figure 14). Moderate hyper-locomotive effects of chronic nicotine (as in literature) was observed. (Figure 14). Noribogaine at 1 mg/L reestablished mobility (mobile and immobile) durations and frequency in nicotine treated fish to control values suggesting noribogaine is able to rescue locomotor effects of nicotine withdrawal state.
(Figure 14).
Conclusion [0724] Noribogaine treatment can reverse the effects of nicotine withdrawal, particularly both anxiogenia and hypolocomotion induced by nicotine withdrawal. The 1 mg/L dose of acute noribogaine evoked a robust anxiolytic-like behavior without any overt hyperactivity/hypoactivity in comparison to control in the repeated nicotine withdrawal zebrafish model. Chronic nicotine, and especially repeated WD, evoke anxiogenic-like and locomotor effects in zebrafish, consistent with zebrafish and rodent literature. Anxiogenic-like and locomotor effects of repeated nicotine withdrawal were fully reversed by noribogaine at dose 1 mg/L. Based on these results, beneficial activity of noribogaine in other behavioral paradigms is relevant to nicotine Date Recue/Date Received 2023-11-27 abuse, as well as other drugs' abuse-related models, can be expected at a potential dose of 1 mg/L.
Example 25. Effect of noribogaine in zebrafish expressed by anxiety-related endpoints Animals [0725] A total of 60 adult wild type short-fin zebrafish (-50:50 male:female ratio) were used in this study. Fish were housed in groups of 20-30 fish per 40-L
tank.
Tanks were filled with filtered water and maintained at 25 C. Illumination (1000-1100 lx) was provided by ceiling-mounted fluorescent lights on a 12-h cycle (on: 6.00 h, off: 18.00 h) according to the standards of zebrafish care. All fish used in this study were experimentally naïve and fed Tetramin Tropical Flakes (Tetra USA, Blacksburg, VA) twice a day. Following behavioral testing, the animals were euthanized in 500 mg/L Tricaine (Sigma¨Aldrich, St. Louis, MO) buffered to pH = 7Ø Animal experimentation in this study fully adhered to national and institutional guidelines and regulations.
Test compounds [0726] Pilot experiments performed at 1-, 5- and 10-mg/mL revealed sub-maximal efficacy of noribogaine at 1 mg/L, a dose that did not promote any locomotors effects susceptible to be confounded with efficacy endpoints of interest in other protocols, while the 5- and 10-mg/L doses caused reduction in selected swimming motor activity levels. As such, a 1 mg/L dose of noribogaine (DMX1 or Cpd) was chosen. A
standard 20-min pre-treatment time was chosen based on experience with a wide range of other neuroactive compounds and the results of pilot studies. This exposure time was also sufficient for provoking physiological (e.g., cortisol and c-fos) responses of zebrafish to multiple drugs. Noribogaine exposure in this study was performed by submerging individual zebrafish in a 1-L plastic beaker for 20 min prior to the testing.
The solution was regularly changed after each exposure, to ensure that each fish is exposed to a consistent concentration of noribogaine. Control fish were exposed to noribogaine-free water for the same treatment time, as described above.
Tests and Procedures Date Recue/Date Received 2023-11-27 [0727] Apparatus: Behavioral testing was performed between 11:00 and 15:00 h using tanks with water adjusted to the holding room temperature (25 C). The study used the novel tank test (NTT) protocol. NTT represents one of the most commonly used neurophenotyping tests for adult zebrafish. To avoid the test battery or handling effects, each assay was performed once, on a separate individual naïve fish each time.
Prior to testing, fish were pre-exposed individually in a 1-L plastic beaker for 20 min to either noribogaine-treated or noribogaine-free water. During testing, zebrafish behavior was recorded by two trained observers blind to the treatments, who manually scored different behavioral endpoints (inter- and intra-rater reliability in all experiments >0.85) with subsequent automated analysis of generated traces by Ethovision XT8.5 software (Noldus IT, Wageningen, Netherlands). The NTT, used to assess zebrafish anxiety and locomotion, was a 1.5-L trapezoidal tank (15 cm height x 28 cm top x 23 cm bottom x 7 cm width; Aquatic Habitats, Apopka, FL) maximally filled with water and divided into two equal virtual horizontal portions by a line marking the outside walls. Fish were individually pre-exposed to water (water control) or noribogaine (1, 5 and 10 mg/L) for 20 min and tested in the standard 5-min NTT.
[0728] Behavioral analyses: Zebrafish behavior was recorded by trained observers, scoring the latency to reach the top half of the tank(s), time spent in top(s), number of transitions to top, as well as the number and duration(s) of freezing bouts.
Freezing was defined as a total absence of movement, except for the gills and eyes, for >2 s.
Trials were also recorded to a computer using a USB webcam (2.0-megapixel, Gigaware, UK) and subsequently analyzed by Ethovision XT8.5, assessing distance traveled (m), velocity (m/s), and meandering endpoints. During manual observation, videos were recorded in MPEG1 format with the maximum sample rate 30 fps for each trial by auto-focusing 2.0 MP USB webcams, placed 25 cm in front of the tanks, and attached to laptop computers. Recorded videos were analyzed with Ethovision XT8.5 software. All environments were calibrated for each arena and the calibration axes were placed to designate the origin (0,0) at the center of each tank. The track data for each fish was exported as raw data into separate spreadsheets. The exported traces were independently evaluated on a consensus basis by two trained observers blinded to the treatments, to illustrate the spatial pattern of zebrafish swimming.

