EP3107546A2 - Méthodes thérapeutiques faisant intervenir de la noribogaïne et des composés apparentés - Google Patents

Méthodes thérapeutiques faisant intervenir de la noribogaïne et des composés apparentés

Info

Publication number
EP3107546A2
EP3107546A2 EP15751574.3A EP15751574A EP3107546A2 EP 3107546 A2 EP3107546 A2 EP 3107546A2 EP 15751574 A EP15751574 A EP 15751574A EP 3107546 A2 EP3107546 A2 EP 3107546A2
Authority
EP
European Patent Office
Prior art keywords
noribogaine
patient
pharmaceutically acceptable
acceptable salt
solvate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP15751574.3A
Other languages
German (de)
English (en)
Other versions
EP3107546A4 (fr
Inventor
Lawrence Friedhoff
Emeline Maillet
Holger Weis
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DemeRx Inc
Original Assignee
DemeRx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2014/019692 external-priority patent/WO2015126434A1/fr
Priority claimed from US14/195,822 external-priority patent/US9345711B2/en
Priority claimed from US14/485,514 external-priority patent/US20150231147A1/en
Application filed by DemeRx Inc filed Critical DemeRx Inc
Publication of EP3107546A2 publication Critical patent/EP3107546A2/fr
Publication of EP3107546A4 publication Critical patent/EP3107546A4/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse

Definitions

  • 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.
  • Noribogaine is sometimes referred to as 12-hydroxyibogaine.
  • US Patent No. 2,813,873 claims noribogaine albeit as "12-O-demethylibogaine" while providing an incorrect structural formula for ibogaine.
  • Noribogaine can be depicted by the following formula:
  • 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 treatment generally requires administration of high doses of noribogaine, typically 0.1 mg to 100 mg per kg body weight.
  • 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.
  • 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.
  • nicotine replacement therapies e.g., nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler
  • nicotine patch e.g., nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler
  • nicotine inhaler do not directly treat nicotine addiction, as the patient remains addicted to nicotine throughout treatment.
  • 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.
  • Alcohol dependence also referred to alcohol abuse, alcohol addiction, or alcoholism
  • 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.
  • 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 longer, with symptoms such as anxiety, depression, sleep disturbance, fatigue, and tension being common.
  • 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.
  • medications such as benzodiazepines
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • ibogaine 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 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.
  • 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).
  • medications e.g., morphine
  • 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.
  • Migraine 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.
  • 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. Depression, Anxiety, Psychiatric Disorders, and Related Disorders
  • 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.
  • 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.
  • 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.
  • 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 DSM-5 (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, internet addiction, trichotillomania, pathological skin picking, and compulsive shopping.
  • Impulse control disorder may be related to anxiety disorder and/or OCD.
  • 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.
  • 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.
  • opioids are addictive opioids.
  • morphine is common among end stage patients suffering from serious pain where addiction is no longer a concern.
  • 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.
  • Drug tolerance requires that the dosage of analgesic be increased in order to provide sustained analgesic effect.
  • high doses of opioids may lead to serious complications and side effects, including physical dependence, addiction, respiratory depression, nausea, sedation, euphoria or dysphoria, decreased gastrointestinal motility, and itching.
  • 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.
  • 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-O-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:
  • 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.
  • Post-traumatic stress disorder as defined by DSM-III-R/IV (American Psychiatric Association, 1987; American Psychiatric Association, 1994a)
  • DSM-III-R/IV American Psychiatric Association, 1987; American Psychiatric Association, 1994a
  • PTSD is classified as an anxiety disorder, PTSD is unique from other anxiety disorders because of the requirement of exposure to a traumatic event.
  • 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.
  • noribogaine has minimal impact on withdrawal symptoms in addicted patients.
  • the previously disclosed broad range has now been found to be insufficient for some human therapies at the lower end of this range.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the initial dose is from about 50 mg to about 120 mg.
  • the one or more additional doses are lower than the initial dose.
  • the one or more additional doses are from about 5 mg to about 50 mg.
  • such a dosing regimen provides an average serum concentration of noribogaine of about 50 ng/mL to about 180 ng/mL.
  • the one or more additional doses maintain an average serum
  • the one or more additional doses are administered periodically.
  • 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
  • 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.
  • 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.
  • 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 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
  • 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.
  • 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 6000 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.
  • 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.
  • 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.
  • 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.
  • 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 a decreasing (tapered) amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof over time until the maintenance dose is reached.
  • a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose.
  • the dose of noribogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the QT prolongation is equivalent to or less than that observed in patients receiving methadone treatment.
  • 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.
  • noribogaine or a pharmaceutically acceptable salt thereof is administered.
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from about 75 mg to about 120 mg.
  • the at least one additional dose is from about 5 mg to about 25 mg.
  • the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose.
  • 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.
  • the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • the maximum serum concentration is between about 40 ng/mL and about 250 ng/mL.
  • the serum concentration of noribogaine is between about 1000 ng*hr/mL and about 5800 ng*hr/mL .
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • the method comprises:
  • the initial dose is from about 75 mg to about 120 mg.
  • the at least one additional dose is from about 5 mg to about 25 mg.
  • the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose.
  • 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.
  • 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 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.
  • the withdrawal symptoms are due to acute withdrawal.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from about 75 mg to about 120 mg.
  • the at least one additional dose is from about 5 mg to about 25 mg.
  • the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose.
  • 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.
  • a method to prevent relapse of opioid or opioid-like drug abuse in a patient previously treated to ameliorate said abuse 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.
  • 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.
  • 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.
  • Noribogaine is believed to bind to several receptors in the brain, including nicotinic acetylcholine receptors (nAChRs) and opiod receptors (e.g., ⁇ -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.
  • nAChRs nicotinic acetylcholine receptors
  • opiod receptors e.g., ⁇ -opiod receptors
  • 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.
  • this invention relates to methods of treating nicotine addiction or preventing relapse of nicotine use, comprising administration of a therapeutic amount of noribogaine.
  • noribogaine includes to noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
  • 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.
  • a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 10 ⁇ g per kg of body weight.
  • the therapeutically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day.
  • 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.
  • 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.
  • noribogaine includes to noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
  • 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.
  • a prophylactically effective amount of noribogaine in one aspect, a
  • prophylactically effective amount of noribogaine is from about 50 ng to less than 10 ⁇ g 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.
  • 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.
  • 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.
  • the therapeutically effective amount is from about 50 ng to about 1 ⁇ g per kg body weight per day.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
  • the therapeutically effective amount is administered once a day.
  • the therapeutically effective amount is administered two or more times per day.
  • 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 ⁇ g per kg body weight per day.
  • the patient is no longer physically addicted to nicotine.
  • the prophylactically effective amount is from about 50 ng to about 1 ⁇ g per kg body weight per day.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered on an as-needed basis as determined by the subject.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered before the nicotine craving occurs.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered after the nicotine craving occurs.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose.
  • the dose of noribogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
  • 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 a single dose.
  • 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.
  • 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 8 mg/kg.
  • 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.
  • 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.
  • 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.
  • the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms.
  • 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.
  • 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.
  • the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable salt and/or solvate thereof is from about 2 mg/kg to about 3 mg/kg per day.
  • the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day.
  • 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.
  • the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
  • the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • 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.
  • 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.
  • the withdrawal symptoms are due to acute withdrawal.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • 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.
  • 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.
  • 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
  • the pharmaceutically acceptable salt and/or solvate thereof is about 2 mg/kg per day.
  • the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.
  • a method to prevent relapse of alcohol abuse in a patient treated to ameliorate said abuse comprising periodically
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the initial dose is from 75 mg to 120 mg.
  • the one or more additional doses are lower than the initial dose.
