CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Prov. Appl. 63/346,647, filed May 27, 2022, the contents of which are incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to the use of entheogens to reduce or ameliorate cognitive decline related to anesthesia or sedation or increase the resilience of patients to the stresses of surgery including physical and psychological sequelae of anesthesia and sedation and the underlying conditions requiring anesthesia or sedation.

BACKGROUND OF THE INVENTION

Postoperative neurocognitive disorders is an overarching term that includes postoperative delirium, an acute state of confusion and inattention; and postoperative cognitive dysfunction (POCD), a prolonged state of cognitive impairment that predominantly affects higher-level cognitive skills and memory. Proposed potential mechanisms for postoperative neurocognitive decline are speculative but include neuroinflammation as a result of perioperative stress, vascular disorders, or the acceleration of neurocognitive decline in patients with a previously undiagnosed neurodegenerative disorder (Mahanna-GabrielliE, SchenningKJ, ErikssonLI, et al. State of the clinical science of perioperative brain health. Br J Anae sth. 2019;123(4):464-478).

In the last decade, the population aged 65 years and older increased by 34.2% in the US and now accounts for a disproportionate number of surgical procedures requiring anesthesia. Among these patients, aging causes a number of changes in the brain that may contribute to decreased cognitive reserve, susceptibility to the stresses of surgery and anesthesia, and increased risk of neurologic injury (Vacas S, Cole DJ et al: Cognitive Decline Associated With Anesthesia and Surgery in Older Patients, JAMA September 7, 2021 Volume 326, Number 9).

Approximately 0.8 million people every year suffer from critical illness requiring mechanical ventilation during their stay in critical care in the United States (Wunsch H, Linde- Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JM. The epidemiology of mechanical ventilation use in the United States. Crit Care Med. 2010;38(10): 1947-1953). Postintensive care syndrome (PICS) is a collection of physical, mental and emotional symptoms that continue to persist after a patient leaves the intensive care unit (ICU) (Inoue S, Hatakeyama J et al: Acute Med Surg 2019 Apr 25;6(3):233-246. doi: 10.1002/ams2.415. eCollection 2019 Jul). Because of the advances in medicine over the last several decades, more people now survive critical illnesses. Clinicians used to focus more on the immediate short-term outcomes of these patients. More recently, medical professionals have shifted their attention to the long-term outcomes of survivors of critical illnesses. What they discovered is that although ICU survival improved, patients did not return to their former level of functioning for weeks, months and even years. Patients developed mind, body and emotional symptoms related to their critical illness and treatment in the ICU. Cognitive impairment has been reported to occur on average in 25% of ICU survivors, but few studies have shown its incidence to be significantly higher, occurring in more than 3/4th of ICU survivors. (Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun B T, et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013; 369:1306-16).

The cumulative incidence of mental health disorders for the year after hospital discharge among patients receiving mechanical ventilation, accounting for death, was 0.9% for receiving 1 or more new psychiatric diagnoses from a psychiatrist and 18.8% for receiving 1 or more prescriptions for psychoactive medications. The 2 most common types of new diagnoses were mood disorders and anxiety disorders (Wunsch H, Christiansen CF, Johansen MB, Olsen M, Ali N, Angus DC, et al. Psychiatric diagnoses and psychoactive medication use among nonsurgical critically ill patients receiving mechanical ventilation. JAMA 2014; 311 : 1133-42).

Entheogens are chemical substances, originating from fungi, plants and animals, that have been ingested for thousands of years for religious or spiritual purposes to produce an altered state of consciousness (Nichols DE: Psychedelics. Pharmacol Rev. 2016 Apr; 68(2): 264-355). There has been increasing interest in the use of entheogens, such as psilocybin, for the treatment of mental health disorders (Geiger HA, Wurst MG et al: DARK Classics in chemical neuroscience. Psilocybin. ACS Chem. Neurosci.).

Studies indicate that psychedelics modulate neuroinflammation, hippocampal neurogenesis, neuroplasticity and brain complexity (Khan, S. M., Carter, G. T., Aggarwal, S. K., & Holland, J. (2021). Psychedelics for Brain Injury: A mini-review. Frontiers in Neurology , 72). These effects are thought to underlie the clinical action of psychedelics in neuropsychiatric disorders and are the current focus of intense research. These observations provide evidence that the effects of psychedelics on neuronal plasticity may be dissociated from their psychological effects (i.e., the psychedelic trip ).