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Claims

What is claimed is:

1. A method for treating opioid or opioid-like drug abuse in a human patient addicted thereto, comprising administering to the patient a therapeutic dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the therapeutic dosage provides an average serum concentration of about 50 ng/mL
to about 180 ng/rnL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.

2. The method of claim 1, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng/mL to about 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of about 50 ng/mL to about 180 ng/mL for a period of time.

3. The method of claim 1, further comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.

4. The method of claim 1 wherein the maximum serum concentration is between about 40 ng/mL and about 250 ng/mL.

5. The method of claim 1 wherein the serum concentration of noribogaine is between about 1000 ng*hr/mL and about 5800 ng*hr/mL.

6. A method for treating opioid or opioid-like drug abuse in a human patient addicted thereto, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval prolongation of less than about 20 ms during said treatment.

7. A method for treating nicotine addiction in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine Date Recue/Date Receiv ed 2023-11-27 derivative, or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is from about 50 ng to less than 101.1g per kg body weight per day.

8. A method for preventing a nicotine craving in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof, wherein said prophylactically effective amount is from about 50 ng to less than 10 lug per kg body weight per day.

9. The method of claim 8, wherein the patient is no longer physically addicted to nicotine.

10. A method for treating alcohol dependence in a human patient suffering therefrom, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of about 50 ng/mL to about 500 ng/mL, said concentration being sufficient to ameliorate said dependence while maintaining a QT interval of less than about 500 ms during said treatment.

11. The method of claim 10, wherein the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg per day.

12. A method for treating substance abuse in a human patient addicted thereto, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval of less than about 500 ms during said treatment.

13. The method of claim 12, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one Date Recue/Date Receiv ed 2023-11-27 additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.

14. A method for treating substance abuse in a human patient addicted thereto, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 1 8 0 ng/mL, said concentration being sufficient to inhibit or ameliorate said abuse while maintaining a QT interval prolongation of less than about 20 ms during said treatment.

15. .. The method of claim 14, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 1 8 0 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.

16. A method for treating pain in a patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL , said concentration being sufficient to alleviate and/or inhibit said pain while maintaining a QT interval of less than about 500 ms during said treatment.

17. The method of claim 16, comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 1 8 0 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.

Date Recue/Date Receiv ed 2023-11-27

18. A method for treating pain in a patient, comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL , said concentration being sufficient to alleviate and/or inhibit said pain while maintaining a QT interval prolongation of less than about 20 ms during said treatment.

19. A method for treating migraine headache and/or symptoms thereof in a patient in need thereof comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the therapeutically effective amount is from about 50 ng to about 10 g per kg body weight per day.

