WO2023114529A2

WO2023114529A2 - Pharmacoactive formulations for delivery of psychedelic compounds

Info

Publication number: WO2023114529A2
Application number: PCT/US2022/053291
Authority: WO
Inventors: Jerry B. Gin; Benjamin F. Ross
Original assignee: Bennes, Inc.
Priority date: 2021-12-17
Filing date: 2022-12-17
Publication date: 2023-06-22
Also published as: WO2023114529A3

Abstract

Lozenges comprising ethyl cellulose and psychedelic compound s for rapid and efficient delivery of medical psychedelic compound s are provided. The lozenge is suitable for administration of the psychedelic compound (s) through the oral mucosa to the bloodstream. Embodiments of the lozenge are disclosed that comprise additives which alleviate other issues related to administration of psychedelic compounds. Additives disclosed include essential oils for flavoring, permeation enhancers, and high-intensity sweeteners. Methods for manufacture of the lozenges and its use in treatment of disease conditions are provided.

Description

PHARMACOACTIVE FORMULATIONS FOR DELIVERY OF PSYCHEDELIC COMPOUNDS

INVENTORS:

Benjamin F. ROSS and Jerry B. GIN

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63/291,333 titled "PHARMACOACTIVE FORMULATIONS FOR DELIVERY OF PSYCHEDELIC COMPOUNDS," the contents of which are incorporated herein in their entirety by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to pharmacological psychedelic formulations, and more particularly, to lozenges and formulations for controlled delivery of psychedelic compounds or combinations thereof into the bloodstream for alleviation or treatment of a clinical condition.

BACKGROUND OF THE INVENTION

[0003] Hallucinogens derived from plants have been used in religious practices for centuries in places like Mexico, Greece and Brazil. (J.G. Bruhn, P.A. De Smet, H.R. ELSeedi, O. Beck Mescaline use for 5700 years Lancet, 359 (2002), p. 1866). In 1938, the Swiss chemist Albert Hofmann synthesized the first synthetic hallucinogen, lysergic acid diethylamide (LSD). In 1947, Sandoz began to market LSD under the trade name DELYSID® as an adjunctive psychotherapy medication. In 1960, Harvard psychologist Timothy Leary began experiments under the Harvard Psilocybin Project to determine whether psilocybin was an effective adjuvant agent in psychotherapy. Clinical experimentation and research with psychedelics were ultimately halted by the Controlled Substances Act of the Comprehensive Drug Abuse Prevention and Control Act of 1970 and the UN Convention on Drugs (1967). The U.S. Drug Enforcement Administration (DEA) currently classifies most psychedelic compounds as Schedule I substances, reflecting a lack of any accepted medical use or safety data and their potential for abuse. (Rucker JJH et al., Neuropharmacology Volume 142, November 2018, Pages 200-218). [0004] On March 5, 2019, esketamine nasal spray (SPRAVATO®) became the first Food and Drug Administration (FDA) approved psychedelic treatment for a psychiatric disorder with intranasal esketamine. (Food and Drug Administration. News Release. https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray- medication-treatment-resistant-depression-available-only-certified [published online March 5, 2019]). In August 2020, the FDA extended its approval for esketamine to adults with major depressive disorder with acute suicidal ideation or behavior.

[0005] Recently, well-designed clinical trials have established the efficacy of psychedelic drugs for use in the treatment of mood and anxiety disorders, trauma- and stress-related disorders, and substance use disorders as well as for end-of-life care. Psychedelic (mindmanifesting) drugs such as d-lysergic acid diethylamide (LSD) and psilocybin have had a resurgence in popular culture. Carhart-Harris has proposed a unified model of the brain mechanisms of psychedelics termed relaxed beliefs under psychedelics (REBUS) and the anarchic brain or “REBUS” for short. The model takes inspiration from two formulations of brain function, namely: 1) the free-energy principle (Friston K, et al., (2007) A free-energy principle for the brain. J. Physiol. Paris 100(1— 3):70— 87) and 2) the entropic brain hypothesis. (Carhart-Harris et al., 2010, Brain 133:1265-1283).

[0006] Therapeutic benefits of psychedelic compounds, such as lysergic acid diethylamide (LSD), ayahuasca, mescalin, psilocybin, and 3,4-methylenedioxymethamphetamine (MDMA), are being actively researched in humans. Long-term beneficial effects on optimism, well-being, openness, obsessive-compulsive disorder (OCD), tobacco addiction, alcoholism, narcotic addiction, depression and anxiety related to the diagnosis of a lifethreatening and terminal illness have been observed in controlled studies.

[0007] Studies from California (USA) have been published on the use of psychedelics in end- of-life anxiety associated with life-threatening illness (Grob et al., Arch. Gen. Psychiatr., 68 (2011), pp. 71-78). Subjects with advanced cancer diagnoses and DSM-IV-defined acute stress disorder, generalized anxiety disorder, or adjustment disorder with anxiety because of the cancer diagnosis, were administered a moderate (0.2 mg/kg) dose of psilocybin versus an active placebo (niacin 250 mg) several weeks apart. (Grob et al., 2011). Significant trends toward improvements in mood were observed.

[0008] Swiss studies on patients with anxiety associated with a life-threatening disease and treated with 20-200 pg LSD showed significant reductions in the state without long-term side effects that were sustained for up to 12 months. (Gasser et al., J. Psychopharmacol., 29 (2015), pp. 57-68).

[0009] Patients administered doses of 0.3 mg/kg psilocybin or 250 mg niacin measured by State Trait Anxiety Inventory and the Beck Depression Inventory as primary outcome measures showed ‘immediate, substantial, and sustained’ clinical benefits that lasted 7-26 weeks. (Ross et al., J. Psychopharmacol., 30 (2016), pp. 1165-1180)

[0010] Psychedelic agents have been administered to a susceptible subject to alleviate or treat stress, anxiety, addiction, depression, compulsive behavior, weight loss, mood and psychological disorders or as performance enhancers. Methods for treating patients with sub- therapeutic or sub-optimal doses of psychedelic compounds, insufficient to produce wholebody effects but high enough to allow a cellular response to be observed, have been disclosed by Russ et al. in US Patent Application Pub. No. 20200147038 (2020).

[0011] Administration of given 2.2 ml/kg of a standardized preparation of ayahuasca containing 0.8 mg/ml DMT and 0.21 mg/ml of harmine showed alleviation of depressive symptoms according to the Hamilton Depression Rating Scale (HAMD) and the Montgomery Asperg Depression Rating Scale (MADRAS). (Sanches et al., J. Clin. Psychopharmacol., 36 (2016), pp. 77-81).

[0012] Administration of psilocybin at 0.3 mg/kg or 0.4 mg/kg has shown beneficial effects on alcoholism among heavy drinkers. (Bogenschutz et al., J. Psychopharmacol., 29 (2015), pp. 289-299).

[0013] Four different doses (25, 100, 200, 300 mcg/kg body weight) of psilocybin each significantly reduced treatment-resistant obsessive-compulsive disorder as measured by the Yale Brown Obsessive Compulsive Scale and the Hallucinogen Rating Scale. (Moreno et al., J. Clin. Psychiatr., 67 (2006), pp. 1735-1740).

[0014] Psychedelic treatments may offer treatment benefits beyond their direct neurobiological effects. The psychedelic experience itself may allow providers an opportunity to work through therapeutical issues with patients, which is the case for psilocybin, the active ingredient of “magic mushrooms” and a 5 -hydroxy tryptamine 2A receptor agonist. (Nutt DJ, Erritzoe D, Carhart-Harris RL. Psychedelic psychiatry’s brave new world [published online April 2, 2020]. Cell. doi.org/10.1016/j.cell.2020.03.020.)