Psilocybin is a naturally occurring psychedelic compound produced by over 200 mushrooms, that is being researched as treatment for a range of psychiatric disorders (Carhart- Harris RL and Goodwin GM. (2017) The therapeutic potential of psychedelic drugs: past, present and future. Neuropsychopharmacology). Five separate trials have reported improvements in depressive symptoms after psilocybin-assisted psychotherapy including in 'treatment-resistant depression' (Carhart-Harris R, Giribaldi B, Watts R et al Trial of Psilocybin versus Escital opram for Depression^ Engl J Med. 2021 04 15; 384(15): 1402-1411, Carhart-Harris RL, Nutt DJ (2016) Question-based drug development for psilocybin - authors' reply. Lancet Psychiatry 3:807; Ross S, Bossis A, Guss J et al (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol 30:1165-1180; Griffiths RR, Johnson MW, Carducci MA et al (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol 30: 1181-1197; Grob CS, Danforth AL, Chopra GS et al (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced- stage cancer. Arch Gen Psychiatry 68:71-78. Psilocybin has shown promise in the treatment of obsessive-compulsive disorder (Moreno FA, Wiegand CB, Taitano EK et al (2006) Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. J Clin Psychiatry 67:1735-1740), alcohol (Bogenschutz MP, Forcehimes AA, Pommy JA et al (2015) Psilocybin-assisted treatment for alcohol dependence: a proof-of- concept study. J Psychopharmacol 29:289-299) and tobacco addiction (Johnson MW, Garcia- Romeu A, Cosimano MP et al (2014) Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol 28:983-992) and anxiety related to terminal diagnoses (Griffiths et al. 2016; Ross et al. 2016; Grob et al. 2011).

Studies involving other serotonergic psychedelics combined with psychological support have found similarly promising outcomes: Sustained reductions in end-of-life anxiety were observed after LSD-assisted psychotherapy (Gasser P, Holstein D, Michel Y et al (2014) Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis 202:513-520), and reduced depressive symptoms were seen after ayahuasca in patients with 'recurrent depression' (Osorio Fde L, Sanches RF, Macedo LR et al (2015) Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Rev Bras Psiquiatr 37: 13-20; Sanches RF, de Lima Osorio F, Dos Santos RG et al (2016) Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a SPECT study. J Clin Psychopharmacol 36:77-81). Naturalistic, observational studies of ayahuasca support its long-term well-being promoting and anti -addiction properties (Thomas G, Lucas P, Capler NR et al (2013) Ayahuasca-assisted therapy for addiction: results from a preliminary observational study in Canada. Curr Drug Abuse Rev 6:30- 42; Bouso JC, Gonzalez D, Fondevila S et al (2012) Personality, psychopathology, life attitudes and neuropsychological performance among ritual users of Ayahuasca: a longitudinal study. PLoS One 7:e42421). Further evidence favoring the therapeutic potential of psychedelics can be found in literature documenting the extensive research carried out with these compounds in the mid-twentieth century, e.g. two relevant meta-analyses have found positive safety and efficacy data for LSD for alcohol dependence (Krebs TS, Johansen PO (2012) Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol 26:994- 1002) and mood disorders (Rucker JJ, Jelen LA, Flynn S et al (2016) Psychedelics in the treatment of unipolar mood disorders: a systematic review. J Psychopharmacol 30:1220-1229). See Sarris J et al. Psychedelic medicines for mood disorders: current evidence and clinical considerations Curr Opin Psychiatry 2021, 33:000 - 000.

Like all serotonergic psychedelics, psilocybin initiates its characteristic effects via serotonin 2A receptor (5-HT2AR) agonism (Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A et al (1998); Vollenweider FX, Smallridge JW: Classic Psychedelic Drugs: Update on Biological Mechanisms. Pharmacopsychiatry. 2022 Jan 25. doi: 10.1055/a-1721-2914. Online ahead of print). 5-HT2AR signaling has been associated with better responses to conventional antidepressants (Qesseveur G, Petit AC, Nguyen HT et al. (2016) Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: a translational approach. Neuropharmacology 105:142-153; Petit AC, Quesseveur G, Gressier F et al (2014) Converging translational evidence for the involvement of the serotonin 2A receptor gene in major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 54:76-82), and preclinical work indicates that 5-HT2AR signalling may mediate (at least some of) the therapeutic effects of SSRIs (Nic Dhonnchadha BA, Ripoil N, Clenet F et al (2005) Implication 5 of 5-HT2 receptor subtypes in the mechanism of action of antidepressants in the four plates test. Psychopharmacology 179:418-429; Buchbom T, Schroder H, Hollt V et al (2014). Repeated lysergic acid diethylamide in an animal model of depression: normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. J Psychopharmacol 28:545-552). 5- HT2AR antagonists have been found to augment the antidepressant effects of SSRIs (Ostroff RB, Nelson JC (1999) Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry 60:256-259) and many effective antidepressant augmentation medications have 5-HT2AR antagonist properties (Carpenter LL, locic Z, Hall JM et al (1999) Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 60:45-49).