21. A method for preventing migraine headache and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt thereof.

22. The method of claim 21, wherein said prophylactically effective amount is from about 50 ng to about 10 g per kg body weight per day.

23. A method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof while maintaining an acceptable QT interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof wherein said unit dose provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which serum concentration imparts an acceptable QT interval in said patient; and b) maintaining said serum concentration by periodically administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof such that the at least one additional dose maintains the therapeutic average serum concentration of 50 ng/mL to 180 ng/mL during treatment;

Date Recue/Date Receiv ed 2023-11-27 wherein said additional dose or doses are continued as necessary to treat said condition, and further wherein said acceptable QT interval is no longer than 500 ms.

24. The method of claim 24, wherein the QT interval is prolonged by less than 50 ms, or by less than 20 ms.

25. A method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof while maintaining an acceptable QT interval prolongation in said patient, the method comprising:
a) administering to the patient an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein said unit dose provides a therapeutic average serum concentration of 50 ng/mL to 180 ng/mL
which serum concentration imparts an acceptable QT interval prolongation in said patient; and b) maintaining said serum concentration by periodically administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the therapeutic average serum concentration of 50 ng/mL to 180 ng/mL during treatment;
wherein said additional dose or doses are continued as necessary to treat said condition, and further wherein said acceptable QT interval prolongation is no longer than 50 ms.

26. The method of claim 25, wherein the QT interval prolongation is less than 20 ms.

27. A method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT
interval of less than about 500 ms during said treatment.

28. The method of claim 27, further comprising interrupting the dosage of the analgesic.

Date Recue/Date Receiv ed 2023-11-27

29. The method of claim 27, further comprising administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic.

30. A method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy, the method comprising interrupting or administering concurrently with said opioid analgesic therapy an amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof that provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to re-sensitize the patient to the opioid as an analgesic while maintaining a QT
interval prolongation of less than about 20 ms during said treatment.

31. The method of any one of clairns 27-30, wherein the opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, and oxymorphone.

32. A method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT
interval of less than about 500 ms during said treatment.

33. A method for treating depression and/or posttraumatic stress disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT
interval prolongation of less than about 20 ms during said treatment.

34. A method for treating an anxiety-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, Date Recue/Date Receiv ed 2023-11-27 wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.

35. A method for treating an impulse control disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.

36. A method for regulating food intake and/or attenuating food craving in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, wherein the patient is not addicted to cocaine or an opiate, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 ms during said treatment.

37. A method for treating an anger-related disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof, and further wherein the therapeutically effective amount provides an efficacious average noribogaine serum level of between about 50 ng/mL and about 180 ng/mL while maintaining a QT interval of less than about 500 rns during said treatment.

38. A method for screening an opioid-addicted patient to determine the patient's tolerance for a therapeutic dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof, the method comprising:
measuring the patient's pre-administration QT interval;
administering to the patient a sub-therapeutic dose of noribogaine or pharmaceutically acceptable salt thereof., and Date Recue/Date Receiv ed 2023-11-27 measuring the patient's post-administration QT interval.

39. The method of claim 38, further comprising one or more of:
determining the difference between pre-administration QT interval and post-administration QT interval to determine a first prolongation;
estimating a second prolongation based on the first prolongation, wherein the second prolongation is the estimated QT interval prolongation expected to be observed in the patient upon administration of a therapeutic dose of noribogaine;
determining the patient's tolerance for the therapeutic dose of noribogaine;
and administering to the patient the therapeutic dose of noribogaine or discontinuing noribogaine treatment, wherein a therapeutic dose is administered if the second prolongation is estimated to be less than about 50 ms.

40. The method of claim 39, wherein the therapeutic dose provides an average serum concentration of 50 ng/mL to 180 ng/mL, said concentration being sufficient to inhibit or ameliorate opioid addiction while resulting in prolongation of the patient's QT interval of less than about 50 ms.

41. The method of claim 39, further comprising:
a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng/mL to 180 ng/mL; and b) administering at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the at least one additional dose maintains the average serum concentration of 50 ng/mL to 180 ng/mL for a period of time.

Date Recue/Date Receiv ed 2023-11-27