  • the one or more additional doses are from 5 mg to 50 mg.
  • such a dosing regimen provides an average serum concentration of noribogaine of 50 ng/mL to 180 ng/mL.
  • the one or more additional doses maintain an average serum concentration of 50 ng/mL to 180 ng/mL over a period of time.
  • the one or more additional doses are administered
  • 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
  • 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.
  • 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.
  • 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 , or any subrange or subvalue there between.
  • 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.
  • 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.
  • 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.
  • a high initial therapeutic dose is administered, followed by administration of a lower therapeutic dose.
  • the dose of noribogaine is tapered over time from the high therapeutic dose to a lower therapeutic dose.
  • 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.
  • 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.
  • the aggregate dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from 1 mg/kg to 3 mg/kg.
  • 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.
  • 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.
  • 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.
  • the maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms.
  • the maintenance dose or therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof provides
  • 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.
  • the QT prolongation is equivalent to or less than that observed in patients receiving methadone treatment.
  • 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
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • the method further comprising selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • 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 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.
  • the withdrawal symptoms are due to acute withdrawal.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • a method to prevent relapse of drug abuse in a patient treated to ameliorate said abuse comprising periodically
  • the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 50 mg to 100 mg per day.
  • 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.
  • 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.
  • the narrow therapeutic doses of ibogaine described above do not prolong the QT interval to unacceptable levels in human patients.
  • patients are administered therapeutic doses of ibogaine in a clinical setting with cardiac monitoring.
  • 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.
  • 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.
  • the patient is not monitored after administration of ibogaine.
  • 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.
  • the dose of ibogaine administered to the patient provides an average serum concentration of about 50 ng/mL to about 400 ng/mL.
  • 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.
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • the aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 70 mg to 150 mg per day.
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • 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.
  • the pain symptoms are due to chronic pain.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • 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.
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • 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.
  • the dose provides both therapeutic results and an acceptable QT interval prolongation of less than about 50 milliseconds (ms) in humans.
  • 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.
  • 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, 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.
  • 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.
  • this invention relates to methods of treating or preventing migraines and/or symptoms thereof, comprising administration of a therapeutic amount of noribogaine.
  • noribogaine includes
  • noribogaine a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
  • the patient is co-administered a therapeutic amount of an agent known to treat migraines in addition to noribogaine.
  • the co-treatment does not result in a QT interval prolongation of greater than 50 ms.
  • both compounds are administered at the same time. In one embodiment, the compounds are administered at different times (e.g., sequentially).
  • 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.
  • a therapeutically effective amount of noribogaine or derivative is from about 50 ng to about 10 ⁇ g per kg of body weight.
  • the therapeutically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day.
  • an agent known to treat and/or prevent migraines is also administered.
  • 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 acceptable salt thereof, wherein the noribogaine or derivative or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, buccal, or intrapulmonary delivery.
  • 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.
  • noribogaine includes noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt of each thereof.
  • an agent known to treat and/or prevent migraines is also administered.
  • 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.
  • a prophylactically effective amount of noribogaine is from about 1 mg to about 2 mg per kg of body weight.
  • a prophylactically effective amount of noribogaine is from about 50 ng to about 10 ⁇ g per kg of body weight.
  • the prophylactically effective amount of noribogaine is from about 50 ng to about 10 ⁇ g per kg of body weight.
  • prophylactically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day.
  • the prophylactically effective amount of noribogaine or noribogaine derivative is administered once a day, twice a day, or more than twice a day.
  • 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.
  • 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.
  • 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 therapeutically effective amount of noribogaine, a noribogaine derivative, a noribogaine prodrug, or a pharmaceutically acceptable salt of each thereof.
  • the method further comprises administering at least one agent known to treat or prevent migraines and/or symptoms thereof.
  • 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 and/or prevent migraines, and optionally a
  • 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.
  • the therapeutically effective amount is from about 50 ng to about 10 ⁇ g 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 mtrapulmonary 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.
  • 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.
  • the prophylactically effective amount is from about 50 ng to about 10 ⁇ g per kg body weight per day. In another embodiment, the prophylactically effective amount is less than about 90% of the therapeutically effective amount.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt thereof is administered by sublingual, intranasal, buccal, or mtrapulmonary delivery. In another embodiment, the noribogaine, noribogaine derivative, or
  • the method further comprises administering at least one agent known to treat and/or prevent migraine and/or symptoms thereof.
  • the at least one agent is selected from the group consisting of: an analgesic, a triptan, an ergotamine, and dexamethasone.
  • 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.
  • 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.
  • the resensitized patient obtains therapeutic effect from a lower dose of the opioid analgesic than before resensitization.
  • the resensitized patient obtains improved therapeutic effect from the same dose of the opioid analgesic compared to before resensitization.
  • noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered concurrently with the opioid analgesic.
  • 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.
  • one dose of noribogaine is administered.
  • two or more doses of noribogaine are administered.
  • the opioid analgesic is interrupted for a period of time while noribogaine is administered.
  • a non-opioid analgesic is administered while the opioid analgesic is interrupted.
  • noribogaine acts as an analgesic.
  • the opioid analgesic is not interrupted during noribogaine treatment.
  • 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 and an acceptable QT interval prolongation of less than 50 milliseconds in opioid-tolerant humans is 2 mg/kg body weight.
  • a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • the method further comprises interrupting the dosage of the analgesic.
  • the method further comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic.
  • the dose of opioid analgesic is reduced.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • a method for modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesic therapy 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered as a single dose or multiple doses.
  • the method further comprising interrupting the dosage of the analgesic.
  • the method further comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof concurrently with the analgesic.
  • the dose of opioid analgesic is reduced.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • 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.
  • the opioid analgesic is morphine.
  • noribogaine 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.
  • nAChRs nicotinic acetylcholine receptors
  • opioid receptors e.g., ⁇ - opiod receptors
  • 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.
  • 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.
  • this invention treats depression.
  • this invention treats PTSD.
  • the patient is not addicted to cocaine or an opiate. Unlike PTSD, conventional anxiety disorders are not within the scope of this invention.
  • 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.
  • the dose of noribogaine or pharmaceutically 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.
  • 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.
  • the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 50 ms.
  • the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 30 ms.
  • the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof provides prolongation of the QT interval of less than 20 ms.
  • 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.
  • 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.
  • 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.
  • 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.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.
  • 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.
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • depression is treated.
  • posttraumatic stress disorder is treated.
  • noribogaine 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.
  • nAChRs nicotinic acetylcholine receptors
  • opioid receptors e.g., ⁇ -opiod receptors
  • 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.
  • 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.
  • 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.
  • this invention treats an anxiety disorder.
  • this invention treats OCD.
  • this invention treats generalized anxiety disorder.
  • this invention treats social anxiety disorder.
  • this invention treats panic disorder.
  • this invention treats impulse control disorder.
  • this invention treats pathological anger and/or violence.
  • this invention treats anger/violence-related disorders.
  • 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.
  • 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.
  • the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof 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.
  • 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.
  • 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.
  • the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof maintains a QT interval of less than about 450 ms.
  • the dose of noribogaine or pharmaceutically acceptable salt and/or solvate thereof maintains a QT interval of less than about 420 ms.
  • 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 with noribogaine, and if clinician determines that the QT prolongation would be an unacceptable risk, noribogaine therapy will be contraindicated.
  • 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.
  • 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.
  • the anxiety-related disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, and social anxiety disorder.
  • a method for treating an impulse control disorder in a patient in need thereof comprising administering to the patient a
  • 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.
  • 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, kleptomania, sexual compulsion, paraphilia, internet addiction, trichotillomania, pathological skin picking, and compulsive shopping.
  • 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.
  • 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.