[0015] However, most studies on psychedelic agents are underpowered due to the concern (and stigma) of off-label use for their psychedelic effects, which may arise from a combination of several interrelated activities. FDA-approved psychedelic compound like SPRAVATO® (esketamine) is classified as a Schedule III substance and must be taken under supervision due to the risk of serious adverse outcomes related to dissociation and sedation. In addition, patients must take an oral antidepressant alongside esketamine and enroll in concurrent therapy sessions. The concern is that esketamine may carry a risk of abuse related to its “opioid properties”.

[0016] There is a need for more efficient, sustained and safer delivery of psychedelic compounds for medical methods that are useful to treat various medical and psychological conditions. The strategy of ‘microdosing’ psychedelics has been discussed for facilitating their positive effect on mood state and cognitive processes such as concentration. It would be desirable if the concentration of the drug being delivered could be lowered while achieving an equivalent local or systemic physiologic effect. Further, it is desirable if the activity or effective delivery of the drug could be enhanced without the need to raise the dosage or drug concentration by altering the pharmacokinetics of drug delivery in order to maximize therapeutic effects and minimize cognitive and subjective drug effects.

[0017] It is postulated that techniques like microdosing, or isolating non-hallucinogenic components of psychedelics such as cannabis-derived cannabidiol (CBD), may help provide unique psychopharmacologic benefits without the risks of getting high. (Kuypers et al., J Psychopharmacol. 2019; 33:1039-1057). Although microdosing became prominent due to the belief it improved cognition, a growing number of cases showed microdose psychedelics improve conditions of pain, cluster headaches or migraine. It seems that the efficacy of microdosing may derive from its non-psychedelic dose range, which provides treatment without affecting cognition. Individuals also reported relief of pain with a long-term psychedelic microdosing regimen. (Johnstad, 2018, Nord Stud Alcohol Dr 35: 39-51.) Thus, psychedelic microdosing might constitute a different paradigm to single psychedelic therapeutic sessions with macrodoses where the nature and content of the experience play a key role in predicting therapeutic outcome (Schenberg, 2018, Front Pharmacol 9: 733.)

[0018] There is a need in the art to devise a way to administer psychedelic compounds to provide a more favorable and pharmacokinetic profile.

SUMMARY OF THE INVENTION

[0019] The invention provides psychedelic lozenges comprising a psychedelic compound embedded in a matrix such as ethyl cellulose. [0020] In some embodiments, the psychedelic compound is selected from 3,4,5- trimethoxyamphetamine (TMA), 5-methoxy-N,N-dimethyltryptamine (5-methoxy-3-[2- (dimethylamino)ethyl]indole; 5-MeO-DMT), Alpha-methyltryptamine (aMT), Bufotenine, Diethyltryptamine (DET), Dimethyltryptamine (DMT), 5-methoxy-N,N- diisopropyltryptamine (5-MeO-DIPT), its isomers, salts and salts of isomers, Ibogaine, Lysergic acid diethylamide (LSD), Marijuana, including cannabis resin, Marijuana extracts; cannabinoids [17], Mescaline, Parahexyl, Peyote, N-ethyL 3 -piperidyl benzilate, N-methyl-

3-piperidyl benzilate, Psilocybin, Psilocin, Tetrahydrocannabinol (THC), Ethylamine analog of phencyclidine (Eticyclidine; PCE), Pyrrolidine analog of phencyclidine (PCPy), Thiophene analog of phencyclidine (TCP), l-[l-(2-thienyl)cyclohexyl]pyrrolidine (TCPy),

4-methylmethcathinone (Mephedrone), 3,4-methylenedioxypyrovalerone (MDPV), 2-(2,5- Dimethoxy-4-ethylphenyl)ethanamine (2C-E), 2-(2,5-Dimethoxy-4- methylphenyl)ethanamine (2C-D), 2-(4-Chloro-2,5-dimethoxyphenyl)ethanamine (2C-C), 2-(4-Iodo-2,5-dimethoxyphenyl)ethanamine (2C-I), 2-[4-(Ethylthio)-2,5- dimethoxyphenyl]ethanamine (2C-T-2), 2-[4-(Isopropylthio)-2,5- dimethoxyphenyl]ethanamine (2C-T-4), 2-(2,5-Dimethoxyphenyl)ethanamine (2C-H), 2- (2,5-Dimethoxy-4-nitro-phenyl)ethanamine (2C-N), 2-(2,5-Dimethoxy-4-(n)- propylphenyl)ethanamine (2C-P), 3,4-Methylenedioxy-N-methylcathinone (methylone), 2- (4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (251-NBOMe; 2C-I- NBOMe; 251; Cimbi-5), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2- methoxybenzyl)ethanamine (25C-NBOMe; 2C-C-NBOMe; 25C; Cimbi-82), 2-(4-bromo- 2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe; 2C-B-NBOMe; 25B; Cimbi-36) or a combination thereof.

[0021] In some embodiments, the psychedelic compound is a 5-HT2A agonist selected from LSD, psilocybin, DOI (±)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride; (R)-DOI ((R)-l-(2,5-dimethoxy-4-iodophenyI)-2-aminopropane); LA-SS-Az (2'S,4'S)-(+)-9, 10- Didehydro-6-methylergoline-8B-(trans-2,4-dimethyl-azetidide); 2C-BCB (4-Bromo-3,6- dimethoxybenzocyclobuten-l-yl) methylamine); ayahuasca; 3,4,5-trimethoxyphenethylamine (mescaline); 5-methoxy-N,N-dimethyltryptamine (5-meo-DMT) and ibogaine, and combinations thereof.

[0022] In some embodiments, the psychedelic compound is a dissociative agent selected from ketamine, esketamine, PCP, dextromethorphan (DXM) and combinations thereof. [0023] In some embodiments, the psychedelic compound is a an empathogenic agent selected from 3,4-Methylenedioxymethamphetamine (MDMA), MDEA, MDA, and combinations thereof.

[0024] In some embodiments, the psychedelic compound comprises a psychedelic agent selected from lysergic acid diethylamide, psilocybin, and pharmaceutically acceptable salts thereof. In some embodiments, the psychedelic agent is selected from a 5-HT2A agonist (e.g., LSD, psilocybin, DOI (±)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride; (R)-DOI ((R)-l-(2,5-dimethoxy-4-iodophenyI)-2-aminopropane); LA-SS-Az (2'S,4'S)-(+)-9,10- Didehydro-6-methylergoline-8B-(trans-2,4-dimethyl-azetidide); 2C-BCB (4-Bromo-3,6- dimethoxybenzocyclobuten-l-yl) methylamine); ayahuasca; 3,4,5-trimethoxyphenethylamine (mescaline); 5-methoxy-N,N-dimethyltryptamine (5-meo-DMT) and ibogaine.

[0025] In some embodiments, the psychedelic lozenges are formulated using ethyl cellulose as the matrix and essential oils (such as peppermint oil) plus sucralose (or other sweeteners such as Stevia®).

[0026] In some embodiments, the psychedelic lozenges last 0.5 to 1.5 hours in the mouth. Pharmaceutical efficacy is noticed within 5, 10, 15, or 20 minutes compared to oral intake which requires 2 hours or more.

[0027] In some embodiments, the psychedelic lozenges are retained for an extended period in the mouth allowing for systemic adsorption through the mucosa into the bloodstream, while observing a clinical effect within about 10 minutes. In particular embodiments, about 50% of the lozenge is retained after about 30 minutes.

[0028] In some embodiments permeation enhancers such as MSM are incorporated in the lozenges for even more efficient absorption through the oral mucosa into blood stream.