Preclinical and clinical evidence support neuroplasticity as a convergent downstream mechanism of action for psychedelics in the treatment of psychiatric disorders. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [ including psilocybin, lysergic acid diethylamide (LSD), 5-MeO-DMT and N, N- dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex (David E. Olson: Biochemical Mechanisms Underlying Psychedelic- Induced Neuroplasticity Biochemistry 2022 61 (3), 127-136. DOI: 10.1021/acs.biochem.lc00812).

It is unclear whether the hallucinogenic effects are necessary for the potential positive therapeutic impact and hence, if consciousness is required to obtain the benefits associated with psychedelic drug administration. Studies are underway to explore psychedelics under ketamine anesthesia, as low dose ketamine is dissociative and approved for the treatment of treatmentresistant depression (see the world wide web atjanssenlabels.com/package-insert/product- monograph/prescribing-information/SPRAVATO-pi.pdf). A randomized controlled trial of ketamine in women undergoing cesarian section showed significantly lower occurrence of postpartum depression versus standard of care (Ma J-H, Wang S-Y et al: Psychiatry Res. 2019 Sep;279:252-258. doi: 10.1016/j.psychres.2019.03.026. Epub 2019 Mar 16). An ongoing study evaluates whether ketamine, given as part of an anesthetic, improves depression symptoms in depressed patients undergoing total joint replacement surgery.) SUMMARY OF THE INVENTION

The present invention relates to the use of entheogens to reduce or ameliorate cognitive decline related to anesthesia or sedation or increase the resilience of patients to the stresses of surgery including physical and psychological sequelae of anesthesia and sedation and the underlying conditions requiring anesthesia or sedation.

In some preferred embodiments, the present invention provides methods of treating a subject comprising administering an entheogen or composition comprising an entheogen to a subject in an unconscious or semi-conscious state or about to be rendered in an unconscious or semi-conscious state. In some preferred methods, the present invention provides entheogens or entheogen compositions for use in treating a condition associated with being in an unconscious or semiconscious state.

In some preferred embodiments, the unconscious or semiconscious state is caused by a modality selected from the group consisting of medically induced unconsciousness or semiconsciousness, trauma induced unconsciousness or semi-consciousness, illness induced unconsciousness or semi-consciousness, and condition induced unconsciousness or semiconsciousness. In some preferred embodiments, the medically induced unconsciousness or semiconsciousness is induced by administration of an agent selected from the group consisting of an anesthetic and a sedative.

In some preferred embodiments, the anesthetic administered to the subject is selected from the group consisting of a general anesthetic agent delivered intravenously selected form the group consisting of propofol, etomidate, ketamine, methohexital and thiopental and a general anesthetic agent delivered via inhalation selected form the group consisting of sevoflurane, desflurane, and isoflurane. In some preferred embodiments, the general anesthetic agent is administered with a adjuvant. In some preferred embodiments, the adjuvant is selected from the group consisting of an opioid, a2-agonist, and NMDA receptor antagonist. In some preferred embodiments, the adjuvant is selected from the group consisting of fentanyl, lidocaine, midazolam, dexamethasone, and dexmedetomidine. In some preferred embodiments, the sedative administered to the subject is selected from the group consisting of a benzodiazepine, an a2- agonist, an opioid, ketamine and nitrous oxide. In some preferred embodiments, the benzodiazepine is selected from the group consisting of diazepam, midazolam and lorazepam. In some preferred embodiments, the neuroleptic agent is selected from the group consisting of haloperidol, droperidol, and phenothiazine. Tn some preferred embodiments, the a2-agonist is clonidine.

In some preferred embodiments, administration of the entheogen inhibits, reduces or prevents cognitive decline related to anesthesia and/or sedation.

In some preferred embodiments, administration of the entheogen increases the resilience of patients to the stresses of surgery and anesthesia including physical and psychological sequelae of anesthesia and/or sedation.