  • the method comprises:
  • the initial dose is from about 75 mg to about 120 mg.
  • the at least one additional dose is from about 5 mg to about 25 mg.
  • the at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose.
  • 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.
  • the QT interval is less than about 450 ms.
  • the method further comprises selecting a patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, buccal, intranasal, or intrapulmonary delivery.
  • 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.
  • Noribogaine is administered to ameliorate acute and post-acute withdrawal symptoms.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 subtherapeutic doses (less than 120 mg) of noribogaine to screen out such patients before therapeutic doses (120 mg) of noribogaine therapy are initiated.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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 a threshold, for example about 50 ms.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the patient is administered a sub-therapeutic dose of noribogaine.
  • the patient is administered a therapeutic dose of noribogaine in multiple administrations.
  • the therapeutic dose is 120 mg per day, 60 mg may be given every 12 hours.
  • multiple administrations will lower the maximum serum concentration of noribogaine experienced by the patient, thereby reducing QT interval prolongation.
  • the patient is administered an initial dose of noribogaine, followed by one or more additional doses.
  • the initial dose is from 75 mg to 120 mg.
  • the one or more additional doses are lower than the initial dose.
  • the one or more additional doses are from 5 mg to 50 mg.
  • such a dosing regimen provides an average serum concentration of noribogaine of 50 ng/mL to 180 ng/mL.
  • such a dosing regimen provides an average serum concentration of noribogaine of 80 ng/mL to 100 ng/mL.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the method further comprises: a) administering an initial dose of noribogaine, noribogaine derivative, or
  • the therapeutic dose is administered in one or more dosings.
  • the sub-therapeutic dose is administered in one or more dosings.
  • the sub-therapeutic dose is 80% or less than the therapeutic dose.
  • the sub-therapeutic dose is 70%> or less than the therapeutic dose.
  • the sub-therapeutic dose is between 60 mg and 100 mg. In another embodiment, the sub-therapeutic dose is about 90 mg.
  • 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.
  • the present invention provides a method for treating a condition in a patient which is treatable with noribogaine, noribogaine derivative, or
  • 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.
  • the therapeutic blood serum concentration is between 50 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 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.
  • the patient is administered an initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses.
  • the initial unit dose is from 50 mg to 120 mg.
  • the one or more additional doses are lower than the initial dose.
  • the one or more additional doses are from 5 mg to 50 mg.
  • such a dosing regimen provides a therapeutic average serum concentration of noribogaine of 50 ng/mL to 180 ng/mL.
  • 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.
  • 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.
  • 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.
  • 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.
  • the patient undergoes cardiac monitoring during a portion of the treatment. In a preferred embodiment, cardiac monitoring is not required.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • the QT interval prolongation is less than 20 ms.
  • the initial unit dose is higher than any of the at least one additional dose.
  • the initial unit dose and at least one additional dose are incorporated into a single controlled release formulation.
  • 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.
  • the initial unit dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • the at least one additional dose is administered from 6 hours to 24 hours after the initial dose.
  • 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.
  • the method further comprises selecting an addicted patient who is prescreened to evaluate tolerance for prolongation of QT interval.
  • noribogaine or a pharmaceutically acceptable salt and/or solvate thereof is administered.
  • 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.
  • the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered in one or more dosings
  • the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg.
  • 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.
  • FIG. 2 represents mean plasma noribogaine glucuronide concentration-time profiles in healthy patients after single oral 30 or 60 mg doses.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • AUC mean area under the curve
  • FIG. 7A illustrates of the mean change in total OOWS 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 OOWS score.
  • 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 OOWS score data given in Figure 7A.
  • AUC mean area under the curve
  • 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.
  • 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.
  • AUC mean area under the curve
  • FIG. 9A illustrates the average change in QT interval (AQTcl) for each cohort (60 mg, squares; 120 mg, triangles; 180 mg, diamonds) or placebo (circles) over the first 24 hours post administration.
  • FIG. 9B illustrates the correlation between serum noribogaine concentration and AQTcl for each patient over time. The equation of the line is given.
  • 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;
  • FIG. 10B represents the effects of noribogaine and varenicline on percentage of inactive lever press during nicotine self-administration. Data represent mean + SEM.
  • 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).
  • 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).
  • FIG. 13 depicts effects of noribogaine on freezing bouts frequency (panel A) and duration of freezing bouts (panels B and C).
  • 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).
  • 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.
  • 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 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).
  • 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).
  • 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).
  • 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
  • Hi-mobile HF and LF
  • HF and LF reflects bouts of accelerated velocity (>60 % of individual average).
  • 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 Etho vision XT8.5 software.
  • the term "about” when used with regard to a dose amount means that the dose may vary by +/- 20%.
  • "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.
  • about 120 mg per unit dose of noribogaine indicates that the unit dose may range from 96 mg to 144 mg.
  • administering 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.
  • 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 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.
  • direct administration which may be administration to a patient by a medical professional or by self-administration by the patient
  • indirect administration which may be the act of prescribing a drug.
  • 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.
  • Periodic administration 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.
  • 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.
  • 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.
  • alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 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 (CH 3 -), ethyl
  • C x alkyl refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C 3 refers to an alkyl group having 3 carbon atoms.
  • 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 (-C ⁇ C-) unsaturation.
  • alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH).
  • 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, ammothiocarbonyl, aminocarbonylamino, ammothiocarbonylammo, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino sulfonylamino, 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 cycloalkyl, substituted
  • heterocyclylthio nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
  • 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, ammothiocarbonyl, aminocarbonylamino, ammothiocarbonylammo, ammocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino sulfonylamino, 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 cycloalkyl, substituted
  • heterocyclylthio nitro, S0 3 H, 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.
  • 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, amino sulfonylamino, 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, substituted cycloal
  • heterocyclylthio nitro, SO 3 H, 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.
  • Alkoxy refers to the group -O-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.
  • Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, substituted
  • Acylamino refers to the groups -NR 38 C(0)alkyl, -NR 38 C(0)substituted alkyl, -NR 38 C(0)cycloalkyl, -NR 38 C(0)substituted
  • R 38 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.
  • Acyloxy refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted
  • heteroaryl-C(0)0- substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, 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.
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR 39 R 40 where R 39 and R 40 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, substituted heterocyclic, -S0 2 -alkyl, -S0 2 -substituted
  • R 39 is hydrogen and R 40 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 39 and R 40 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 39 or R 40 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 39 nor R 40 are hydrogen.
  • Aminocarbonyl refers to the group -C(0)NR 41 R 42 where R 41 and R 42 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 R 41 and R 42 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
  • Aminothiocarbonyl refers to the group -C(S)NR 41 R 42 where R 41 and R 42 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 R 41 and R 42 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
  • Aminocarbonylamino refers to the group -NR 38 C(0)NR 41 R 42 where R 38 is hydrogen or alkyl and R 41 and R 42 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 R 41 and R 42 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 cycl
  • Aminothiocarbonylamino refers to the group -NR 38 C(S)NR 41 R 42 where R 38 is hydrogen or alkyl and R 41 and R 42 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 R 41 and R 42 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,
  • Aminocarbonyloxy refers to the group -0-C(0)NR 41 R 42 where R 41 and R 42 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 R 41 and R 42 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
  • Aminosulfonyl refers to the group -S0 2 NR 41 R 42 where R 41 and R 42 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 R 41 and R 42 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, ary
  • Aminosulfonyloxy refers to the group -0-S0 2 NR 41 R 42 where R 41 and R 42 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 R 41 and R 42 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, substituted cyclo
  • Aminosulfonylamino refers to the group -NR 38 -S0 2 NR 41 R 42 where R 38 is hydrogen or alkyl and R 41 and R 42 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 R 41 and R 42 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, cycloalken
  • 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.,
  • Preferred aryl groups include phenyl and naphthyl.