[0029] The present invention includes a variety of other useful aspects, which are detailed herein. These aspects of the invention can be achieved by using the articles of manufacture and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the invention. In addition, a variety of other aspects and embodiments of the present invention are described herein.

[0030] The summary of the invention described above is not limiting and other features and advantages of the invention will be apparent from the following detailed description, as well as from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0032] FIG. 1 shows release in vivo of ketamine with sustained release lozenge of the present invention as determined by immunoassay. Results over time are shown in the curve in Fig. 1.

[0033] FIG. 2 shows kinetics of dissolution of ketamine from sustained-release lozenges into water over time.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where such term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0035] The specific embodiments describing the ranges and values provided below are for illustration purposes only, and do not otherwise limit the scope of the disclosed subject matter, as defined by the claims.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.

[0037] Studies with psilocybin, ayahuasca, MDMA and LSD in healthy volunteers have shown long-term increases in trait optimism (Carhart- Harris et al., Psychological Medicine 2016, 46:1379-1390), well-being (Carhart-Harris and Nutt, J. Psychoact. Drugs, 45 (2013), pp. 322-328; Griffiths et al., Psychopharmacology 2011, 218:649-665), and openness (Carhart-Harris et al., Psychological Medicine 2016, 46:1379-1390; MacLean et al., Journal of Psychopharmacology 2011, 25:1453-1461), and studies in patients have found long-term improvements in obsessive compulsive disorder (Moreno et al., Journal of Clinical Psychiatry 2006, 67:1735-1740), tobacco addiction (Garcia-Romeu et al., Current Drug Abuse Reviews 2014, 7:157-164), alcoholism (Krebs and Johansen, Psychopharmacology 2012, 26.7:994- 1002; Bogenschutz et al., Journal of Psychopharmacology 2015, 29.3:289-299), narcotic addiction (Savage and McCabe, Psychiatry 1973, 28.6:808-814), depression and anxiety related to diagnosis of a life-threatening or terminal illness (Grob et al., Archives of General Psychiatry 2011, 68:71-78; Griffiths et al., Journal of Psychopharmacology 2016, 30(12): 1181-1197; Ross et al., Journal of Psychopharmacology 2016, 30(12): 1165-1180), and depression (Carhart-Harris et al., The Lancet Psychiatry 2016; Sanches et al., Journal of Clinical Psychopharmacology 2016, 36:77-81) after treatment with psychedelics.

[0038] Psychedelics can be divided into four classes based on their pharmacological profiles and chemical structures: classic psychedelics (serotonin 2A [5-HT2A] receptor agonists), empathogens or entactogens (mixed serotonin and dopamine reuptake inhibitors and releasers), dissociative anesthetic agents (N-methyl-D-aspartate [NMDA] antagonists), and atypical hallucinogens, which affect multiple neurotransmitter systems. (Garcia-Romeu A, Kersgaard B, Addy PH: Clinical applications of hallucinogens: a review. Exp Clin Psychopharmacol 2016; 24:229-268)

[0039] In various embodiments throughout this disclosure, the term psychedelic compounds include but a not limited to: psychedelic agent (a 5-HT2A agonist such as lysergic acid diethylamide, psilocybin, etc.), a dissociative agent (ketamine, etc.), or an empathogenic agent (3,4-Methylenedioxymethamphetamine (MDMA), etc.)

[0040] In some embodiments, the psychedelic compound comprises a psychedelic agent selected from lysergic acid diethylamide, psilocybin, and pharmaceutically acceptable salts thereof. In some embodiments, the psychedelic agent is selected from a 5-HT2A agonist (e.g., LSD, psilocybin, DOI (±)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride; (R)-DOI ((R)-l-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane); LA-SS-Az (2'S,4'S)-(+)-9,10- Didehydro-6-methylergoline-8B-(trans-2,4-dimethyl-azetidide); 2C-BCB (4-Bromo-3,6- dimethoxybenzocyclobuten-l-yl) methylamine); ayahuasca; 3,4,5-trimethoxyphenethylamine (mescaline); 5-methoxy-N,N-dimethyltryptamine (5-meo-DMT) and ibogaine. [0041] In some embodiments, the psychedelic compound is selected from 3,4,5- trimethoxyamphetamine (TMA), 5-methoxy-N,N-dimethyltryptamine (5-methoxy-3-[2- (dimethylamino)ethyl]indole; 5-MeO-DMT), Alpha-methyltryptamine (aMT), Bufotenine, Diethyltryptamine (DET), Dimethyltryptamine (DMT), 5-methoxy-N,N- diisopropyltryptamine (5-MeO-DIPT), its isomers, salts and salts of isomers, Ibogaine, Lysergic acid diethylamide (LSD), Marijuana, including cannabis resin, Marijuana extracts; cannabinoids [17], Mescaline, Parahexyl, Peyote, N-ethyL 3 -piperidyl benzilate, N-methyl-

[0042] A psychedelic lozenge formulation may comprise physiologically active and psychoactive alkaloids and amines including but not limited to psychedelic agents such as a compound selected from acetorphine, acetylmethadol, allylprodine, alphacetylmethadol, bufotenine, dextromoramide, diethyltryptamine, etorphine, heroin, ibogaine, ketobemidone, lysergic acid diethylamide, mescaline, methaqualone, 3, 4-methylenedioxy amphetamine, 3,4- methylenedioxymethamphetamine, N-ethyL 1 -phenylcyclohexylamine, peyote, 1-(1- phenylcyclohexyl)pyrrolidine, psilocybin, psilocin, l-{l-(2-thienyl)-cyclohexyl}-piperidine, alphaprodine, anileridine, cocaine, dextropropoxyphene, diphenoxylate, ethylmorphine, glutethimide, hydrocodone, hydromorphone, levo-alphaacetylmethadol, levorphanol, meperidine, methadone, morphine, opium, oxycodone, oxymorphone, poppy straw, thebaine, amphetamine, methamphetamine, methylphenidate, phencyclidine, codeine, benzphetamine, ketamine, alprazolam, chlorodiazepoxide, clorazepate, diethylpropion, fenfluramine, flurazepam, halazepam, lorazepam, mazindol, mebutamate, midazolam, oxazepam, pemoline, pentazocine, phentermine, prazepam, quazepam, temazepam, triazolam, zolpidem, and buprenorphine, or a combination thereof.

[0043] A dosage of the psychedelic compound is administered to the subject, such that the dosage is insufficient to produce whole-body effects but is high enough to allow a clinical response.

[0044] Microdosing psychedelics has been described as a practice to use sub-threshold doses of psychedelic drugs in an attempt to enhance cognitive tasks, boost physical energy levels, promote emotional balance, and treat anxiety, depression and addiction, resulting in typically subtle though noticeable effects The term microdosing is not a uniquely psychedelic term. In pharmacology, microdosing is a process used in drug development and drug selection (Lappin et al., 2006, Clin. Pharmacol. Ther. 80: 203-215.) where a minute dose of a substance is used to assess the pharmacokinetics of a drug. A microdose, in this regulatory arena, has been defined by a position paper from the European Medicines Agency 2004, guidelines from the U.S. Food and Drug Administration in 2006, and the Ministry of Health, Labour and Welfare in Japan in 2008, and the current definitive international guideline being a dose of a drug that is 1% of the pharmacologically active dose, up to a maximum of 100 pg. Thus, psychedelic microdosing "5-10 pg of LSD" would be 5-10% of a usual psychoactive dose and lie somewhere between a full pharmacological dose (100%) and a ‘pharmacological microdose’ .

[0045] Existing oral dosing categories for psychedelics (such as psilocin, ibogaine, DMT) when used in research are very low dose (<lmg/kg), low dose (3-40mg/kg), medium dose (8- lOmg/kg), and high dose (>20mg/kg).

[0046] However, the quantity and quality of the source material may cause variations in the dosages of the psychedelic agent. The most widely distributed species of psychedelic mushrooms are Psilocybe cubensis and those of the genus Copelandia. The psilocin (the active metabolite of psilocybin) and psilocybin content in the whole body of these mushrooms when dried was estimated to be in the range of 0.14-0.42% (psilocin) and 0.37- 1.30% (psilocybin) for P. cubensis and 0.43-0.76% (psilocin) and 0.08-0.22% (psilocybin) for Copelandia, respectively. Thus, the former is more psilocybin-rich than the latter, and the latter contains more psilocin compared to the former. Psilocybe semilanceata is the most common British species. This mushroom only contains psilocybin, in the range from 0.17 to 1.96%, A hallucinogenic dose of dried P. cubensis, for example, is between 3 and 5 g. These values equate to a recreational dosing range of 8.6 to 14.7 mg of psilocin per dose. Thus, a microdose would range from 0.43 to 0.73 mg of psilocin per dose because a microdose of psilocybin is generally one-tenth of a full dose. That positions a recreational dose of psilocin between a low and medium dose and a microdose below a very low dose. However, variations in psilocin content between doses of dried mushroom may be seen due to variations between individual fungi within a species.

[0047] Intensity, somaesthesia, affect, perception, cognition and volition measured on the Hallucinogen Rating Scale all increased after administration of a 5 mg/70 kg dose of psilocybin. (Griffiths et al., 2011, Psychopharmacology 218: 649-665.) However, repeated administration of even lower doses (<0.05 mg/kg) showed an antidepressant-like effect with minimal hallucinogenic effects in laboratory rats.

[0048] Recent studies have shown limited duration of clinical effects and increased incidence of side effects at the more effective doses of a psychedelic compound. In one Phase 2 doubleblind trial, psilocybin — a psychoactive compound found in magic mushrooms — was found to effectively treat depression when combined with psychotherapy. After one 25-milligram dose of Comp360® psilocybin, alongside psychotherapy, one in three participants no longer met the diagnostic criteria for depression at three weeks, and one in five sustained that improvement through week 12. However, while both 10 milligrams and 25 milligrams produced psychoactive effects, only the 25-milligram dose produced significant antidepressant effects compared to the baseline one-milligram dose. However, with a large single dose, some participants in the study experienced increased suicidal ideation or suicidality from baseline to week three of the study. In the clinically effective 25-milligram group, 14 percent experienced a worsening suicidal state. (Goodwin GM et al., N. Engl. J. Med. 2022; 387:1637-1648).

[0049] In another aspect of the invention, once the desired anti-depressive effect has been achieved with psychedelic-assisted therapy the patient could continue therapy with an acceptable level of the psychedelic agent, without additional unacceptable side effects through the use of a controlled release lozenge. This can be done through self-medication, by managing delivery rate or residence time (how long they keep the delivery system in the mouth). [0050] Psychedelic formulation of the instant invention are useful for treating at least one symptom selected from symptom selected from obsessive compulsive disorder (OCD), pain, chronic pain, anxiety disproportionate to severity of physical complaints, psychological disorder, major depression, melancholic depression, atypical depression, dysthymia, pain disorder, body dysmorphia, conversion, hysteria, neurological conditions without identifiable cause, psychosomatic illness, pain management in relation to existing physical condition, irritability, fibromyalgia, post-traumatic stress disorder (PTSD), cluster headaches, paranoia, psychosis, anxiety, panic attacks, flashbacks, smoking addiction, alcohol addiction, cocaine addiction, improving creativity, boosting physical energy level, attaining emotional balance, increasing performance on problem- solving tasks, treating anxiety, treating depression, treating addiction, or any combination thereof.

[0051] In specific embodiments, the psychedelic compound is selected from the group consisting of psilocybin, psilocin, baeocystin, mescaline, LSD, ketamine, salvinorin A, ibotenic acid ((S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid), muscimol, DMT, MDMA, MDEA, MDA, and combinations thereof.

[0052] The psychedelic compound can be at least one of psilocybin, psilocin and baeocystin. The psychedelic compound can be obtained from the genera Copelandia, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, or Psilocybe, or from a purified extract therefrom. The psychedelic compound may comprise an extract from mushrooms.

[0053] In some instances, the therapeutic dose of the psychedelic agent is lower than the amount required for hallucinogenic effect. These can lead to abuses. DXM, which is safe and effective as a cough suppressant and expectorant when used at recommended doses (typically 15 to 30 milligrams), can lead to serious side effects when abused. For example, use of DXM at doses from 200 to 1,500 milligrams can produce dissociative effects similar to PCP and ketamine and increase the risk of serious central nervous system and cardiovascular effects such as respiratory distress, seizures, and increased heart rate from the antihistamines found in cough medicines.

Ketamine

[0054] Ketamine is a non-barbiturate, rapid-acting, induction and general anesthetic agent that acts primarily via N-methyl-D-aspartate (NMDA) receptor antagonism in the CNS. The drug has been available in the United States since 1970 under the tradename KETALAR®. Pharmaceutical compositions of ketamine and esketamine have been administered to healthy subjects and patients via a variety of routes of administration including intravenously, intranasally and orally. The relative bioavailability of oral ketamine as being 17% and of intramuscular ketamine as being 93%.

[0055] Ketamine is a US Schedule III compound and is usually administered intravenously (IV). However, oral administration is an easier and less expensive method. Clinical trials for assessing treatment-resistant major depression use ketamine at 0.5mg/kg IV. Since only 20- 25% orally administered reaches systemic circulation the psychedelic lozenge dosage form is designed to administer about 2-2.5 mg/kg.

[0056] The present invention is directed to methods of treating a major depressive disorder in a human patient in need thereof, by administering an effective amount of a psychedelic compound in a lozenge dosage form over an induction regimen of one or more days, and orally administering to said patient an oral psychedelic sustained-release lozenge form according to the invention comprising between about 1 mg to about 50 mg of esketamine over a treatment regimen of one or more days. Figure 1 illustrates the release profile of ketamine from a psychedelic lozenge comprising ketamine. Figure 2 illustrates that nearly 20% of the ketamine can be released from a sustained-release lozenge within the initial 10 minutes.

[0057] As used herein, the term "major depressive disorder," or MDD, is characterized as a psychiatric disorder meeting five criteria: 1) the presence during the same 2 week period which together represent a change from previous functioning, of a depressed/sad mood or a loss of interest and pleasure, together with five (or more) of the following additional criteria occurring nearly every day i) depressed/sad mood ii) loss of interest and pleasure iii) significant weight loss when not dieting or weight gain or a decrease or increase in appetite iv) insomnia or hypersomnia v) psychomotor agitation or retardation vi) fatigue or loss of energy vii) feelings of worthlessness or excessive or inappropriate guilt viii) diminished ability to think or concentrate or indecisiveness ix) recurrent thoughts of death or suicidal ideation, planning or attempt: 2) the symptoms cause clinically significant distress or impairment in social, occupational or other functioning: 3) the episode is not better accounted for by a psychotic disorder: 4) the episode is not attributable to the physiological effects of a substance or to another medical condition: 5) there has never been a manic or hypomanic episode (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, American Psychiatric Association, 2013). Other indications contemplated include treating, preventing, or ameliorating one or more symptoms of a disorder including, but not limited to, Rett syndrome, depression, refractory depression, suicidality, obsessive-compulsive disorder, fibromyalgia, post-traumatic stress syndrome, autism spectrum disorder, and depression associated with genetic disorders.