In some preferred embodiments, administration of the entheogen improves cognitive recovery, and prevents or reduces reactive depression or prevents or reduces PTSD in subject following being in the unconscious or semi-conscious state.

In some preferred embodiments, the subject in an unconscious or semi-conscious state or about to be rendered in an unconscious or semi-conscious state is subject to heart surgery or surgery for major trauma.

In some preferred embodiments, the subject is in an intensive care unit.

In some preferred embodiments, the subject in an unconscious or semi-conscious state or about to be rendered in an unconscious or semi-conscious state is subject to an obstetrical intervention. In some preferred embodiments, administration of the entheogen reduces or prevents post-natal depression.

In some preferred embodiments, administration of the entheogen inhibits, reduces or prevents a condition in the subject selected from the group consisting of post-traumatic stress disorder, depression, obsessive-compulsive disorder, an addictive disorder, and schizophrenia.

In some preferred embodiments, administration of the entheogen improves cognitive function or neuroplasticity in the subject.

In some preferred embodiments, the entheogen is psilocybin. In some preferred embodiments, the entheogen composition comprises psilocybin. In some preferred embodiments, the entheogen composition is a combination psilocybin and one or more compounds selected from the group consisting of psilocybin, baeocystin, aurugeniscin, norpsilocin, and norbaeocystin. In some preferred embodiments, the entheogen composition is a mushroom extract composition comprising one or more compounds selected from the group consisting of psilocybin, baeocystin, aurugeniscin, norpsilocin, and norbaeocystin. In some preferred embodiments, the mushroom extract is free of psilocybin. Tn some preferred embodiments, the entheogen is 5-rnethoxy-N,N-dimethyltryptamine (5- MeO-DMT). In some preferred embodiments, the entheogen composition comprises 5-methoxy- N,N-dimethyltryptamine (5 -MeO-DMT) .

In some preferred embodiments, entheogen is provided in a psychedelic dose.

In some preferred embodiments, the entheogen is provided in a sub-psychedelic dose.

In some preferred embodiments, the entheogen is administered intravenously.

Tn some preferred embodiments, the entheogen is co-administered with a 5-HT1 A agonist. Tn some preferred embodiments, 5-HT1A agonist is buspirone.

DEFINITIONS

A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

"Administering" or "administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a PBP can be administered, intravenously, arterially, intradermally, intra-muscularly, intraperitonealy, intravenously, subcutaneously, sublingually, orally (by ingestion), intranasally (by inhalation), intrapulmonary (by nebulization or instillation) intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. In some aspects, the administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug, or to have the drug administered by another and/or who provides a patient with a prescription for a drug is administering the drug to the patient.

A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent, such as the entheogen compositions described herein, is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of symptoms of the condition being treated. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

A “prophylactically effective amount” or a “prophylactically effective dose” of a drug or agent, such as an entheogen composition, is an amount of a drug or an agent that, when administered to a subject will have the intended prophylactic effect. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, the nature and extent of symptoms of the condition being treated. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

“Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation, amelioration, or slowing the progression, of one or more symptoms associated with the disease or disorder being treated. In certain embodiments, treatment may be prophylactic.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of entheogens to reduce or ameliorate cognitive decline related to anesthesia or sedation or increase the resilience of patients to the stresses of surgery including physical and psychological sequelae of anesthesia and sedation and the underlying conditions requiring anesthesia or sedation.

Entheogens are naturally occurring compounds with psychedelic properties that have historically been used for religious and spiritual ceremonies and also for medicinal purposes. In spite of legal barriers, there is rapidly increasing interest among clinicians and researchers in the use of natural or synthetic psychedelics for the treatment of psychiatric disorders. Tn some preferred embodiments, the present invention provides methods of using psilocybin and other fungal/plant/animal-derived entheogens in different formulations (including IV), dosages and schedules in semi-conscious and unconscious (including medically induced, trauma-induced, illness or condition-induced) states to prevent and treat a range of conditions including psychiatric conditions (including PTSD, depression and OCD and addictive disorders, schizophrenia etc.) and to specifically prevent and treat cognitive decline related to anesthesia and sedation or increase the resilience of patients to the stresses of surgery and anesthesia including physical and psychological sequelae of anesthesia and sedation. Semiconscious and unconscious states may be induced by, anesthesia, sedation, drugs, trauma, vegetative states, hyperthermia, hypothermia, Electro-Convulsive-Therapy, major surgery, medically induced coma, drug induced coma, cardiac arrest, asphyxia, prematurity, psychiatric conditions, etc.