  • 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,
  • Aryloxy refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the
  • 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.
  • heteroaryl -NR 38 -C(0)0-heterocyclic, and -NR 38 -C(0)0-substituted heterocyclic
  • R 38 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.
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl
  • 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.
  • Cyano refers to the group -CN.
  • 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.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • Other examples of cycloalkyl groups include
  • 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,
  • heteroarylthio heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Cycloalkenyloxy refers to -O-cycloalkenyl.
  • Substituted cycloalkenyloxy refers to -0-(substituted cycloalkenyl).
  • Cycloalkenylthio refers to -S-cycloalkenyl.
  • Substituted cycloalkenylthio refers to -S-(substituted cycloalkenyl).
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • 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.
  • 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.
  • 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.
  • 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.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfmyl, and/or sulfonyl moieties.
  • Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • 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.
  • Heteroaryloxy refers to -O-heteroaryl.
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” 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.
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” 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.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
  • Heterocyclylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
  • 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
  • Niro refers to the group -N0 2 .
  • Spiro ring systems refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
  • Substituted sulfonyl refers to the group -S0 2 -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -S0 2 -substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cylcoalkyl, -S0 2 -cycloalkenyl, -S0 2 -substituted cylcoalkenyl, -S0 2 -aryl, -S0 2 -substituted aryl, -S0 2 -heteroaryl, -S0 2 -substituted heteroaryl, -S0 2 -heterocyclic, -S0 2 -substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, substituted al
  • Substituted sulfonyl includes groups such as methyl-S0 2 -, phenyl-S0 2 -, and 4-methylphenyl-S0 2 -.
  • alkylsulfonyl refers to -S0 2 -alkyl.
  • haloalkylsulfonyl refers to -S0 2 -haloalkyl where haloalkyl is defined herein.
  • (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.
  • alkyl -OS0 2 -alkenyl, -OS0 2 -substituted alkenyl, -OS0 2 -cycloalkyl, -OS0 2 -substituted cylcoalkyl, -OS0 2 -cycloalkenyl, -OS0 2 -substituted
  • 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
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • 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.
  • 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.
  • the term "monophosphate” refers to the group -P(0)(OH) 2 .
  • diphosphate refers to the group -P(0)(OH)- OP(0)(OH) 2 .
  • triphosphate refers to the group -P(0)(OH)- (OP(0)(OH)) 2 OH.
  • esters of the mono-, di- or triphosphate group means esters of the monophosphate can be represented by the formula -P(0)(OR 45 ) 2 , where each R 45 is independently hydrogen, Ci-Ci 2 alkyl, C3-C10 cycloalkyl, C 6 -Ci4 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 R 45 is not hydrogen.
  • exemplary esters of the di- or triphosphate can be represented by the formulas -P(0)(OR 45 )-OP(0)(OR 45 ) 2
  • hydrolyzable group refers to a group that can be hydro lyzed to release the free hydroxy group under hydrolysis conditions.
  • hydrolysable group include, but are not limited to those defined for R above.
  • Preferred hydro lysable 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(O)O- or -OC(O)-), an amide -based linker (-C(O)NR 46 - or -NR 46 C(0)-), or a phosphate-linker (-P(0)(OR 46 )-0-, -0-P(S)(OR 46 )-0-, - 0-P(S)(SR 46 )-0-, -S-P(0)(OR 46 )-0-, -0-P(0)(OR 46 )-S-, -S-P(0)(OR 46 )-S- , -0-P(S)(OR 46 )-S-, -S-P(S)(OR 46 )-0-, -0-P(0)(R 46 )-0-, -0-P(S)(R 46 )-0- , -S-P(0)(R 46 )-0-, -S-P(S)(R 46 )-0-, -S
  • Substituted groups of this invention do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group can be substituted up to five times.
  • Neoribogaine refers to the compound: as well as noribogaine derivatives or pharmaceutically acceptable salts and
  • noribogaine is mentioned herein, one more polymorphs of noribogaine can be utilized and are contemplated. In some embodiments, noribogaine is noribogaine glucuronide.
  • Noribogaine can be prepared by demethylation of naturally occurring ibogaine:
  • 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.
  • Nonibogaine derivatives refer to, without limitation, esters or O-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.
  • 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 that provides the desired maximum serum concentrations and efficacious average noribogaine serum levels.
  • noribogaine refers to a compound that metabolizes, in vivo, to noribogaine.
  • 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.
  • the prodrug moiety is selected to facilitate binding to the ⁇ and/or ⁇ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the ⁇ 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.
  • 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.
  • 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.
  • 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.
  • “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 molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.
  • 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.
  • solvate is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of solvent trapped inside.
  • solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are certainly not limited to, water, methanol, ethanol, isopropanol, butanol, Ci-C 6 alcohols in general (and optionally substituted),
  • tetrahydrofuran acetone
  • ethylene glycol propylene glycol
  • acetic acid formic acid
  • water and solvent mixtures thereof.
  • biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention.
  • 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.
  • the solvent is water
  • the solvate can be referred to as a hydrate.
  • 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.
  • solvate also is meant to include such compositions where another compound or complex co-crystallizes with the compound of interest.
  • solvate refers to complexes with solvents in which noribogaine is reacted or from which noribogaine is precipitated or crystallized.
  • 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.
  • Therapeutically effective 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood
  • a lower dose of the compound may be administered.
  • a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 100 ⁇ g 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.
  • 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.
  • a "sub-therapeutic level" of noribogaine or pharmaceutical salt and/or solvate thereof that is less than the therapeutic level described above.
  • the subtherapeutic 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
  • 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.
  • 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.
  • 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).
  • a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount.
  • 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.
  • 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.
  • 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.
  • Treatment 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.
  • beneficial or desired clinical results include, but are not limited to: treating nicotine addiction; treating, preventing, and/or attenuating cravings for nicotine; and 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.
  • 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.
  • 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.
  • the term "patient” refers to mammals and includes humans and non-human mammals.
  • opioid 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.
  • 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, 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
  • 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.
  • opioids also encompasses opioid intermediates, including 4-cyano-2-dimethylamino-4,4- diphenyl butane, 2-methyl-3-morpholino-l,l-diphenylpropane-carboxylic acid, 4-cyano-l- methyl-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and l-methyl-4- phenylpiperidine-4-carboxylic acid.
  • 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.
  • 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.
  • 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.
  • DSMIV-TR criteria for dependency include: Dependence or significant impairment or distress, as manifested by 3 or more of the following during a 12 month period:
  • the term "nicotine addict in remission” refers to any patient who has quit using nicotine for a period of time.
  • 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.
  • 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.
  • the patient does not exhibit psychological symptoms of nicotine addiction.
  • 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
  • GLB gamma-hydroxybutyrate
  • DXM dextromethorphan
  • LSD lysergic acid diethylamide
  • 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.
  • Obsessive compulsive disorder 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.
  • 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 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
  • Social anxiety disorder also known as social phobia
  • 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) interferes 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.
  • 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).
  • 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 DSM-5 (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, internet addiction, trichotillomania, pathological skin picking, and compulsive shopping.
  • Impulse control disorder may be related to anxiety disorder and/or OCD.
  • 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.
  • pain refers to all categories and classifications of pain, which are summarized below for purposes of illustration.
  • Example injuries that produce cutaneous pain include paper cuts, minor burns (e.g., first degree burns) and superficial lacerations.
  • 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.
  • 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.
  • Myocardial ischaemia i.e., the loss of blood flow to a part of the heart muscle tissue
  • 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. This phenomena—also known as deafferentation pain— is almost universally reported by amputees and quadriplegics.