[0058] In some embodiments, the major depressive disorder is with anxious distress. In another embodiment, the disorder is with mixed features. The features are selected from melancholic features, mood-congruent psychotic features, mood-incongruent psychotic features, catatonia, peripartum onset, or related atypical patterns.

[0059] In some embodiments, the major depressive disorder has not responded to adequate doses and treatment duration of antidepressants other than ketamine or esketamine. In some aspects, the non-responder has failed to demonstrate an improvement of up to 25% in MADRS score, or a similar psychometric score, after adequate doses and treatment duration of antidepressants other than ketamine or esketamine.

MDMA

[0060] 3,4-methylenedioxymethamphetamine (MDMA) is a US Schedule I drug. It is in the empathogen-class of psychoactive drugs which induces serotonin release and has been shown to enhance fear memory extinction, modulate fear memory reconsolidation, and bolster social behavior in animal models.. It is usually administered per os (PO). In a 3 arm clinical trial for chronic PTSD was evaluated at 30mg, active placebo, 80mg and 120 mg followed by half doses administered 1.5-2.0 hours later. Compared with manualized therapy with inactive placebo, MDMA-assisted therapy was found to be highly efficacious in individuals with severe PTSD as determined 2 months after baseline. (Mitchell, JM et al. , Nature Medicine volume 27, pp. 1025-1033 (2021)).

Psilocybin

[0061] Psilocybin is a naturally occurring prodrug that also is being produced synthetically. It is usually administered per os (PO). Clinical trial for major depressive disorder evaluated at 25 mg psilocybin with Niacin at 100 mg as a placebo.

[0062] The invention provides psychedelic compound dosage forms for the release of a psychedelic compound in the mouth. Delivery to a mucosal surface within the oral cavity may be used within the context of systemic drug administration, in which case the beneficial agent is actually delivered transmucosally, e.g., through the buccal mucosa of the gums. In one embodiment, the dosage form is a psychedelic lozenge that comprises a sustained release wet matrix of a biocompatible, water-insoluble polymer, e.g., elhylcellulose, and a psychedelic compound. In this embodiment, the dosage form is composed of a wet matrix formulated so as to have a surface that is sufficiently tacky to enable the dosage form to adhere to the teeth or a mucosal surface within the mouth. This may be accomplished by using a relatively low molecular weight biocompatible polymer, as discussed infra, and/or by incorporating one or more adhesive polymers that are conventionally used in buccal drug delivery systems, e.g., polyisobutylene, polyisoprene, acrylic acid polymers and copolymers (e.g., those known as "carbomers," polyalkylene oxides (e.g., polyethylene glycol and copolymers thereof), polyvinyl lactams (e.g., polyvinyl pyrrolidone), and cellulosic materials (e.g., hydroxypropylmethylcellulose). Preferably, the dosage form is made adhesive by using a lower molecular weight hydrophilic polymer rather than by incorporation of additional polymers not contained within the wet matrix. When the dosage forms of the invention serve as transmucosal delivery systems, various carriers and additives may be incorporated as is well known in the art of transmucosal (e.g., buccal) drug delivery. Typical additives include permeation enhancers such as methylsulfonylmethane (MSM), polyethylene glycol esters, long-chain fatty acid esters of diols and triols (e.g., glycerol monolaurate, propylene glycol monolaurate), lower alkanols, and the like.

[0063] The fraction of each component in the dosage form is not particularly important, although, typically, in a lozenge, the hydrophilic polymer and the psychedelic compound each represents approximately 0.5-49.5 wt. % of the lozenge, and optional additives, e.g., added beneficial agents, sweeteners, and excipients typically represent about 1-50 wt. %, preferably about 1-45 wt. %, of the lozenge.

[0064] The hydrophilic polymer is both water-insoluble and biocompatible as those terms are defined herein. That is, the polymer component of the dosage form has: an octanol-water partition coefficient P of less than 1.0, preferably less than 0.5; solubility in water of less than 5 wt. %, preferably less than 3 wt. %, most preferably less than 1 wt. % at 0° C.; and does not give rise to undesirable biological effects or interact in an adverse manner with any of the other components of the dosage form.

[0065] When the dosage form is a lozenge, varying the molecular weight or viscosity of the polymer can impart certain properties to the dosage form. More specifically, a lower molecular weight polymer (e.g., ethylcellulose having a solution viscosity of about 6 to 15 cP) can give rise to a pliable, sticky lozenge, while a higher molecular weight polymer can provide a soft, rubbery, and non-tacky lozenge. Molecular weight also impacts on release rate and time to disintegration in the mouth, i.e., on the rate at which flavoring agent and/or other components in the dosage form are released and on the time the dosage form remains intact, respectively.

[0066] The particle size of the polymer is also relevant to the properties of the dosage forms made therewith. Generally, the polymers useful in conjunction with the invention have a particle size in the range of about 1 micron to about 250 microns. Micronized polymers, e.g., micronized ethylcellulose, are preferred for the formation of strong polymer matrix systems, while matrices manufactured with polymers having a larger particle size tend to break apart faster. Micronized polymers generally have a particle size of less than 75 microns, with a mean of about 20 microns, and a typical size range in the range of about 1 micron to about 50 microns.

[0067] An exemplary cellulosic polymer is ethylcellulose. The ethylcellulose should have a solution viscosity in the range of approximately 1 to 120 cP, with a preferred solution viscosity in the range of approximately 3 to 100 cP, and a most preferred solution viscosity in the range of approximately 6 to 49 cP. The ethoxyl content is typically in the range of about 45.0% to 52.0%, preferably in the range of about 48.0-49.5%. Suitable ethylcellulose polymers that are available commercially include, without limitation, those that may be obtained from the Dow Chemical Company (Midland, Mich.) as ETHOCEL® ethylcellulose, e.g., ETHOCEL® Standard 4 Premium (solution viscosity range approximately 3 to 5.5 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Standard 7 Premium (solution viscosity range approximately 6 to 8 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Standard 10 Premium (solution viscosity range approximately 9 to 11 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Standard 14 Premium (solution viscosity range approximately 12.6 to 15.4 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Standard 20 Premium (solution viscosity range approximately 18 to 22 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Standard 45 Premium (solution viscosity range approximately 41 to 49 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Standard 100 Premium (solution viscosity range approximately 90 to 110 cP, ethoxyl content 48.0-49.5%), ETHOCEL® Medium 50 (solution viscosity range approximately 43 to 55 cP, ethoxyl content 45.0-47.0%), ETHOCEL® Medium 70 (solution viscosity range approximately 63 to 85 cP, ethoxyl content 45.0-47.0%), ETHOCEL® Medium 100 (solution viscosity range approximately 90 to 110 cP, ethoxyl content 45.0- 47.0%), and ETHOCEL® HE 10 (solution viscosity range approximately 9 to 11 cP, ethoxyl content 49.5-52.0%), with all solution viscosities determined using an Ubbelohde viscometer and a solvent mixture of 80% toluene and 20% alcohol. [0068] Some psychedelic compounds or extracts comprising such agents may have an unpleasant taste and the lozenges according to the invention mask the unpleasant taste by incorporating flavoring agents. Flavoring agents may be combined, if desired, to produce a particular flavor mix. Ideal flavoring agents in this regard are pharmaceutically acceptable essential oils and chemical constituents of essential oils that can impart a desired flavor. Essential oils, as known in the art, are naturally occurring compounds or compositions that accumulate in the oil cells, glandular trichomes, and oil or resin ducts of aromatic plants. Essential oils also exhibit anti-bacterial activity. Essential oils that can be incorporated into the present flavored dosage forms as suitable flavoring agents include, without limitation, citrus oils such as lemon oil, lime oil, neroli oil, and orange oil, mint oils such as peppermint oil and spearmint oil, and other oils such as anise oil, wintergreen oil, cardamom oil, cinnamon oil, clove oil, coriander oil, Eriodictyon fluid extract, eucalyptus oil, fennel oil, glycyrrhiza extract, lemongrass oil, and nutmeg oil. Citrus and mint oils are generally preferred.

[0069] As is widely appreciated in the art, essential oils contain a number of constituents, many of which can by themselves serve as additives. Of these, the most well-known essential oil constituents that are widely used as flavoring agents are hydrocarbons, particularly terpenes and sesquiterpenes. "Terpenes" generally refer to hydrocarbons of the formula C10H16, and, as the term is used herein, also encompass terpene analogs of the formula C_nH2n- 4, as well as terpenes and terpene analogs substituted with one or more nonhydrogen substituents and/or containing a heteroatom such as N, O, or S. Analogously, "sesquiterpenes" generally refer to hydrocarbons of the formula C15H24, but for the purpose of the present invention also encompass sesquiterpene analogs of the formula C_nH2n-6 as well as substituted and/or heteroatom-containing derivatives thereof.

[0070] To enhance the taste of the dosage form, at least one sweetener is preferably incorporated into the formulation. In preferred embodiments, the sweetener is a high-intensity sweetener. The sweetener may be a sugar, e.g., sucrose, fructose, or dextrose, or, more preferably, a non-sugar sweetening agent to reduce both caloric intake and the likelihood of dental caries. Because high-intensity sweeteners are many times sweeter than table sugar (sucrose), smaller amounts of high- intensity sweeteners are needed to achieve the same level of sweetness as sugar. Sweeteners falling within the latter group include well known artificial sweetening agents, such as Stevia® (a sugar substitute extracted from the leaves of the plant species Stevia rebaudiana), stevioside, steviol, aspartame, saccharin, saccharin salts (e.g., sodium saccharin, calcium saccharin), sucralose, acesulfame-K (potassium acetosulfam), sorbitol, xylitol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, and thaumatin. In lozenges of the invention, the sweetener is generally incorporated within the wet matrix, i.e., physically entrapped therein. Six high-intensity sweeteners are FDA-approved as food additives in the United States: saccharin, aspartame, acesulfame potassium (Ace-K), sucralose, neotame, and advantame. GRAS notices have been submitted to FDA for two other types of high- intensity sweeteners: certain steviol glycosides obtained from the leaves of the stevia plant (Stevia rebaudiana Bertoni); and extracts obtained from Siraitia grosvenorii Swingle fruit, also known as Luo Han Guo or monk fruit.

[0071] The dosage form optionally contains a colorant and/or other conventional additives as well. With respect to colorants, some essential oils are already colored. For example, peppermint oil imparts a yellow color, while cinnamon oil imparts a brown color. Without an added colorant, and in the absence of a colored flavoring agent, the lozenges of the present invention will tend to be off-white or slightly darker, and may have some degree of translucence. Accordingly, a colorant must be added if a colored dosage form is desired. Suitable colorants include natural colorants, i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, and quercetin. Synthetic colorants may also be used, and will typically be an FD&C or D&C dye, e.g., an approved dye selected from the so- called "coal-tar" dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, a phthalein, a quinoline, or a "lake" thereof, i.e., an aluminum or calcium salt thereof. Particularly preferred colorants are food colorants in the "GRAS" (Generally Regarded as Safe) category.

[0072] Other optional additives include, for example: adhesion modifiers (including adhesion-increasing agents and adhesion-reducing agents) such as ingestible solvents (e.g., ethyl acetate and ethanol increase tack when admixed with ethylcellulose), mineral oil and vegetable oils (which tend to decrease tack when admixed with ethylcellulose), and additional polymers and polymer compositions, including polymers typically used to form hydrogels, e.g., ethylene vinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, cellulose acetate, cellulose diacetate, and other cellulose esters, which may increase or decrease tack depending on the particular polymer or polymer composition; pH-adjusting agents (e.g., acids, bases, buffer systems); preservatives (e.g., antioxidants, antimicrobial agents, etc.); fillers (e.g., maltodextrin, microcrystalline cellulose, lactose, mannitol, etc.); and enhancers to increase permeation of psychedelic compound(s) into the tissues of the oral cavity and/or through the oral mucosa and into the bloodstream, to achieve enhanced systemic levels of the psychedelic compound(s). Methyl sulfonyl methane ("MSM") represents a preferred enhancer.

[0073] Other beneficial agents that may be incorporated in the psychedelic lozenges include, but are not limited to: one or more drugs in addition to the psychedelic compound. In some embodiments, a combination of two abusable drugs may be included in the formulation. Two such drugs may, e.g., have different properties, such as half-life, solubility, potency, etc. Additional drugs can provide analgesia, and include, but are not limited to, aspirin; acetaminophen; non-steroidal anti-inflammatory drugs ("NS AIDS"), N-methyl-D-aspartate receptor antagonists, cyclooxygenase-II inhibitors and/or glycine receptor antagonists. Such additional drugs may or may not act synergistically with the opioid analgesic. Further drugs include antiallergic compounds, antianginal agents, anti-inflammatory analgesic agents, steroidal anti-inflammatory agents, antihistamines, local anesthetics, bactericides and disinfectants, vasoconstrictors, hemostatics, chemotherapeutic drugs, antibiotics, keratolytics, cauterizing agents, hormones, growth hormones, growth hormone inhibitors, analgesic narcotics and antiviral drugs.

[0074] The dosage forms of the invention are useful for the delivery of a psychedelic compound to the mucosal surface within the oral cavity. In one embodiment, the dosage form is a psychedelic lozenge that comprises a sustained release wet matrix of a biocompatible, water-insoluble hydrophilic polymer, e.g., ethylcellulose, a psychedelic compound, flavoring agents selected from essential oils, constituents of essential oils, and mixtures thereof, wherein, in an aqueous environment, the matrix gradually releases the psychedelic compound therein over a time period of at least 15 minutes, generally over a time period of 30 to 90 minutes, while the lozenge is capable of providing sustained release over a time period of one, two, three, or even four or more hours. The lozenges of the invention do not dissolve within the mouth, but rather remain intact until removed by the user and/or until a substantial fraction of the psychedelic compound has been released. In the latter case, the release of a substantial fraction of the psychedelic compound results in the degradation of the wet matrix into small fragments.

[0075] In an exemplary embodiment, the lozenge is formulated with the desired amount of a psychedelic agent, ethylcellulose and one or more of sucralose, corn starch and gum arabic. [0076] Each lozenge dosage form comprises 0.1 to 50 mg of a psychedelic agent. In various embodiments, each contains 0.01, 0.05, 0.25, 0.50, 1.0, 2.0, 5.0, 10, 25, or 50 mg of the active ingredient or an amount within the range of any two amounts listed hereinabove. In some embodiments, 0.1 to 5 mg of the psychedelic substance is used. In particular embodiments, the lozenge comprises 1-50 mg of the psychedelic agent.

[0077] The length of time that the lozenge can remain in the mouth and provide sustained release is controlled in part by the appropriate selection of hydrophilic polymer and psychedelic compound, and in part by the relative amounts of the hydrophilic polymer and the psychedelic compound. In general, the weight ratio of the hydrophilic polymer to the psychedelic compound is within the range of approximately 0.1:5 to 1:5. Accordingly, the aforementioned ratio is not intended to be limiting, and ratios outside of the recited range may be desirable to provide a different type of composition, e.g., compositions having a particularly soft consistency or a tendency to degrade more quickly.

[0078] Any of the optional additives may be in the form of a salt, ester, amide, prodrug, active metabolite, isomer, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite, isomer, or analog is pharmaceutically acceptable and retains at least some degree of the desired activity. Salts, esters, amides, prodrugs, metabolites, analogs, and other derivatives of the beneficial agents herein may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described inter alia in Smith MB, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (Wiley, 2013). Other agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry or may be deduced by reference to the pertinent literature. In addition, chiral active agents may be in isomerically pure form, or they may be incorporated as a racemic mixture of isomers.

[0079] The lozenges are prepared by admixture of the hydrophilic polymer and the flavoring agent and any additional components, including sweeteners, colorants, other additives discussed herein, and additional beneficial agents. Admixture can generally be carried out at room temperature and ambient humidity, unless a particular beneficial agent or other component of the lozenge requires a protected environment, a lower temperature, or lower humidity. Using the appropriate weight ratio of the hydrophilic polymer to the flavoring agent as discussed supra, admixture of the components results in a pliable wet matrix that can be formed into a roll or sheet. After allowing the composition to set, typically over a 24-hour period, the lozenges are then created by cutting of the roll or die cutting of the sheet. In a preferred embodiment, the mixture of the components is compressed to form lozenges. For example, the mixture can be compressed in a two-part lozenge- shaped mold, wherein after the mixture is added to a recess within the lower half of the mold, the upper half is aligned therewith and pressure is applied to compress the mixture. Compressed lozenges can be formulated to remain intact within the mouth for extended time periods, on the order of five hours or more. It will be appreciated by one of skill in the art, however, that the present process can be tailored to provide compressed lozenges that degrade more quickly, for example by varying the proportion of flavoring agent(s) and/or excipients.

[0080] If a somewhat tacky lozenge is desired, e.g., a dosage form that adheres to the buccal mucosa for delivery of a beneficial agent, the same procedures are followed except that a lower molecular weight hydrophilic polymer is used to impart adhesive strength to the lozenge by virtue of the tacky surface provided. Alternatively, or in addition, one or more adhesive polymers can be incorporated into the lozenge formulation to provide the desired degree of adhesion, as described elsewhere herein.

[0081] The dosage forms of the invention may be prepared in any number of shapes and sizes, and the invention is not limited in this regard. Different shapes and sizes may be desirable for different applications. Typical dimensions, however, are on the order of 0.4" x 0.5" x 0.125" for lozenges, while lozenge weight is generally in the range of about 0.4 to 0.8g.

[0082] Lozenges are clinically tested for pharmaceutical efficacy. Preferred lozenges typically last 0.5 to 1.5 hours in the mouth. Pharmaceutical efficacy is noticed within 10 minutes and is due to absorption through the oral mucosa into the bloodstream. In contrast, oral intake requires longer time periods, typically 2 hours or more, to make its way from the intestinal tract to the bloodstream. While lozenges enable an immediate and prolonged period of efficacy lasting hours, currently used edibles require longer periods to take effect.

[0083] Level of clinical efficacy is proportional to dosage. Efficacy is noticed even at low dosages. Another advantage of lozenge is the ability of the user to self-regulate medication either by using higher (or lower) doses or by adjusting the length of time lozenges are retained in the mouth, or both.

[0084] The actives used in the embodiments of the present invention affect the human brain and physiology in positive ways. Those skilled in the art will recognize that the lozenges of the present invention may be used to treat any and all medical conditions that respond favorably.

EXAMPLES

[0085] Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the present invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.

Example 1 : Preparation of Flavored Lozenges

[0086] Lozenges were prepared by mixing 10-200 mg of a psychedelic substance (ketamine), 0.4g of ETHOCEL® Standard 100 Premium (The Dow Chemical Company, Midland, Mich.), 0.38 g peppermint oil, and 0.16 g sucralose at room temperature and ambient humidity. Admixture of the components resulted in a soft, wet composition that was allowed to set for 24 hours in the form of a sheet, and lozenges were then cut therefrom. The lozenges were soft, pliable, and tacky, and typically weighed 0.45 to 0.5 g. The oral dosage form is designed to administer about 3mg of the psychedelic substance per kg body weight of the subject.

Example 2: Pharmacokinetics of Lozenges

[0087] Lozenges formulated according to the instant invention with ethyl cellulose and like matrices, typically lasted 0.5 to 1, 1.5, 2, 3 and 4 hours or more while pharmaceutical efficacy is noticed within 10 minutes.

Example 3: Measurement of depressive symptoms

[0088] Measurement of depressive symptoms is performed with the clinician rated Hamilton Depression Rating Scale (HAMD) and the Montgomery Asperg Depression Rating Scale (MADRAS). Baseline measurements are compared with measurements taken at 1 day, 1 week, 2 weeks and 3 weeks after treatment. Significant reductions in depressive symptoms are observed at 1 day, 1 week, 2, weeks, 3 weeks after treatment, both with the HAMD and MADRAS. The treatment is administered safely without any serious adverse events. A follow up open-label study on patients with recurrent depressive disorder given the same dose of the psychedelic. Identical outcome measures are observed. Example 4: Release of Ketamine from sustained release lozenge into saliva

[0089] Release of Ketamine from sustained-release lozenge according to the invention was assayed in saliva. 0.05 mg of ketamine per sustained release lozenge was used and the release rate of ketamine in saliva was determined by immunoassay. Results are shown in the Fig. 1.

Example 5 : Release of Ketamine from sustained release lozenge over time

[0090] Sustained release lozenges containing 10 mg ketamine each were produced. Kinetics of dissolution was carried out in 200 ml of water with continuous stirring with a magnetic stirrer. Kinetics of the dissolution were monitored at 220 nm using a Bausch & Lomb Spectronic 21 Spectrophotometer. The below graph shows the percent release of ketamine over time. As demonstrated, nearly 20% of the ketamine was released within the initial 10 minutes.

[0091] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0092] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claim.

Claims

CLAIMS What is claimed is:

1. A lozenge for rapid delivery of a psychedelic compound through the oral mucosa, the lozenge comprising: a water-insoluble polymer; and one or more psychedelic compounds.

2. The lozenge of claim 1, wherein the water-insoluble polymer is ethyl cellulose.

3. The lozenge of claim 1, wherein the psychedelic compound is selected from 3,4,5- trimethoxyamphetamine (TMA), 5-methoxy-N,N-dimethyltryptamine (5-methoxy-3-[2- (dimethylamino)ethyl]indole; 5-MeO-DMT), Alpha-methyltryptamine (aMT), Bufotenine, Diethyltryptamine (DET), Dimethyltryptamine (DMT), 5-methoxy-N,N- diisopropyltryptamine (5-MeO-DIPT), its isomers, salts and salts of isomers, Ibogaine, Lysergic acid diethylamide (LSD), marijuana, cannabis resin, marijuana extracts; cannabinoids [17], Mescaline, Parahexyl, Peyote, N-ethyL 3 -piperidyl benzilate, N-methyl-

24

4. The lozenge of claim 1, wherein the psychedelic compound is selected from a 5-HT2A agonist selected from LSD, psilocybin, DOI (±)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride; (R)-DOI ((R)-l-(2,5-dimethoxy-4-iodophenyI)-2-aminopropane); LA-SS-Az (2'S,4'S)-(+)-9,10-Didehydro-6-methylergoline-8B-(trans-2,4-dimethyl-azetidide); 2C-BCB (4-Bromo-3,6-dimethoxybenzocyclobuten-l-yl) methylamine); ayahuasca; 3,4,5- trimethoxyphenethylamine (mescaline); 5-methoxy-N,N-dimethyltryptamine (5-meo-DMT) and ibogaine, and combinations thereof.

5. The lozenge of claim 1, wherein the psychedelic compound is a dissociative agent selected from ketamine, esketamine, PCP, DXM and combinations thereof.

6. The lozenge of claim 1, wherein the psychedelic compound is a an empathogenic agent selected from 3,4-Methylenedioxymethamphetamine (MDMA), MDEA, MDA, and combinations thereof.

7. The lozenge of claim 1, wherein the psychedelic compound comprises microdose amount of a psychedelic agent.

8. The lozenge of claim 1, wherein the psychedelic agent is used to treat at least one symptom selected from of obsessive compulsive disorder (OCD), pain, chronic pain, anxiety disproportionate to severity of physical complaints, psychological disorder, major depression, melancholic depression, atypical depression, dysthymia, pain disorder, body dysmorphia, conversion, hysteria, neurological conditions without identifiable cause, psychosomatic illness, pain management in relation to existing physical condition, irritability, fibromyalgia, post-traumatic stress disorder (PTSD), cluster headaches, paranoia, psychosis, anxiety, panic attacks, flashbacks, smoking addiction, alcohol addiction, cocaine addiction, improving creativity, boosting physical energy level, attaining emotional balance, increasing performance on problems-solving tasks, treating anxiety, treating depression, treating addiction, or any combination thereof.

9. The lozenge of claim 1, wherein the psychedelic lozenges are formulated using ethyl cellulose as the matrix.

10. The lozenge of claim 9, wherein the psychedelic lozenge further comprising essential oils (peppermint oil) and sucralose or other sweeteners.

11. The lozenge of claim 1, further comprising an essential oil, a constituent of an essential oil, or a mixture thereof.

12. The lozenge of claim 11, wherein the essential oil is selected from the group consisting of: a citrus oil, lemon oil, lime oil, neroli oil, orange oil, a mint oil, peppermint oil, spearmint oil, wintergreen oil, anise oil, ginger oil, mango oil, tangerine oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eucalyptus oil, fennel oil, lemongrass oil, nutmeg oil, eriodictyon fluid extract, glycyrrhiza extract, and combinations thereof.

13. The lozenge of claim 12, wherein the essential oil comprises a terpene, a sesquiterpene, or combinations thereof.

14. The lozenge of claim 1, further comprising an effective amount of a sweetener selected from a sugar, a non-sugar sweetening agent, and a mixture thereof.

15. The lozenge of claim 1, wherein the non-sugar sweetening agent is selected from stevia extract powder, stevioside, steviol, aspartame, saccharin, saccharin salts, sucralose, potassium acetosulfam, sorbitol, xylitol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, and thaumatin.

16. The lozenge of claim 1, further comprising at least one additive selected from the group consisting of: release rate accelerants, release rate retardants, adhesion-increasing agents, adhesion-reducing agents, flavor stabilizers, flavor diluents, pH-adjusting agents, preservatives, other lubricants, and fillers.

17. The lozenge of claim 16, wherein the pH-adjusting agent is an alkali metal bicarbonate.

18. The lozenge of claim 1, further comprising a permeation enhancer.

19. The lozenge of claim 1, wherein the permeation enhancer is methyl sulfonyl methane (MSM).

20. A method for making a lozenge according to claim 1, the method comprising:

(i) preparing an admixture of 0.10-200 mg of a desired psychedelic compound, ethyl cellulose, and optionally, an essential oil and a sweetening agent; and

(ii) setting the admixture at room temperature and ambient humidity until a soft, pliable, and tacky lozenge material is formed.

21. The method of claim 20, wherein the essential oil is selected from the group consisting of: a citrus oil, lemon oil, lime oil, neroli oil, orange oil, a mint oil, peppermint oil, spearmint oil, anise oil, wintergreen oil, ginger oil, tangerine oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eucalyptus oil, fennel oil, lemongrass oil, nutmeg oil, eriodictyon fluid extract, glycyrrhiza extract, and combinations thereof.

22. The method of claim 20, wherein the sweetening agent is a high intensity sweetening agent selected from stevia extract powder, stevioside, steviol, aspartame, saccharin, saccharin salts, sucralose, potassium acetosulfam, sorbitol, xylitol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, thaumatin, monk fruit and admixtures thereof.

23. The method of claim 20, further comprising: adding to the admixture at least one additive selected from the group consisting of: release rate accelerants, release rate retardants, adhesion-increasing agents, adhesion-reducing agents, flavor stabilizers, flavor diluents, pH- adjusting agents, preservatives, other lubricants, and fillers.

24. The method of claim 23, wherein the pH-adjusting agent is an alkali metal bicarbonate.

25. The method of claim 20, further comprising: adding to the admixture a permeation enhancer.

26. The method of claim 25, wherein the permeation enhancer is methyl sulfonyl methane (MSM).

27. A method for treating, preventing, or alleviating a disease or condition responsive to the administration of a psychedelic compound in a subject, the method comprising: administering a lozenge according to any of claims 1-26 for a time between 10 minutes to 2 hours to a subject in need thereof; wherein the lozenge comprises one or more psychedelic compounds at an amount and ratio sufficient to treat, prevent or alleviate the condition.

28. The method of claim 27 wherein the disease or condition is selected from at least one symptom selected from of obsessive compulsive disorder (OCD), pain, chronic pain, anxiety disproportionate to severity of physical complaints, psychological disorder, major depression, melancholic depression, atypical depression, dysthymia, pain disorder, body dysmorphia, conversion, hysteria, neurological conditions without identifiable cause, psychosomatic

27 illness, pain management in relation to existing physical condition, irritability, fibromyalgia, post-traumatic stress disorder (PTSD), cluster headaches, paranoia, psychosis, anxiety, panic attacks, flashbacks, smoking addiction, alcohol addiction, cocaine addiction, improving creativity, boosting physical energy level, attaining emotional balance, increasing performance on problem- solving tasks, treating anxiety, treating depression, treating addiction, or any combination thereof.

29. The method of claim 27, wherein the psychedelic compound is selected from a 5-HT2A agonist selected from LSD, psilocybin, DOI (±)-l-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride; (R)-DOI ((R)-l-(2,5-dimethoxy-4-iodophenyI)-2-aminopropane); LA-SS-Az (2'S,4'S)-(+)-9,10-Didehydro-6-methylergoline-8B-(trans-2,4-dimethyl-azetidide); 2C-BCB (4-Bromo-3,6-dimethoxybenzocyclobuten-l-yl) methylamine); ayahuasca; 3,4,5- trimethoxyphenethylamine (mescaline); 5-methoxy-N,N-dimethyltryptamine (5-meo-DMT) and ibogaine, and combinations thereof; a dissociative agent selected from ketamine, esketamine, PCP, DXM and combinations thereof; and an empathogenic agent selected from 3,4-Methylenedioxymethamphetamine (MDMA), MDEA, MDA, and combinations thereof.

30. The method of claim 27, wherein a pharmaceutical effect of the psychedelic compound is experienced by the subject within 10 minutes.

31. The method of claim 27, wherein the lozenge is administered following achievement of a desired anti-depressive effect with psychedelic-assisted therapy, and wherein the administration is continued by providing an effective level of the psychedelic agent, and wherein the effective level does not produce additional unacceptable side effects.

32. The method of claim 31, wherein the administration is by managing delivery rate or oral residence time.

33. The method of claim 31, wherein the administration is by self-medication.

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