In some embodiments, an anesthetic agent administered to the subject is a general anesthetic agent delivered intravenously selected form the group consisting of propofol, etomidate, ketamine, methohexital and thiopental or a general anesthetic agent delivered via inhalation selected form the group consisting of sevoflurane, desflurane, and isoflurane. In some preferred embodiments, one or more adjuvants are administered with the general anesthetic agent. Suitable adjuvants include, but are not limited to, opioids, a2-agonists, NMD A receptor antagonists. In some preferred embodiments the adjuvant is selected from the group consisting of opioid agents (e.g., morphine or fentanyl), lidocaine, midazolam, dexamethasone, and dexmedetomidine.

In some preferred embodiments, a sedative administered to the subject is a benzodiazepine, a2-agonists (e.g., clonidine), opioid (neuroleptic agents (e.g., haloperidol, droperidol, phenothiazines), ketamine or nitrous oxide. In some preferred embodiments, the benzodiazepine is selected from the group consisting of diazepam, midazolam and lorazepam.

In some preferred embodiments, the methods comprise administration (e.g., intravenous administration) of psilocybin or other entheogens pre- or during anesthesia for example in patients being operated on for heart disease or major trauma with the specific purpose of improving cognitive recovery and preventing reactive depression or PTSD. Tn some preferred embodiments, the methods comprise administration (e.g., intravenous administration) of psilocybin or other entheogens pre- or during obstetrical interventions such as Caesarian section in order to prevent post-natal depression.

In some preferred embodiments, the methods comprise administration (e.g., intravenous administration) of psilocybin or other entheogens to patients in a semi-conscious or unconscious state in critical care and ICU settings over various periods of time in order to improve cognitive and other outcomes and prevent depression and PTSD.

In some preferred embodiments, the methods comprise administration (e.g., intravenous administration) of psilocybin or other entheogens to these patients in a semi-conscious or unconscious state to improve outcome in terms of cognitive function (improving neuroplasticity) and the prevention of depression, OCD and other negative psychological outcomes.

The present invention is not limited to any particular mechanism of action. Indeed, a mechanism of action is not necessary to practice the present invention. Nevertheless, it is contemplated that psilocybin or other entheogens play a prophylactic ( or therapeutic) role in the management of unconscious or semi-conscious patents in a similar manner to antacids (prevention of gastric damage) and antibiotics (prevention of infection) and anti -coagulants (prevention of hemorrhagic disorders) are generally used in operating rooms and critical care settings as preventive modalities. Hence, the psilocybin and entheogens are administered as prophylaxis against cognitive decline and negative psychological outcomes such as depression and PTSD associated with the underlying condition that required anesthesia or sedation and/or caused an unconscious or semi-conscious state.

Preferred entheogens for use in the present invention include those derived from mushrooms, including psilocybin, alone or in combination with one or more of baeocystin, aurugeniscin, norpsilocin, norbaeocystin, as well as 5-methoxy-N,N-dimethyltryptamine (5- MeO-DMT).

The entheogen compositions may be prepared by a variety of methods including, but not limited to, chemical synthesis, extraction and/or purification from plants or fungi, and extraction and/or purification from mushroom cell cultures. In some preferred embodiments, the entheogen compositions comprise psilocybin. In some particularly preferred embodiments, the entheogen compositions comprise psilocybin and additionally one or more compounds selected from the group consisting of baeocystin, aeruginascin, norpsilocin, norbaeocystin, and combinations thereof. Tn some preferred embodiments, the entheogen composition comprises one or more compounds selected from the group consisting of baeocystin, aeruginascin, norpsilocin, norbaeocystin, and combinations thereof and is essentially free of psilocybin.

Exemplary entheogen compositions are provided below. The compounds listed may, for example, be chemically synthesized (see, e.g., Sherwood et al., (2020) Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin; J. Nat. Prod. 83(2) 461-67, incorporated herein by reference in its entirety), may be provided in an extract from mushrooms or from mushroom cell cultures as described in detail below, or be isolated from mushrooms or mushroom cell cultures as described in detail below. In some preferred embodiments, he listed composition comprises the listed compounds. In some preferred embodiments, the listed compositions consist essentially of the listed compounds. In some preferred embodiments, the listed compositions consist of the listed compounds.