  • neuropathic pain 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.
  • 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).
  • medications e.g., morphine
  • 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.
  • 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.
  • 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.
  • opioid analgesics such as, for example, buprenorphin, codeine, hydrocodone, oxycodone, morphine, and the like.
  • 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.
  • Neuroopathic 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.
  • the cause of neuropathic pain may be unclear or unknown.
  • “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.
  • an addictive compound 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.
  • addictive compounds include, without limitation, addictive opioids, and the like.
  • 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.
  • 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 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.,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial,
  • intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery In one
  • 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.
  • 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.
  • 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. [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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ g per kg body weight per day.
  • 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 composition is formulated for sublingual, intranasal, or intrapulmonary delivery.
  • 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.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 50 ⁇ g per kg body weight per day.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 10 ⁇ g per kg body weight per day.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 1 ⁇ g per kg body weight per day.
  • 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.
  • 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. COMPOUNDS UTILIZED
  • the noribogaine derivative is represented by Formula I:
  • R is hydrogen or a hydrolyzable group such as hydrolyzable esters of from about 1 to 12 carbons.
  • R is hydrogen or a group of the formula:
  • X is a C ⁇ -Cn group, which is unsubstituted or substituted.
  • 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.
  • X may be a phenyl group or benzyl group, either of which may be substituted with lower alkyl groups or lower alkoxy groups.
  • the lower alkyl and/or alkoxy groups have from 1 to about 6 carbons.
  • the group R may be acetyl, propionyl or benzoyl. However, these groups are only exemplary.
  • groups X may either be unsubstituted or substituted with lower alkyl or lower alkoxy groups.
  • substituted X may be o-, m- or p-methyl or methoxy benzyl groups.
  • C1-C12 groups include C1-C12 alkyl, C3-C12 cycloalkyl, C 6 -Ci2 aryl, C7-C12 arylalkyl, wherein C x indicates that the group contains x carbon atoms.
  • Lower alkyl refers to C1-C4 alkyl and lower alkoxy refers to C1-C4 alkoxy.
  • the noribogaine derivative is represented by Formula II:
  • R 1 is halo, OR 2 , or C 1 -C 12 alkyl optionally substituted with 1 to 5 R ;
  • R 2 is hydrogen or a hydrolysable group selected from the group consisting of - C(0)R x , -C(0)OR x and -C(0)N(R y ) 2 where each R x is selected from the group consisting of Ci-C 6 alkyl optionally substituted with 1 to 5 R 10 , and each R y is independently selected from the group consisting of hydrogen, Ci-C 6 alkyl optionally substituted with 1 to 5 R 10 , C 6 -Ci 4 aryl optionally substituted with 1 to 5 R 10 , C3-C 10 cycloalkyl optionally substituted with 1 to 5 R 10 , C 1 -C 10 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C 1 -C 10 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , and where each R y , together with the nitrogen atom bound thereto form a Ci-C 6 heterocyclic having 1 to 4 hetero
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl optionally
  • R 4 is selected from the group consisting of hydrogen, -(CH 2 ) m OR 8 , -
  • n 0, 1, or 2;
  • L is a bond or C 1 -C 12 alkylene;
  • R 5 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl substituted with 1 to 5 R 10 , C 1 -C 12 alkenyl substituted with 1 to 5 R 10 , -X J -R 7 , -(X ⁇ Y ⁇ -X 1 - R 7 , -S0 2 NR 7 R 8 , -0-C(0)R 9 , -C(0)OR 8 , -C(0)NR 7 R 8 , -NR 7 R 8 , - NHC(0)R 9 , and -NR 7 C(0)R 9 ;
  • each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 6 -Cio aryl, Ci-C 6 heteroaryl having 1 to 4 heteroatoms, and Ci-C 6 heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 10 ;
  • X 1 is selected from the group consisting of O and S;
  • Y is C 1 -C 4 alkylene or C 6 -Cio arylene, or a combination thereof;
  • n 1, 2, or 3;
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl optionally substituted with 1 to 5 R 10 , Ci-C 6 heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , C 3 -C 10 cycloalkyl optionally substituted with 1 to 5 R 10 , C 6 -Cio aryl optionally substituted with 1 to 5 R 10 and Ci-C 6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 ;
  • R 9 is selected from the group consisting of C 1 -C 12 alkyl optionally substituted with 1 to 5 R 10 , Ci-C 6 heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 , C 3 -C 10 cycloalkyl optionally substituted with 1 to 5 R 10 , C 6 -Cio aryl optionally substituted with 1 to 5 R 10 and Ci-C 6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 ;
  • R 10 is selected from the group consisting of C 1 -C 4 alkyl, phenyl, halo, -OR 11 , -
  • R 11 is independently hydrogen or C 1 -C 12 alkyl
  • R 5 when L is a bond, then R 5 is not hydrogen; when is a double bond, R 1 is an ester hydrolyzable group, R 3 and R 4 are both hydrogen, then -L-R 5 is not ethyl;
  • R 1 when is a double bond, R 1 is -OH, halo or C1-C12 alkyl optionally
  • R 4 is hydrogen
  • R 1 when is a double bond, R 1 is OR 2 , R 4 is hydrogen, -L-R 5 is ethyl, then R 2 not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.
  • the noribogaine derivative is represented by Formula III:
  • R 12 is halo, -OH, -SH, -NH 2 , -S(0) 2 N(R 17 ) 2 , -R'-I ⁇ -R 18 , -R'-I ⁇ -R 19 , -R'-I ⁇ -R 20 or - R'-I ⁇ -CHR ⁇ R 19 , where R z is O, S or NR 17 ;
  • L 1 is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0- alkylene, -C(O)NR 20 -alkylene, -C(O)NR 20 -arylene, -C(NR 20 )NR 20 -alkylene or -C(NR 20 )NR 20 -arylene, wherein L 1 is configured such that -O-I ⁇ -R 18 is - OC(0)-alkylene-R 18 , -OC(0)0-arylene-R 18 , -OC(0)0-alkylene-R 18 , - OC(0)-arylene-R 18 , -OC(O)NR 20 -alkylene-R 18 , -OC(O)NR 20 -arylene-R 18 , -OC(NR 20 )NR 20 -alkylene-R 18 or -OC(NR 20 )NR 20 -arylene-R 18 , and wherein the alkylene and
  • R 13 is hydrogen, -S(0) 2 OR 20 , -S(0) 2 R 20 , -C(0)R 15 , -C(0)NR 15 R 15 , -C(0)OR 15 , C Ci 2 alkyl optionally substituted with 1 to 5 R 16 , Ci-Ci 2 alkenyl optionally substituted with 1 to 5 R 16 , or aryl optionally substituted with 1 to 5 R 16 ;
  • R 14 is hydrogen, halo, -OR 17 , -CN, Ci-Ci 2 alkyl, Ci-Ci 2 alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R 16 ; each R is independently selected from the group consisting of hydrogen, C1-C12 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 R 16 ;
  • R 16 is selected from the group consisting of phenyl, halo, -OR 17 , -
  • each R 17 is independently hydrogen or C1-C12 alkyl optionally substituted with from 1 to 3 halo;
  • R 18 is hydrogen, -C(0)R 20 , -C(0)OR 20 , -C(O)N(R 20 ) 2 or -N(R 20 )C(O)R 20 ;
  • R 19 is hydrogen, -
  • each R 20 is independently selected from the group consisting of hydrogen, C1-C12 alkyl and aryl;
  • R 14 is hydrogen
  • R 12 is -O-I ⁇ -R 18 , -O-I ⁇ -R 19 , -O-L 1 - R 20
  • L 1 is alkylene, then -O-I ⁇ -R 18 , -O-I ⁇ -R 19 , -O-I ⁇ -R 20 are not methoxy;
  • R 14 when is a double bond, R 14 is hydrogen, R z is O, L 1 is -C(O)- alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(0)NR 20 -
  • the noribogaine derivative is represented by Formula IV:
  • R 21 is selected from the group consisting of hydrogen, a hydro lysable group selected from the group consisting of -C(0)R 23 , -C(0)NR 24 R 25 and -C(0)OR 26 , where R 23 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R 24 and R 25 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, R 26 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substitute
  • L 2 is selected from the group consisting of a covalent bond and a cleavable linker group
  • R 22 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;
  • R 21 is selected from the group consisting of -C(0)NR 24 R 25 and -C(0)OR 26 ;
  • R 21 is hydrogen or -C(0)R 23 and L 2 is a covalent bond, then R 22 is not hydrogen.
  • the noribogaine derivative is represented by Formula V:
  • - ⁇ ' refers to a single or a double bond provided that when
  • Formula V refers to the corresponding dihydro compound
  • R 27 is hydrogen or S0 2 OR 29 ;
  • R 28 is hydrogen or S0 2 OR 29 ;
  • R is hydrogen or Ci - C 6 alkyl;
  • the noribogaine derivative is represented by Formula VI:
  • ⁇ refers to a single or a double bond provided that when ⁇ is a single bond, Formula VI refers to the corresponding vicinal dihydro compound;
  • R 30 is hydrogen, a monophosphate, a diphosphate or a triphosphate
  • R 31 is hydrogen, a monophosphate, a diphosphate or a triphosphate
  • R 30 and R 31 are not hydrogen
  • R 30 and R 31 are optionally esterified with one or more Ci-C 6 alkyl esters.
  • 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.
  • the compound utilized herein is noribogaine or a salt thereof. In a more preferred embodiment, the compound utilized herein is noribogaine.
  • 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.
  • this invention provides 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, 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.
  • 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.
  • 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.
  • the patient is addicted to nicotine.
  • the patient is physically addicted to nicotine.
  • the patient is psychologically addicted to nicotine.
  • the therapeutically effective amount of the compound is from about 50 ng to less than 10 ⁇ g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 ⁇ 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 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 ⁇ g per kilogram body weight per day.
  • the therapeutically effective amount of the compound is from about 1 ⁇ g 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 ⁇ g, about 6 ⁇ g, about 7 ⁇ g, about 8 ⁇ , about 9 ⁇ , about 10 ⁇ per kilogram body weight per day.
  • the therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints.
  • 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.
  • 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 ⁇ g noribogaine per kg body weight per day would take 90 ⁇ g once a day, 45 ⁇ g twice a day, or 30 ⁇ g three times a day, etc.
  • 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.
  • 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.”
  • 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.
  • 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.
  • 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 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.
  • 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.
  • nicotine cravings are attenuated, interrupted, or prevented for at least 2, 3, 4, 5, 6, 7, 8, 10, 15, or 24 hours.
  • the noribogaine is administered on an as-needed basis by the patient.
  • the noribogaine may be administered before the nicotine craving occurs.
  • 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.
  • 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.
  • 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.
  • the prophylactically effective amount of the compound is from about 50 ng to less than 10 ⁇ g per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 ⁇ g per kilogram body weight per day. In another embodiment, the
  • prophylactically 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 prophylactically effective amount of the compound is from about 500 ng to less than 10 ⁇ g per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 1 ⁇ g to less than 10 ⁇ g per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints. [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.
  • 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 ⁇ g noribogaine per kg body weight per day would take 90 ⁇ g once a day, 45 ⁇ g twice a day, or 30 ⁇ g three times a day, etc.
  • 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.”
  • 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
  • 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.
  • 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 to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a dosing regimen provides an average serum concentration of noribogaine of about 50 ng/mL to about 180 ng/mL.
  • the one or more additional doses maintain an average serum
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the first tapered dose is 50% to 95% of the first or original dose.
  • the second tapered dose is 40%> to 90%> of the first or original dose.
  • the third tapered dose is 30%> to 85% of the first or original dose.
  • the fourth tapered dose is 20% to 80%> of the first or original dose.
  • the fifth tapered dose is 10%> to 75% of the first or original dose.
  • 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.
  • 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.
  • second, third, fourth, etc. tapered doses 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.
  • one tapered dose is given to achieve the desired lower therapeutic dose.
  • two tapered doses are given to achieve the desired lower therapeutic dose.
  • three tapered doses are given to achieve the desired lower therapeutic dose.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • noribogaine noribogaine derivative, or a
  • the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • the patient may suffer from addiction to any opioid or opiate or opioid-like drug.
  • the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, oxycodone, hydrocodone, and methamphetamine.
  • the opioid or opioid-like drug is heroin.
  • the opioid or opioid-like drug is methadone.
  • the opioid or opioid-like drug is morphine.
  • 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.
  • 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
  • the patient undergoes long-term (e.g., one year or longer) treatment with maintenance doses of noribogaine, noribogaine derivative, or salt or solvate thereof.
  • 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.
  • 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.
  • 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.
  • 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 dose is 20% of the therapeutic dose. In some embodiments, the maintenance dose is 10% of the therapeutic dose.
  • 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.
  • 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
  • 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.
  • 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 AUC/24 h of noribogaine.
  • 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.
  • the therapeutic dose is tapered over time until the desired maintenance dose is reached.
  • the first tapered dose is 50%) to 95%) of the therapeutic dose.
  • the second tapered dose is 40%) to 90%o of the therapeutic dose.
  • the third tapered dose is 30%> to 85%) of the therapeutic dose.
  • the fourth tapered dose is 20%> to 80%) of the therapeutic dose.
  • the fifth tapered dose is 10%> to 75% of the therapeutic dose.
  • one tapered dose is given to achieve the maintenance dose.
  • two tapered doses are given to achieve the maintenance dose.
  • three tapered doses are given to achieve the maintenance dose.
  • 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.
  • 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.
  • 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.
  • 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, 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.
  • 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.
  • 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.
  • 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,
  • 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).
  • noribogaine noribogaine derivative, or a
  • the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • the patient may suffer from addiction to any opioid or opiate, or opioid-like drug.
  • the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, hydrocodone, oxycodone, and methamphetamine.
  • the opioid or opioid-like drug is heroin.
  • the opioid or opioid-like drug is methadone.
  • the opioid or opioid-like drug is morphine.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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/mL. In one
  • 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.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is from greater than about 1 mg/kg to about 8 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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 aggregate dosage of noribogaine, noribogaine derivative, or salt and/or solvate thereof is about 5 mg/kg body weight per day.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 week after cessation of alcohol use, although acute withdrawal may last as long as six weeks or more.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • the withdrawal symptoms are symptoms of acute withdrawal.
  • 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 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • the withdrawal symptoms are symptoms of acute withdrawal.
  • 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.
  • the patient may suffer from addiction to any addictive drug or substance.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • 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 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.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt and/or 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.
  • the therapeutically effective amount of the compound is from 0.1 mg to 3 mg per kg body weight per day.
  • the therapeutically effective amount of the compound is from 0.1 mg to 2 mg per kg body weight per day.
  • the therapeutically effective amount of the compound is from 0.1 mg to 1.5 mg per kg body weight per day.
  • 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.
  • 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.
  • 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. 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.
  • 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.
  • unit dose of noribogaine 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.
  • 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.
  • 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.
  • the method further comprises administering at least one agent known to treat or prevent migraines and/or symptoms thereof.
  • treatment with noribogaine and/or the agent does not result in a QT interval prolongation of more than about 50 ms.
  • 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.
  • the subject or patient may be any patient who exhibits migraine and/or symptoms thereof.
  • the patient is subject to recurrent migraines.
  • 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).
  • this invention relates to a method for treating migraine and/or symptoms thereof in a 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 treat said migraine and/or symptoms while maintaining a QT interval of less than about 500 ms during said treatment.
  • the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 420 ms during treatment.
  • 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.
  • 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.
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the therapeutically effective amount of the compound is from about 50 ng to about 10 ⁇ g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 ⁇ 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 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 ⁇ g per kilogram body weight per day.
  • the therapeutically effective amount of the compound is from about 1 ⁇ g 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 ⁇ g, about 6 ⁇ g, about 7 ⁇ g, about 8 ⁇ g, about 9 ⁇ g, 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.
  • 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.
  • 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 ⁇ g noribogaine per kg body weight per day would take 90 ⁇ g once a day, 45 ⁇ g twice a day, or 30 ⁇ g three times a day, etc.
  • 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).
  • noribogaine noribogaine derivative, or a
  • 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.
  • 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
  • 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.
  • 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.
  • 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, concurrently or substantially concurrently with) noribogaine or derivative.
  • the noribogaine is administered on an as-needed basis by the patient.
  • the noribogaine may be administered before the migraine and/or symptoms thereof occurs.
  • 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).
  • 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.
  • 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.
  • the prophylactically effective amount of the compound is from about 50 ng to less than 10 ⁇ g per kilogram body weight per day. In another embodiment, the prophylactically effective amount of the compound is from about 50 ng to about 5 ⁇ g per kilogram body weight per day. In another embodiment, the
  • prophylactically 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 prophylactically effective amount of the compound is from about 500 ng to less than 10 ⁇ g per kilogram body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is from about 1 ⁇ g to less than 10 ⁇ per kilogram body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges, including endpoints.
  • 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.
  • 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.
  • 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 ⁇ g noribogaine per kg body weight per day would take 90 ⁇ g once a day, 45 ⁇ g twice a day, or 30 ⁇ g three times a day, etc.
  • 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.
  • 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.
  • 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.”
  • 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 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.
  • 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.
  • the patient is treated for acute pain.
  • the patient is treated for chronic pain.
  • the patient is treated for nociceptive pain.
  • the patient is treated for neuropathic pain.
  • the pain is caused by surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, central pain syndrome, tissue damage, physical injury, and the like.
  • the source of the pain is unknown or unclear.
  • 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.
  • 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 100 ng/mL.
  • the ranges include both extremes as well as any subranges between.
  • 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.
  • 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.
  • the patient may be receiving any addictive opioid analgesic for the treatment of pain.
  • 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.
  • 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.
  • 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.
  • depressive disorders and PTSD are 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.
  • 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
  • HDRS Depression Rating Scale
  • CGI Clinical Global Impressions
  • 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.
  • 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.
  • 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.
  • the compounds utilized herein can be effective in treating PTSD in patients who have been diagnosed as having PTSD based upon the administration 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, IES, 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.
  • CAPS Clinician-Administered PTSD Scale Part 2
  • IES patient-rated Impact of Event Scale
  • the compounds described herein will be effective in inducing improvements in the scores of the CAPS, IES, 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.
  • 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.
  • 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.
  • 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.
  • the average noribogaine serum level provided by the dosage is less than about 50 ng/mL.
  • the therapeutically effective amount is between 0.5 mg to 4 mg per kg of body weight.
  • the therapeutically effective amount is between 50 ng to less than 100 ⁇ g per kg of body weight.
  • depression is treated.
  • posttraumatic stress disorder is treated.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
  • the composition is administered via sublingual, intranasal, or intrapulmonary delivery.
  • 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 50 ng to less than 100 ⁇ g per kg body weight per day.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 50 ⁇ g per kg body weight per day.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of 50 ng to 10 ⁇ 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 1 ⁇ g per kg body weight per day. In some aspects, the composition is administered once per day. In some aspects, the composition is
  • the composition is administered two or more times per day.
  • 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.
  • the composition is administered via oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial,
  • 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.
  • the dosage or aggregate dosage of compound is from 1 mg to 4 mg per kg body weight per day.
  • the dosage or aggregate dosage of compound is about 1 mg to 3 mg per kg body weight per day.
  • the dosage or aggregate dosage of compound is from 1 mg to 2 mg per kg body weight per day.
  • the dosage or aggregate dosage of compound is from 1.5 mg to 3 mg per kg body weight per day.
  • 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.
  • the dosage or aggregate dosage of compound is about 4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of 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.
  • 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.
  • 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.
  • 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
  • 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • anxiety disorders and impulse control disorders 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.
  • Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic 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.
  • 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.
  • 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.
  • YBOCS Yale Brown Obsessive Compulsive Scale
  • NIMH GOCS National Institute of Mental Health Global OCD Scale
  • CGI-Severity of Illness scale CGI-Severity of Illness scale. It is further contemplated
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • LSAS Liebowitz Social Anxiety Scale
  • HAM-A Hamilton Rating Scale for Anxiety
  • HAM-D Hamilton Rating Scale for Depression
  • ICD-10 World Health Organization Disability Assessment
  • DAS-2 World Health Organization Disability Assessment
  • 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.
  • LSAS Liebowitz Social Anxiety Scale
  • 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.
  • 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.
  • 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.
  • 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.
  • Impulse control disorders include pathological gambling (PG), kleptomania, trichotillomania (TTM), intermittent explosive disorder (IED), 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 internet addiction.
  • Symptoms of impulse control disorders include: repetitive participation in behavior despite adverse
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the compounds described herein will be effective in treating Munchausen 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 of one or more symptoms.
  • Munchausen syndrome also includes Munchausen syndrome by proxy, in which a caregiver exaggerates, fabricates, or induces illness in someone in his/her care.
  • This invention provides a method of treating Munchausen 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 Munchausen syndrome.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds utilized herein can be effective in regulating food intake and/or reducing food cravings in patients in need thereof.
  • the patient is overweight.
  • the patient is obese.
  • 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.
  • 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 180 ng/ml. In some embodiments, the average noribogaine serum level provided by the dosage is less than about 50 ng/mL.
  • 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 ⁇ g per kg of body weight.
  • 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.
  • food intake is regulated. In one embodiment, food cravings are attenuated.
  • the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof is administered by sublingual, intranasal, or intrapulmonary delivery.
  • the composition is administered via sublingual, intranasal, or intrapulmonary delivery.
  • 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 ⁇ g per kg body weight per day.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 50 ⁇ g per kg body weight per day.
  • the therapeutically effective amount of noribogaine is an amount that delivers an aggregate amount of noribogaine of about 50 ng to about 10 ⁇ 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 about 50 ng to about 1 ⁇ g 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
  • 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.
  • the composition is administered via oral, buccal, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery.
  • 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.
  • 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.
  • 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
  • noribogaine derivative, or salt or solvate thereof which is about 50 mg to about 200 mg per dose.
  • 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.
  • 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.
  • 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.
  • 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 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 cravings while maintaining a QT interval of less than about 500 ms during said treatment.
  • the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said cravings while maintaining a QT interval of less than about 420 ms during treatment.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • the 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.
  • 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 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.
  • 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.
  • 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.
  • the aggregate dose provides a therapeutic serum concentration of 80 ng/mL to 150 ng/mL.
  • the subdoses are administered every 15 minutes to 6 hours until the unit dose is achieved.
  • 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.
  • 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
  • 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
  • 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 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.
  • 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.
  • 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.
  • 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.
  • the first tapered dose is 50% to 95% of the initial or at least one additional dose.
  • the second tapered dose is 40% to 90% of the initial or at least one additional dose.
  • the third tapered dose is 30% to 85% of the initial or at least one additional dose.
  • the fourth tapered dose is 20%> to 80%> of the initial or at least one additional dose.
  • the fifth tapered dose is 10%> to 75% of the initial or at least one additional dose.
  • 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.
  • 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.
  • second, third, fourth, etc. tapered doses 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.
  • 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.
  • 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.
  • At least one additional dose is administered 4 hours to 24 hours after the initial unit dose. In some embodiments, the additional doses are
  • the 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.
  • the doses are administered at varying time points. That is, each dose need not be administered at the same interval as the previous dose.
  • 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.
  • 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).
  • the patient undergoes long-term (e.g., one year or longer) treatment with maintenance doses of noribogaine, noribogaine derivative, or salt or solvate thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the concentration is sufficient to attenuate said abuse or symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • 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.
  • 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.
  • patients may be selected based on any criteria as determined by the skilled clinician.
  • 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.
  • 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.
  • the methods can include selecting and/or administering/providing noribogaine to a patient that lacks one more of such criteria.
  • 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.
  • a patient at risk for prolongation of the QT interval beyond a safe level is not administered noribogaine.
  • a patient at risk for prolongation of the QT interval beyond a safe level is administered noribogaine at a limited dosage.
  • this invention relates to monitoring a patient who is administered a therapeutic dose of noribogaine.
  • the dose of noribogaine is reduced if the patient has serious adverse side effects.
  • the noribogaine treatment is discontinued if the patient has serious adverse side effects.
  • the adverse side effect is a QT interval that is prolonged beyond a safe level. The determination of a safe level of prolongation is within the skill of a qualified clinician.
  • 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.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 470 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 450 ms during treatment.
  • the concentration is sufficient to attenuate said symptoms while maintaining a QT interval of less than about 420 ms during treatment.
  • 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.
  • kits 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 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).
  • the kit of parts further comprises instructions for dosing and/or administration of the composition.
  • 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.
  • the dosing treatment schedule includes the amount of noribogaine required to achieve each average serum level is provided.
  • 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.
  • 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.
  • the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit.
  • 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
  • delivery vehicle 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.
  • readable medium 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).
  • a machine-readable medium includes read-only memory (ROM); random access memory (RAM); magnetic disk storage media; optical storage media; and flash memory devices.
  • the machine-readable medium is a CD-ROM.
  • the machine -readable medium is a USB drive.
  • the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode.
  • the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of noribogaine and optionally other drug information.
  • the software may be interactive, such that the attending clinician or other medical professional can enter patient
  • 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
  • the kit of parts comprises multiple delivery vehicles in a variety of dosing options.
  • 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.
  • all of the delivery vehicles within a kit are intended for one patient.
  • the delivery vehicles within a kit are intended for multiple patients.
  • kits of parts for the treatment, prevention, or attenuation of a disease or disorder or symptoms of a disease or disorder 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 60 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • kits 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.
  • 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
  • the initial dose is from 75 mg to 120 mg.
  • the at least one additional dose is from 5 mg to 25 mg.
  • 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.
  • unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form.
  • the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • noribogaine is provided in saline for intravenous administration.
  • 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 ⁇ g per kg body weight per day.
  • the unit dose of noribogaine is administered in one or more dosings.
  • This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or
  • the amount of noribogaine is sufficient to provide and/or maintain an average serum concentration of about 50 ng/mL to about 180 ng/mL when administered to a patient.
  • the amount of noribogaine is sufficient to provide and/or maintain an average serum concentration of 80 ng/mL to 100 ng/mL when administered to a patient.
  • the unit dose of noribogaine is administered in one or more dosings.
  • 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 180 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 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.
  • 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 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 about 80 ng/mL to about 100 ng/mL. The ranges include both extremes as well as any subranges between.
  • the initial unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 50 mg to about 120 mg.
  • the unit dose is about 50 mg.
  • the unit dose is about 55 mg.
  • the unit dose is 60 mg.
  • the unit dose is about 65 mg.
  • the unit dose is about 70 mg.
  • the unit dose is about 75 mg.
  • the unit dose is about 80 mg.
  • the unit dose is about 85 mg.
  • the unit dose is about 90 mg.
  • the unit dose is about 95 mg.
  • the unit dose is about 100 mg. In one embodiment, the unit dose is 105 mg. In one
  • 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.
  • the at least one additional dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from 5 mg to 75 mg.
  • the unit dose is 5 mg.
  • the unit dose is 10 mg.
  • the unit dose is 15 mg.
  • the unit dose is 20 mg.
  • the unit dose is 25 mg.
  • the unit dose is 30 mg.
  • the unit dose is 35 mg.
  • the unit dose is 40 mg.
  • the unit dose is 45 mg.
  • the unit dose is 50 mg.
  • the unit dose is 55 mg.
  • the unit dose is 60 mg.
  • the unit dose is 65 mg.
  • the unit dose is 70 mg.
  • the unit dose is 75 mg.
  • the formulation comprises a delivery vehicle, as described above.
  • the delivery vehicle comprises 5 mg to 120 mg noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.
  • the formulation is a controlled release formulation.
  • 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.
  • 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.
  • 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 about 80 ng/mL to about 100 ng/mL.
  • the ranges include both extremes as well as any subranges between.
  • 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.
  • 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 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/mL when administered to a patient.
  • 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.
  • 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.
  • 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 60 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.
  • 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.
  • 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.
  • 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).
  • the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form.
  • the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • 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 nonaqueous 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.
  • compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal 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.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • 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.
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine.
  • 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.
  • compositions utilized herein may be formulated for sublingual
  • 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.
  • compositions for oral use may be formulated to utilize taste -masking technologies.
  • taste -masking technologies include 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.
  • Example 1 Pharmacokinetics and pharmacodynamics of noribogaine in humans
  • 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 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-200 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.
  • 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 ⁇ 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 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.
  • 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 ⁇ 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 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%.
  • 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.
  • B.P. water 5:95, v/v) containing 0.1% (v/v) formic acid.
  • the compounds were separated by a l50 x 2.0 mm Luna 5 ⁇ 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.
  • Analyst ® 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.
  • 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 dilution of the sample with 0.1% (v/v) formic acid.
  • the compounds were separated by a 150 x 2.0 mm Luna 5 ⁇ 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 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%.
  • 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 concentration used for Ctf was the last determined value above the LLOQ at the time point.
  • the total AUCo_ ⁇ was obtained by adding AUC tf and AUC t - ⁇ .
  • Total urine noribogaine was the sum of both analytes.
  • 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 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).
  • 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 C max 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.
  • 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 Cmax of 14.5 ng/ml was observed 2.9 hours after administration, while the mean AUC/24 hr of 10.6 ng/ml was obtained.
  • 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 Cmax 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.

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US201461941387P 2014-02-18 2014-02-18
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PCT/US2014/019692 WO2015126434A1 (fr) 2014-02-18 2014-02-28 Méthodes de traitement aigu et à long terme de la toxicomanie
US14/195,822 US9345711B2 (en) 2014-02-18 2014-03-03 Methods for acute and long-term treatment of drug addiction
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US9561232B2 (en) 2014-02-18 2017-02-07 Demerx, Inc. Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use
US9591978B2 (en) 2014-03-13 2017-03-14 Demerx, Inc. Methods and compositions for pre-screening patients for treatment with noribogaine
US9549935B2 (en) 2014-07-14 2017-01-24 Demerx, Inc. Methods and compositions for treating migraines using noribogaine
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US7220737B1 (en) * 1997-09-04 2007-05-22 Novoneuron, Inc Noribogaine in the treatment of pain and drug addiction
US20030153552A1 (en) * 2002-02-14 2003-08-14 Mash Deborah C. Method of treating chemical dependency in mammals and a composition therefor
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