Composition Compounds in composition

1. psilocybin, baeocystin, aeruginascin, norpsilocin, norbaeocystin

2. psilocybin, baeocystin

3. psilocybin, baeocystin, aeruginascin

4. psilocybin, baeocystin, aeruginascin, norpsilocin

5. psilocybin, baeocystin, norpsilocin, norbaeocystin

6. psilocybin, baeocystin, norbaeocystin

7. psilocybin, baeocystin, norpsilocin

8. psilocybin, aeruginascin

9. psilocybin, aeruginascin, norpsilocin

10 psilocybin, aeruginascin, norbaeocystin

11 psilocybin, aeruginascin, norpsilocin, norbaeocystin

12 psilocybin, norpsilocin

13 psilocybin, norpsilocin, norbaeocystin

14 psilocybin, norbaeocystin

15 baeocystin, aeruginascin, norpsilocin, norbaeocystin

16 baeocystin 17. baeocystin, aeruginascin

18. baeocystin, aeruginascin, norpsilocin

19. baeocystin, norpsilocin, norbaeocystin

20. baeocystin, norbaeocystin

21. baeocystin, norpsilocin

22. aeruginascin

23. aeruginascin, norpsilocin

24. aeruginascin, norbaeocystin

25. aeruginascin, norpsilocin, norbaeocystin

26. norpsilocin

27. norpsilocin, norbaeocystin

28. norbaeocystin

29. psilocin, baeocystin, aeruginascin, norpsilocin, norbaeocystin

30. psilocin, baeocystin

31. psilocin, baeocystin, aeruginascin

32. psilocin, baeocystin, aeruginascin, norpsilocin

33. psilocin, baeocystin, norpsilocin, norbaeocystin

34. psilocin, baeocystin, norbaeocystin

35. psilocin, baeocystin, norpsilocin

36. psilocin, aeruginascin

37. psilocin, aeruginascin, norpsilocin

38. psilocin, aeruginascin, norbaeocystin

39. psilocin, aeruginascin, norpsilocin, norbaeocystin

40. psilocin, norpsilocin

41. psilocin, norpsilocin, norbaeocystin

42. psilocin, norbaeocystin

Biotechnology -based production of entheogens offers a promising route to ensure a cost- effective, cGMP, robust supply for clinical development. Naturally derived psychedelic compounds may offer significant therapeutic advantages over synthetic molecules because of entourage effects. These reflect the action of additional components that may act synergistically or additively with the principal molecule or have pharmacokinetic effects. A case in point is psilocybin which is derived from multiple mushroom species that contain a wealth of additional active components. Anecdotal and clinical reports as well as preclinical studies suggest a discernible difference between the effects of chemically synthesized psilocybin and those of psychedelic mushrooms and also differences among the effects of different mushroom strains.

In some preferred embodiments, the entheogen compounds utilized in the present invention are derived from cell culture and in particular on mushroom cell cultured, psychoactive compound-containing mushroom compositions. As used herein, the term "mushroom culture compositions" refers to compositions comprising a mushroom cell culture and products derived therefrom specifically including 1) fractions, such as aqueous fractions, prepared from the mushroom cell culture that contain one or more psychoactive compounds, 2) extracts, such as aqueous solvent extracts or organic solvent extracts, prepared from the mushroom cell culture that comprise one or more psychoactive compounds, and 3) purified preparations of one or more psychoactive compounds prepared from a mushroom cell culture by methods including one or more of solvent extraction, concentration by solvent removal, chromatography and other methods of extraction, purification and fractionation. As used herein, the term "psychoactive compounds" refers to chemical substances that change a person's mental state by affecting the way the brain and nervous system work, and specifically, includes, but is not limited to psilocybin, baeocystin, aurugeniscin, norpsilocin, norbaeocystin, and combinations thereof.

In some preferred embodiments, and specifically for treatment of the disorders described herein, the effective dosage of the mushroom cell culture compositions is a sub-psychedelic dose.

A "sub-psychedelic dose" as used herein is a sub-hallucinogenic doses of a psychedelic substance such as a psilocybin. Sub-psychedelic dosing can be achieved via several schedules: 1) sub-chronic, sub-psychedelic doses of psilocybin given over several days with or without other components of mushroom cell culture extract, 2) a sustained release preparation of psilocybin with or without other components of the mushroom cell culture extract which will allow the full psychedelic dose to be administered over 24 hours and thus avoid acute psychotogenic effects; 3) a psychedelic dose of psilocybin with or without other components of mushroom cell culture spectrum extract in conjunction with a 5-HT2A receptor antagonist, that blocks psilocybin- induced psychedelic effects. 4) Use of a psychedelic dose of psilocybin with or without other components of mushroom cell culture extract in conjunction with a 5-HT1 A agonist such as buspirone which will prevent the possible psychosis enhancing effects while at the same time exerting a possible dopaminergically mediated beneficial effect via dopamine D2 receptor antagonist effects of buspirone.

In some preferred embodiments, the biomass used to prepare a mushroom extract useful in the compositions of the present invention is any fungi (including hybrids) of part thereof (e.g., mycelia, primordia, fruiting bodies, etc.) containing the psilocybin biosynthetic gene cluster (psiD, psiH, psiK, psiM) or other mushrooms, fungi, lichens, etc. producing psilocybin or psilocybin analogs or related tryptamines. In some preferred embodiments, the biomass is mycelial biomass. Exemplary mushroom species include, but are not limited to, Conocybe sp., Copelandia sp., Galerina sp., Gerronema sp., Gymnopilus sp., Hypholoma sp., Inocybe sp., Mycena sp., Panaeolina sp., Panaeolus sp., Pluteus sp., andPsilocybe sp. Exemplary Psilocybes include, but are not limited to, P. acutipilea, P. angustipleurocystidiata, P. antioquensis, P. aquamarine, P. argentipes, P. armandii, P. aucklandii, P. Australiana, P. aztecorum, P. aztecorum bonetii, P. azurescens, P. baeocystis, P. banderiliensis, P. barrerae, P. bohemica, P. brasiliensis, P. brunneocystidiata, P. caeruleoannulata, P. caendescens, P. caerulescens ombrophila, P. caerulipes, P. carbonaria, P. chiapanensis, P. collybioides, P. Columbiana, P. coprinifacies, P. cordispora, P. cubensis, P. cyanescens, P. cyanofibrillosa, P. dumontii, P. eucalypta, P. fagicola, P. fagicola mesocystidiata, P. farinacea, P. fimetaria, P. fuliginosa, P. furtadoana, P. galindoi, P. goniospora, P. graveolens, P. guatapensis, P. guilartensis, P. heimii, P. heliconiae, P. herrerae, P. hispanica, P. hoogshagenii hoogshagenii, P. hoogshagenii convexa, P. inconspicua, P. indica, P. isabelae, P. jacobsii, P. jaliscana, P. kumaenorum, P. laurae, P. lazoi, P. liniformans, P. liniformans americana, P. mairei, P. makarorae, P. mammillata, P. meridensis, P. Mexicana, P. moseri, P. muliercula, P. natalensis, P. natarajanii, P. ochreata, P. papuana, P. paulensis, P. pelliculosa, P. pericystis, P. pintonii, P. pleurocystidiosa, P. plutonia, P. portoricensis, P. pseudoaztecorum, P. puberula, P. quebecensis, P. ramulosa, P. rostrata, P. rzedowskii, P. samuiensis, P. sanctorum, P. schultesii, P. semilanceata, P. septentrionalis, P. serbica, P. sierrae, P. sylvatica, P. singerii, P. strictipes, P. stuntzii, P. subacutipilea, P. subaeruginascens, P. subaeruginosa, P. subcaerulipes, P. subcubensis, P. subtropicalis, P. subyungensis, P. subzapotecorum, P. tampanensis, P. tasmaniana, P. uruguayensis, P. uxpanapensis, P. venenata, P. veraecrucis, P. villarrealii, P. wassoniorum, P. weilii, P. weldenii, P. wrightii, P. xalapensis, P. yungensis, and P. zapotecorum Tn some preferred embodiments, the entheogen (e g., a mushroom extract containing psilocybin) may be further formulated with one or more pharmaceutically acceptable carriers or delivery vehicles. As used herein, "pharmaceutically of physiologically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated.

The entheogens of the present invention may be formulated with different types of carriers depending on whether it is to be administered in solid, liquid or aerosol form, and whether it need to be sterile for such routes of administration as injection. The cell extracts of the present invention can be administered intravenously, intradermally, transdermally, intrathecally, intraarterially, intraperitoneally, intranasally, intravaginally, intrarectally, topically, intramuscularly, subcutaneously, mucosally, orally, topically, locally, inhalation and nebulization (e.g., aerosol inhalation), injection, infusion, continuous infusion, localized perfusion bathing target cells directly, via a catheter, via a lavage, in cremes, in lipid compositions (e.g., liposomes), or by other method or any combination of the forgoing as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, incorporated herein by reference).

Upon formulation, entheogens of the present invention will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as formulated for parenteral administrations such as injectable solutions, or aerosols for delivery to the lungs, or formulated for alimentary administrations such as drug release capsules and the like.

Further in accordance with the present invention, the entheogens of the present invention suitable for administration is provided in a physiologically acceptable carrier with or without an inert diluent. The carrier should be assimilable and includes liquid, semi-solid, i.e., pastes, or solid carriers. Except insofar as any conventional media, agent, diluent or carrier is detrimental to the recipient or to the therapeutic effectiveness of the composition contained therein, its use in administrable composition for use in practicing the methods of the present invention is appropriate. Examples of carriers or diluents include fats, oils, water, saline solutions, lipids, liposomes, resins, binders, fillers and the like, or combinations thereof. The composition may also comprise various antioxidants to retard oxidation of one or more component. Additionally, the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.

In accordance with the present invention, the entheogens are combined with the carrier in any convenient and practical manner, i.e., by solution, suspension, emulsification, admixture, encapsulation, absorption and the like. Such procedures are routine for those skilled in the art.

Stabilizing agents can be also added in the mixing process in order to protect the composition from loss of therapeutic activity, i.e., denaturation in the stomach. Examples of stabilizers for use in the composition include buffers, amino acids such as glycine and lysine, carbohydrates such as dextrose, mannose, galactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol, etc.

The actual dosage amount of the entheogen of the present invention administered to an animal patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration: Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

Example 1 (Prophetic)

Behavioral phenotypic profiling of zebrafish following exposure to psilocybin in a “full spectrum” psychedelic mushroom extract (FSME) while under propofol anesthesia

Introduction The “classic psychedelics” including psilocybin have great potential as treatments for a range of mental disorders, and psilocybin is in advanced clinical development for major depressive disorder (MDD). To date, it has been extremely challenging to understand the respective roles of the subjective experience (“trip”) and that of neuropharmacological effects, in the therapeutic action of psilocybin. One possible avenue of research to distinguish between the role of the subjective experience and the direct pharmacological action of psilocybin, could be to “remove” or substantially attenuate the subjective experience using sedation or anesthesia. It remains unclear as to whether animals such as rodents and zebrafish do indeed have similar or analogous systems of “experience” or “consciousness” to primates.

Aims

In order to better understand the interaction between “classic psychedelics” and anesthetics, we will compare the behavioral phenotypic profiles of zebrafish following exposure to FSME under anesthesia in zebrafish results with those of zebrafish exposed to FSME while not under anesthesia.

Methods

Animals: Adult zebrafish (Danio rerio , Drugs: Propofol is a short-acting hypnotic drug that produces a rapid anesthesia induction with short duration being rapidly metabolized and without cumulative effects, being also capable of causing cardiorespiratory depression. FSME is “full spectrum” psychedelic mushroom extract - a purified, methanol extract of Psilocybe mushroom with precise quantitation of psilocybin and psilocin and tryptamines of the psilocybin biosynthetic chain (baeocystin, norbaeocystin, aerugenascin norpsilocin).

Treatment groups, dosing, experimental design: Four groups: Control (tank water); propofol only; propofol plus FSME; FSME only. Dosing: FSME - 5mg/L; Propofol - 1.25mg/L.

Experimental design: Vehicle group: 60 minute exposure to tank water in 200ml dosing tank followed by 60 minute rest, followed by behavioral phenotypic testing. Propofol only group: propofol induction and intubation (propofol only) - total anesthesia time (following induction) = 80 minutes, followed by 1 hour rest, followed by behavioral phenotypic testing. Propofol and FSME group: propofol induction followed by intubation with administration propofol and FSME for 20 minutes, followed by propofol only for 60 minutes (total anesthesia time (following induction) = 80 minutes), followed by 60 minutes rest, followed by behavioral phenotypic testing. Experimental models: Behavioral phenotyping is undertaken including the open field arena, novel object, social interaction, light-dark preference and other behavioral phenotyping tests. Other possible tests that may be conducted include brain metabolomics, brain synaptic proteins and microbiome metagenomics may be included. These experiments will subsequently be conducted in disease models for psychiatric and neurological disorders.

The scope of the present invention is not limited by what has been specifically shown and described hereinabove. Those skilled in the art will recognize that there are suitable alternatives to the depicted examples of materials, configurations, constructions, and dimensions. Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and scope of the invention.

Numerous references, including patents and various publications, are cited and discussed in the description of this invention. The citation and discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any reference is prior art to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety.