Compositions containing neuroplastic agents administered in non-psychedelic / psychotometic doses and formulations and methods of use

Abstract

Compositions and methods of use comprising serotonin (5-HT) receptor agonists and NMDAR modulators, including some of the substances classified as 5-HT2A agonists of the present disclosure, administered as modulators of neuroplasticity (neuroplastogens) in non-psychedelic / psychotometic doses, topologies, and formulations for the treatment of diseases and conditions and improvement of function, and which provide, among other things, NMDAR modulating effects.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority and benefit under 35 U.S.C. § 119(e) to U.S. Patent Application No. 62 / 814,929, filed on March 7, 2019, and U.S. Patent Application No. 62 / 844,151, filed on May 7, 2019, the disclosures of which are hereby incorporated by reference in their entireties.

[0002] Various aspects of the present invention relate to compositions containing substances that induce neuroplasticity, and methods that include the step of administering such substances in non - psychedelic and / or non - psychotomimetic dosages.

Background Art

[0003] The following sections are intended to introduce the reader to various aspects of the technology that may be relevant to the various aspects of the present invention described and / or claimed below. This discussion is thought to be useful in providing the reader with background information that facilitates a better understanding of the various aspects of the present invention. It should be understood, therefore, that these descriptions are to be construed from this perspective and are not to be construed as an admission of prior art.

[0004] Both the medical community and common perception define psychedelic substances (including those belonging to the tryptamine family and substances classified as 5 - HT2A agonists) by their ability to determine some changes in consciousness, emotion, and cognition, including positive and negative psychotomimetic symptoms (e.g., psychedelic effects, psychedelic experiences, psychotomimetic effects). These psychedelic / psychotomimetic effects are known to non - experts and physicians as potential for recreational abuse, and to researchers in the field of psychiatry as potential for therapeutic use in research applications to psychiatry and brain function research. In the case of substances of the tryptamine family, these psychedelic / psychotomimetic effects are thought to be mainly induced by agonist action at the 5 - HT2A receptor of the 5 - HT receptor family.

[0005] Psychedelic substances are currently being studied for the treatment of several psychiatric disorders and symptoms, including depression, PTSD, OCD, addictions, and end-of-life cancer-related anxiety. From available scientific literature and other disclosures (including patents and patent applications) and ongoing clinical studies, psychedelic experiences, including the positive and negative psychedelic effects induced by serotonin agonist substances, are an integral part of the intended treatment, research applicability, and even the recreational misuse of these substances. Particularly for therapeutic purposes, serotonin agonist psychedelic drugs are administered in a specific "set and setting," with counseling and / or psychotherapy taking place before, during, and after the drug administration, and the entire session being supervised and closely monitored (Johnson M, Richards W, Griffiths R., Human hallucinogen research: guidelines for safety, J Psychopharmacol., August 2008; 22(6):603-20). According to researchers and therapists, to achieve therapeutic efficacy for specific psychiatric disorders, administering serotonin agonists at doses that produce psychedelic and / or psychedelic symptoms should be paired with adjunctive treatments, including a specific physical setting, in addition to counseling and / or psychotherapy (talk therapy) before, during, and after drug administration. Thus, psychedelic experiences (including changes in consciousness, emotion, and cognition, as well as positive and negative psychedelic symptoms) have, to date, been considered an integral part of the potential therapeutic efficacy of psychedelic drugs by researchers and scientists.

[0006] Psychedelic drugs are generally administered once per single session (single administration of a psychedelic substance), and the acute psychedelic / psychotomimetic effects last for about 4 to 6 hours. In addition to the acute effects, psychological beneficial effects that last for several months after a single session have been described, contributing to the current understanding of the potential beneficial effects of 5-HT agonist drug treatment [Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R., Mystical-type Experiences Occasioned by Psilocybin Mediate the Attribution of Personal Meaning and Spiritual Significance 14 Months Later, J Psychopharmacol., August 2008;22(6):621-632; Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Nienke J Pannekoek, Wall MB, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R, Curran HV, Nutt DJ., Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms, Scientific Reports, Volume 7, Article number: 13187 (2017)].

[0007] The mechanisms underlying the potential efficacy of 5-HT2A agonists administered at "psychedelic / psychotomimetic" high doses (single session) for depression have recently been associated with the BDNF and mTOR pathways and potentially related to neural plasticity (Ly C, Greb AC, Cameron LP et al., Psychedelics Promote Structural and Functional Neural Plasticity, Cell Rep., 2018;23(11):3170-3182).

[0008] The selected NMDAR antagonists (open-channel blockers) have been found to be effective in neurological and psychiatric disorders (e.g., memantine, amantadine, and the dextromethorphan-quinidine combination have been FDA-approved for the treatment of Alzheimer's dementia, Parkinson's disease, and emotional lability associated with pseudobulbar palsy, respectively, and esketamine has been FDA-approved for treatment-resistant depression). Further, another NMDAR antagonist, dextromethadone, is under investigation for psychiatric disorders, a number of neurological diseases, syndromes, and signs and symptoms (hereinafter defined as "neuropsychiatric disorders"), ophthalmological and metabolic disorders, and disorders associated with aging (U.S. Patent No. 9,468,611 and International Application PCT / US2018 / 016159). Dextromethorphan in combination with bupropion is under investigation for depression and agitation in dementia (Axsome Therapeutics).

[0009] Moreover, there is increasing evidence regarding the role of NMDAR antagonists, particularly ketamine and dextromethadone, in regulating neuroplasticity (Li N, Lee B, Liu RJ, et al., mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists, Science, 2010;329(5994):959-964, doi:10.1126 / science.1190287; Vitolo OV, Manfredi PL, Inturrisi CE, DiGuglielmo G, Hanania T, Bernstein G, DeMartin S, Fogaca M, Duman R, Traversa S., Development of the N-Methyl-D-Aspartate Receptor (NMDAR) Antagonist d-Methadone (REL 1017) for the Treatment of Depression and Other CNS Disorders, American Society of Clinical Psychopharmacology annual meeting, May 2019; Fogaca MV, Fukumoto K, Franklin T, et al., N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects, Neuropsychopharmacology, 2019;44(13):2230-2238).

[0010] Therefore, the therapeutic potential of NMDAR antagonists at doses that do not cause psychedelic or psychotomimetic effects is well established for the drugs selected and the diseases selected (memantine, adamantine, and dextromethorphan / quinidine are FDA approved for the treatment of emotional lability associated with Alzheimer's dementia, Parkinson's disease, and pseudobulbar palsy, respectively). Notably, the doses of esketamine recently approved by the FDA for the treatment of depression remain high enough to cause some psychedelic / psychotomimetic effects (dissociative effects), and at present, the treatment with esketamine is limited to treatment-resistant depression and requires supervision in a clinic.

[0011] More notably, the mechanisms underlying the potential effects of 5-HT2A agonists on the treatment of depression (Ly et al., 2018) and the mechanisms underlying the potential efficacy of NMDAR antagonists against a number of disorders and pathologies are both thought to be mTORR- and BDNF-dependent (International Application PCT / US2018 / 016159; De Martin S, Vitolo OV, Bernstein G, Alimonti A, Traversa S, Inturrisi CE, Manfredi PL, The NMDAR Antagonist Dextromethadone Increases Plasma BDNF levels in Healthy Volunteers Undergoing a 14-day In-Patient Phase 1 Study, ACNP annual meeting, December 9-13, 2018; Hollywood, Florida; Li N, Lee B, Liu RJ et al., mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists, Science, 2010; 329(5994):959-964, doi:10.1126 / science.1190287; Fogaca MV, Fukumoto K, Franklin T et al., N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects, Neuropsychopharmacology, 2019; 44(13):2230-2238). However, these mechanisms that induce neuroplasticity are thought to be different mechanisms, one of which is mediated via the 5-HT2A receptor and the other of which is mediated by the open channel block of NMDAR.

Prior Art Documents

Patent Documents

[0012] [Patent Document 1] U.S. Patent No. 9,468,611 [Patent Document 2] International Application PCT / US2018 / 016159 [Patent Document 3] U.S. Patent No. 5,593,876 [Non-Patent Document]

[0013] [Non-Patent Document 1] Johnson M, Richards W, Griffiths R., Human hallucinogen research: guidelines for safety, J Psychopharmacol., August 2008; 22(6): 603 - 20 [Non-Patent Document 2] Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R., Mystical-type Experiences Occasioned by Psilocybin Mediate the Attribution of Personal Meaning and Spiritual Significance 14 Months Later, J Psychopharmacol., August 2008; 22(6): 621 - 32 [Non-Patent Document 3] Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Nienke J Pannekoek, Wall MB, Tanner M, Kaelen M, McGonigle J, Murphy K, Leech R, Curran HV, Nutt DJ., Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms, Scientific Reports, Volume 7, Article number: 13187 (2017) [Non-Patent Document 4] Ly C, Greb AC, Cameron LP, et al., Psychedelics Promote Structural and Functional Neural Plasticity, Cell Rep., 2018;23(11):3170 - 3182

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Summary of the Invention

Means for Solving the Problems

[0014] Some exemplary embodiments of the present invention are described below. These embodiments are presented only to provide the reader with a brief overview of some of the forms that the present invention can take and should not be construed as limiting the scope of the present invention. In fact, the present invention can encompass various aspects that cannot be explicitly set forth below.

[0015] One aspect of the present invention is directed to compounds comprising structural analogs of psilocin, norpsilocin, psilocybin, baeocystin, norbaeocystin, or N,N-dimethyltryptamine according to formula I

[0016] [Chemical formula]

[0017] [wherein, (1) R 1 and R 2 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, (independently or closed-ring with nitrogen) C 3 ~C 8 cycloalkyl, (independently or closed-ring with nitrogen) C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (2) R 3 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8is cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (3)R 4 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl, and any of them may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, aryl carbamoyl, nitro, cyano, nitrate, or R 4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamide, alkylamide, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino, and (4)R 5 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 represents 1 to 3 substituents selected from the group consisting of cycloalkenyl, aryl or heterocyclyl, and may be substituted with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions, (5)R 6 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, any of which may be substituted with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions, or R 6 is halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH) 2 、-OC(O)R 7 、-OSO 2OH, -OC(O)NHR 7 , -OC(O)NR 7 R 8 or is selected from the group consisting of -SONH, and (6) n is from 1 to 5].

[0018] Another aspect of the present invention is directed to compounds comprising a structural analog of 2,5-dimethoxy-4-iodoamphetamine according to formula II

[0019] [Chemical formula]

[0020] [wherein, (1) A is C 1 ~C 6 alkylene, C 2 ~C 6 alkenylene, or C 2 ~C 6 alkynylene, (2) R 1 and R 2 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, (independently or closed-ring with nitrogen) C 3 ~C 8 cycloalkyl, (independently or closed-ring with nitrogen) C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, (3) R 3 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (4)R 4 and R 5 are independently hydrogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thi -ol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 4 and R 5is independently, in each instance, selected from the group consisting of alkyl esters, alkyl sulfonyls, alkyl carbamoyls, aryl carbamoyls, nitrates, (5)R 6 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, representing 1 to 3 substituents selected from the group, and being optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkyl sulfonyl, alkyl carbamoyl, aryl carbamoyl, nitro, cyano, nitrate].

[0021] Another aspect of the present invention is directed to compounds comprising a structural analog of diethylamide lysergic acid according to formula III

[0022] [Chemical formula]

[0023] [wherein, (1) R 1 and R 2 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, (independently or in a ring closed with nitrogen) C 3 ~C 8 cycloalkyl, (independently or in a ring closed with nitrogen) C 3 ~C 8is cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (2) R 3 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (3) R 4 and R 7 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8Cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl and may be substituted by nitro, cyano, nitrate, (4)R 5 and R 6 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 5 and R 6 are independently, in each occurrence, selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, (5)R 8 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3~C 8 Cycloalkyl, C 3 ~C 8 represents 1 to 3 substituents selected from the group consisting of cycloalkenyl, aryl or heterocyclyl, and may be substituted with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions]。

[0024] Another aspect of the present invention is directed to compounds containing a structural analog of ibogaine according to formula IV

[0025]

Chemical formula

[0026] [Wherein, (1) R 1 is deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions, (2) R 2 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 2 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (3) R 3 is hydrogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3 is alkyl ester, alkyl is selected from the group consisting of sulfonyl, alkylcarbamoyl, arylcarbamoyl, nitrate, and (4) R 4represents one to three substituents selected from the group consisting of hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions].

[0027] Formulas I - IV also appear in Table 1A (Table 1) below.

[0028] Another aspect of the present invention is a method for preventing or treating a disease and condition, or improving a function in a patient or subject, comprising administering a compound described as Formulas I - IV in a dose, dosage, posology, or formulation having a clinical effect comparable to the clinical effect brought about by a clinically meaningful psychedelic or psychotomimetic action or effect, or a clinical effect comparable to the clinical effect brought about by a human plasma psilocin Cmax of 4 ng / ml or less or a human 5-HT2A CNS receptor occupancy of 50% or less, or a PD effect comparable to the PD effect brought about by a human plasma psilocin Tmax of more than 60 minutes.

[0029] Another aspect of the present invention is a method for preventing or treating a disease and condition, or improving a function, in a patient or subject, comprising administering a 5-HT2A agonist substance in a dose, dosage, posology, or formulation having a clinical effect comparable to that brought about by a clinically meaningful psychedelic or psychotomimetic effect or effect, or a clinical effect comparable to that brought about by a human plasma psilocin Cmax of 4 ng / ml or less or a human 5-HT2A CNS receptor occupancy of 50% or less, or a PD effect comparable to that brought about by a human plasma psilocin Tmax of more than 60 minutes.

[0030] The accompanying drawings, which are incorporated herein and constitute a part of this specification, illustrate embodiments of the invention and, together with the general description of the invention above and the detailed description of the embodiments below, serve to explain the principles of the invention.

Brief Description of the Drawings

[0031]

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Mode for Carrying Out the Invention

[0032] One or more specific embodiments of the present invention will be described below. In an attempt to briefly describe these embodiments, not all features of actual implementation may be described herein. As with any engineering or design project, in the development of any such actual implementation, it should be understood that numerous implementation-specific decisions must be made to achieve the specific goals of the developer, such as complying with system-related and business-related constraints that may vary from one implementation to another. Furthermore, although such development efforts can be complex and time-consuming, it should be understood that they are routine tasks in design, fabrication, and manufacture for an ordinary skilled person who will benefit from the present disclosure.

[0033] Definitions In the present disclosure, the inventors define "disease" as human and veterinary diseases / disorders / syndromes / symptoms at various stages from the pre-onset stage to the progression stage (including symptoms and signs of the disease, including prodromal symptoms and other signs of the disease).

[0034] In the present disclosure, the inventors define "symptom" as the sign of the disease defined above.

[0035] In the present disclosure, the inventors define "pathological condition" as a performance lower than the potential ability and goal of an individual in terms of cognitive, motor, and social abilities, and a performance lower than the potential ability and goal of an individual in terms of special senses.

[0036] In the present disclosure, the inventors define "function" as the function of special senses (vision, smell, taste, hearing, and sense of balance), including for visual improvement.

[0037] In the present disclosure, the inventors define "aging" as the accumulation of biological changes over time that lead to deficits or declines in physical, psychological, and social capabilities. In this definition, the inventors include physical and chemical factors, including environmental factors, toxins, and drugs, lack of food, nutrients and vitamins, and accelerated aging and diseases caused by drug treatment. Osteoporosis, a form of bone aging, is particularly relevant because NMDARs are known to be present on osteoblasts and osteoclasts (Chenu C, Serre CM, Raynal C, Burt-Pichat B and Delmas PD, (1998), Glutamate receptors are expressed by bone cells and are involved in bone resorption, Bone 22: 295-299).

[0038] In the present disclosure, the inventors define "treatment" to include the treatment of conditions, symptoms, disorders, syndromes and diseases and / or prevention including primary and secondary prevention, and improvement.

[0039] In the present disclosure, the inventors define "neuroplasticity" as changes in the structure and function of the nervous system that occur at any time during the lifespan, including neurogenesis, regulation of the size, shape and length of neuron or astrocyte cell bodies or neurites, synaptogenesis, synaptic strengthening, spine formation, pruning of synaptic spines, changes in synaptic spine volume, changes in synaptic density, including synaptic plasticity, and changes in specific synaptic proteins and pathways (including PD95, PD93, synapsin, GLUR1, particularly including mRNA encoding synaptic density proteins and receptor subunits, particularly including protein subunits of AMPAR and NMDAR, regulation of the mTOR pathway and TrkB pathway, and changes in the pathway of neurotrophic factors, particularly including BDNF).

[0040] In the present disclosure, the inventors define a "neuroplasticogen drug" or "neuroplasticogen" as a drug having the potential ability to regulate neuroplasticity as defined above. For a neuroplasticogen drug to be potentially useful for the treatment of diseases and conditions, the drug should be safe and well-tolerated, and the regulatory effect on neuroplasticity should occur in the absence of clinically significant side effects, including in the absence of psychedelic / psychotomimetic effects. A neuroplasticogen drug should be administered at a neuroplasticogen dosage, dose, posology, and / or formulation as defined below.

[0041] In the present disclosure, the inventors define a "neuroplasticogen dosage", particularly a "neuroplasticogen dosage of a drug classified as a 5-HT2A agonist", as a dosage, dose, posology, and / or formulation that, when administered, is well-tolerated, safe, and has an effect on 5-HT2A agonism and neuroplasticity, including regulation of NMDAR, without causing a clinically significant psychedelic / psychotomimetic effect. A neuroplasticogen drug regulates NMDAR through gene regulation of NMDAR subunits and gene regulation of trophic factors including BDNF, without causing clinically significant off-target effects, including not causing changes in clinically significant consciousness, emotion, and cognition, including positive and negative psychotomimetic symptoms (psychedelic effects, psychedelic experiences, psychotomimetic effects). The novel mechanism of action of a neuroplasticogen drug proposed by the inventors for use in the treatment of diseases and conditions is composed of the differential downregulation of excessive Ca 2+ influx through only subtypes A to D of overactive NMDAR (selective open channel blockers) in selected cell populations and / or cell networks. Excessive Ca 2+The influx block restores cellular functions, including functions essential for physiological neural plasticity (e.g., mobilization and synthesis of synaptic proteins including NMDAR subunits, and synthesis of neurotrophic factors including BDNF).

[0042] Description of various aspects of the present invention The inventors herein provide new experimental evidence demonstrating the NMDAR-modulating effect of the neuroplasticogen 5-HT2A agonist (see Example 3 below). This experimental evidence indicates that neural plasticity can occur with low doses of the 5-HT2A agonist in the absence of psychedelic / psychotomimetic effects, and thus these psychedelic / psychotomimetic effects may be regarded as side effects rather than therapeutic effects (as in the case of some NMDAR antagonists).

[0043] The potential therapeutic effects of substances of the triptan family (5-HT agonists, including 5-HT2A agonists) administered chronically, continuously or intermittently at doses and formulations that do not cause psychedelic / psychotic effects have not been fully explored previously. The scientific literature on the administration of low-dose psychedelic drugs is limited, and the scientific publications available to date state that they preclude the use of these substances for the treatment of diseases. Findings from Anderson et al. (Anderson T, Petranker R, Rosenbaum D, Weissman CR, Dinh-Williams LA, Hui K, Hapke E, Farb NAS., Microdosing psychedelics: personality, mental health, and creativity differences in microdosers, Psychopharmacology (Berl), January 20, 2019) and the 2019 review and study by Polito and Stevenson (Polito V, Stevenson RJ, (2019), A systematic study of microdosing psychedelics, PLOS ONE 14(2): e0211023, https: / / doi.org / 10.1371 / journal.pone.0211023), which emphasize that the "beneficial" effects of low-dose psychedelic substances can at best be defined as a general "increase in psychological functioning", state that the use of low-dose psychedelic substances as neuroplasticogens for the treatment of diseases, including neurological or ophthalmological diseases, or for deficits associated with aging and senescence, or even for general improvement in cognitive function (nootropic effects), is precluded. In particular, Polito and Stevenson conclude that "recent findings suggest that the well-known accounts of the effects of microdosing may not fit the experiences of long-term microdosers, and that promising avenues for future investigation are the effects of microdosing on improved mental health, attentional ability, and neuroticism."The study by Fadiman and Korb (Fadiman J, Korb S, Might Microdosing J Psychedelics Be Safe and Beneficial? An Initial Exploration, Psychoactive Drugs, March 29, 2019: 1-5) suggests that negative mood was improved after microdosing. These conclusions highlight how the focus and understanding of the current research on "microdosing" of psychedelic substances to date has remained limited to the field of psychiatric experimentation, and state that the potential use of 5-HT agonist substances at sub-psychedelic doses for the treatment and prevention of neurological and ophthalmological diseases, metabolic diseases, and other clinical indications and conditions listed in this application, including the treatment of psychiatric disorders defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), is excluded. The possibility of treating mental disorders is not expected by potential improvements to "negative mood", as hypothesized by Fadiman.

[0044] Furthermore, current knowledge about non-psychedelic / psychotomimetic doses of 5-HT agonists states that their use for therapeutic indications, including psychiatric indications, is precluded. The potential effectiveness of 5-HT agonists for the treatment of diseases, specifically psychiatric diseases, is currently closely related to their ability to cause psychedelic / psychotomimetic symptoms. Thus, the potential therapeutic effectiveness of currently investigated psychedelic substances is within the range of their ability to cause a "psychedelic experience", and psychedelic substances are administered in a single dose for the treatment of several psychiatric diseases and symptoms, together with psychotherapy, and together with counseling / interactive therapy before, during, and after drug administration, under careful supervision in a special setting. Psychedelic drugs administered in such a specific form are currently in various stages of development, including phase 2 clinical studies. The potential for non-psychedelic / psychotomimetic doses of 5-HT agonists for the treatment of diseases, conditions, and aging is not currently under clinical investigation, and current scientific knowledge states that the therapeutic use of 5-HT2A agonists at non-psychedelic / psychotomimetic doses is precluded.

[0045] Patients who are particularly sensitive to the mind-altering effects and psychedelic / psychotomimetic effects of 5-HT2A agonists may benefit from neuroplastic 5-HT2A agonists, including the release modulation (MR) formulations detailed below, and thus 5-HT2A agonists may be administered repeatedly over several days or months or even chronically without the need for specific settings, or the need for counseling and / or psychotherapy, or the need for frequent monitoring and supervision. This is because the psychedelic / psychotomimetic effects do not occur with appropriate posology and formulation.

[0046] The induction of neuroplasticity can potentially enable effective treatment of conditions, symptoms, disorders, syndromes, and diseases in which it may be beneficial, particularly in patients in whom the manifestation of mental abnormalities and the repeated induction of psychedelic effects are contraindicated and / or harmful, by the administration of a 5-HT2A drug over a period of time, from several days to several months, or by chronic, continuous, or intermittent repeated administration. The therapeutic time range of psilocybin and other 5-HT2A agonist drugs can be extended by changing the drug formulation to a release-modulating formulation, as will be disclosed in more detail below. Notably, the inventors also present experimental evidence that intermittent repeated treatment, including intermittent long-term treatment such as once every other day, twice every other day, weekly, once a week, once a month, can provide advantages over continuous long-term treatment (daily treatment).

[0047] Therefore, 5-HT2A agonists administered chronically at non-psychedelic low doses (neuroplasticogen doses) can be therapeutic not only for psychiatric indications but also for a number of diseases and conditions, and are of interest to researchers considering the psychedelic dosing of 5-HT2A agonists.

[0048] As shown by some of the novel experimental studies detailed below, there may be potential allosteric effects with potential synergistic effects among selected molecules in these two drug classes.

[0049] Therefore, the inventors disclose that for many patients in whom 5-HT receptor agonists with neuroplastic effects may be beneficial, particularly those who may potentially benefit from a neuroplastic effect maintained over a period of time, the psychedelic experience and the effects of manifesting mental abnormalities and other mind-altering effects of these drugs are harmful side effects that pose a problem of relative drug overdose and are not the essential activity of the therapeutic agent, as considered by ongoing research activities in the field of 5-HT2A agonists.

[0050] In short, drugs or pharmaceutical formulations that have a neuroplastic effect but no psychedelic effect can benefit patients and individuals and can improve or prevent pathological conditions, symptoms, disorders, syndromes, and diseases in human subjects. Further, specific settings and frequent personal supervision / counseling / psychotherapy are unnecessary for the action of 5-HT2A agonists on neuroplasticity when non-psychedelic dosages and formulations are administered. The inventors disclose the potential benefits from these novel compositions, as well as the use of 5-HT2A agonists for the treatment of a number of pathological conditions, symptoms, disorders, syndromes, and diseases, including ophthalmological, neurological, psychiatric, metabolic pathological conditions, symptoms, disorders, syndromes, and diseases, and for the treatment of deficits associated with aging.

[0051] Psychedelic drugs, as their name implies, determine their psychedelic / psychotomimetic effects, and their potential intended therapeutic benefits for psychiatric disorders are essentially associated with these psychedelic / psychotomimetic effects. However, their current therapeutic use under consideration is generally induced in a single session using high doses of 5-HT agonists in a specific setting, and is focused on psychiatric diseases and conditions in which the "psychedelic experience" that occurs before and after counseling and / or psychotherapy may be beneficial (Griffiths RR, Richards WA, Johnson MW, McCann UD, Jesse R., Mystical-type Experiences Occasioned by Psilocybin Mediate the Attribution of Personal Meaning and Spiritual Significance 14 Months Later, J Psychopharmacol., August 2008;22(6):621-632). The compositions and uses described in the present application are rather characterized by the ability to modulate neuroplasticity, which does not cause psychedelic / psychotomimetic effects, over a period of time, by repeated administration, daily or intermittently for several days to several months, or even chronically, in doses and formulations that are administered to a number of diseases, conditions, disorders, syndromes and diseases, including neuropsychiatric, metabolic and ophthalmological conditions, symptoms, disorders, syndromes and diseases that require current, several days or months, or even chronic regulation of neuroplasticity. Thus, in the case of 5-HT2A neuroplasticogens, the psychedelic effect is not a therapeutic effect but an undesirable side effect, and these side effects make these drugs contraindicated for patients and subjects for whom the neuroplastic effects of these drugs could otherwise be beneficial.

[0052] The pharmacology, including dosage, dosing frequency and timing (dosage regimen), the formulation including the release-modulated formulation, the treatment period, several days or chronic as opposed to once, and in some cases the route and method of administration, thus the PK parameters (especially Cmax, Tmax) as well as PD parameters including acute and chronic receptor occupancy, receptor down-regulation effects, and downstream effects including trophic effects on cells, including effects on neurogenesis, promotion of branching, neurite outgrowth, synaptogenesis, synaptic strengthening, spine formation, increase in synaptic spine volume, increase in synaptic density, including regulation of specific synaptic proteins including PD95, synapsin, GLUR1, and protein subunits of NMDAR, various subtypes, subunits and subtypes of AMPAR, including regulation of the mTOR pathway and TrkB pathway and regulation of neurotrophins including BDNF, anti-inflammatory effects including effects on TNF-α, IL-10, IL-6 and other inflammatory markers and neuroplasticity markers described in our experiments in neurons, astrocytes, oligodendrocytes, Schwann cells, potentially leading to trophic effects on additional selected cells including, for example, especially retinal pigment cells and other cells that support sensory receptors including auditory, vestibular, olfactory, gustatory and tactile receptors, and ultimately the clinical effects vary greatly. Furthermore, the adjuvant treatment and treatment-related preventive measures, and ultimately the clinical indications and treatment indications are likely to be substantially different from current use and misuse by researchers, therapists and non-experts.

[0053] Based on the observations and findings of the present inventors, the present inventors disclose that for many patients as well as numerous pathologies, symptoms, disorders, syndromes and diseases, the psychedelic experience and psychopathological manifestation effects are side effects due to an overdose of substances with a potential neuroplasticogen effect that is useful for treatment at lower, non-psychedelic doses. Further, the psychedelic effect / psychopathological manifestation effect may be useful for treatment in some situations for selected indications and selected patients outside the scope of the present disclosure, such as for a subset of patients suffering from currently investigated disorders (depression, PTSD, anxiety, addiction) using psychedelic drugs, but the present inventors disclose that for a number of pathologies, symptoms, disorders, syndromes and diseases for which the neuroplasticogen effect may be beneficial, including a subset of patients suffering from the same psychiatric disorders (depression, PTSD, anxiety, addiction) (a complete list of these potential indications is disclosed below), the psychedelic experience / psychopathological manifestation effect is a side effect of an overdose of a drug administered at supra-therapeutic doses. For further explanation, the psychedelic experience and psychopathological manifestation symptoms are generally caused by overdosing on 5-HT2A agonists and / or NMDAR antagonist neuroplasticogens, but the therapeutic neuroplasticogen effect is brought about by much lower and safer doses (about 1 / 10) of the same drugs, and these neuroplasticogen effects are potentially useful for treatment for a number of pathologies, symptoms, disorders, syndromes and diseases listed below in the absence of the psychedelic effect. Further, the tolerance, safety and efficacy of selected neuroplasticogens can be enhanced by novel MR formulations. The present inventors hereby disclose the potential neuroplasticogen effects of serotonin agonist substances, particularly substances with an action at the 5-HT2A receptor and other serotonin receptors, particularly psilocin carbamate, psilocybin and baeocystin and their derivatives. Moreover, the present inventors disclose the neuroplasticogen effects of psilocin, norpsilocin, norbaeocystin and their derivatives at doses and formulations that do not cause psychedelic or psychopathological manifestation symptoms.Furthermore, the inventors disclose the potential therapeutic actions of selected structural modified derivatives of serotonin neuroplastogens (including nitro derivatives of 5-HT2A receptor agonists described below, SMSN) having neuroplastogen effects in accordance with the neuroplastogen definition outlined above.

[0054] These neuroplastogen effects can be the regulation of the transcription and synthesis of glutamate receptors, as described in the inventors' novel experiments, and are also associated with, or can be promoted by, anti-inflammatory effects on neural tissue and other mammalian tissues, as represented by the inventors' experiments. These neuroplastogen effects can be particularly important for preventing, alleviating, and treating a number of pathologies, symptoms, disorders, syndromes, and diseases at dosages and formulations that do not produce psychedelic effects, or psychotomimetic effects or other clinically significant side effects on thought, emotion, and cognition. Thus, in the case of neuroplastogens, the psychedelic and psychotomimetic effects are side effects, not therapeutic effects, but their potential effects on learning, including academic / scholastic learning, motor, and social skills learning, and on emotional pathway dysfunction affected by learning are rather potential therapeutic targets.

[0055] Accordingly, the inventors disclose that in the case of neuroplastogens, when following appropriate dosages, formulations and posologies, not only the effect on neuroplasticity, but also the trophic effect and anti-inflammatory effect exist in the absence of psychedelic / psychotomimetic manifestation symptoms. Furthermore, apart from improving neuropsychiatric, metabolic and ophthalmological symptoms, diseases and pathologies, the inventors disclose that the neuroplastogen effect can improve various functions including sensory functions including vision, that these improvements can last longer than the pharmacological actions at the 5-HT2A receptor and other receptors, i.e., the therapeutic effect is due to their effect on neuroplasticity, and thus the therapeutic effect of these drugs can exist and be maintained after almost all of the clinically active amount of the drug has disappeared. Furthermore, the inventors disclose that multiple administrations over several days or months, rather than single administration, are required for the treatment of a number of diseases and pathologies (e.g., administered 1 to 4 times a day for 2 to 3 days or 2 to 3 weeks or 2 to 3 months or more, or indefinitely, or even once a day or every other day or weekly or every other week or monthly for several weeks or months or indefinitely), and that different indications are likely to require different posologies, but that the treatment of chronic pathologies, symptoms, disorders, syndromes and diseases for which drugs that modulate neuroplasticity can be beneficial is likely to require repeated administrations of non-psychedelic / non-psychotomimetic dosages and formulations over a certain period of time, as shown by the inventors' experimental studies.

[0056] In selected circumstances, administration of a single non-psychedelic-psychotomimetic dose of a neuroplasticogen, for example intranasally for social anxiety or panic attacks or acute enhancement of vision, may be useful. However, the potential therapeutic and beneficial effects of neuroplasticogen drugs for the treatment of a number of pathologies, symptoms, disorders, syndromes and diseases are potentially due to the somewhat prolonged effect over time on neuroplasticity of neuroplasticogen administered multiple times over a long period (from several days to several months, or chronically), as well as other trophic and anti-inflammatory effects. By combining the neuroplasticity effect, the trophic effect on neurons and other cells and the anti-inflammatory effect, the effects of some 5-HT2A agonists administered multiple times over a period of time in a non-psychedelic-symptom-causing dose and formulation, either repeatedly, intermittently (e.g., every other day or every two days or once a week) or continuously (e.g., daily or several times a day), are useful for the treatment of a number of pathologies, symptoms, disorders, syndromes and diseases, including ophthalmological, neurological, psychiatric and metabolic diseases, including improvement of function, and for the treatment of aging and age-related deficits, including accelerated aging and aging induced by harmful factors including medical treatments including cancer treatments including chemotherapy and radiotherapy, and are potentially useful for improving vision in particular ophthalmological diseases (e.g., macular degeneration) and brain diseases (e.g., CVA), and for improving vision (visual acuity improvement) in subjects with normal vision, including improvement of the special senses (vision, smell, taste, hearing and balance).

[0057] The novel experimental and observational studies of the inventors described below and the inventors' disclosures regarding neuroplastic drugs act via the 5-HT2A receptor and are useful for the treatment of a number of diseases and conditions, including ophthalmological, neurological, psychiatric and metabolic diseases, and for the treatment of aging and age-related deficits, including accelerated aging induced by deleterious agents, including medical treatments, and deficits associated with aging and age, including deficits of the special senses (vision, smell, taste, hearing and balance) caused by aging, drug treatment or other causes. They also clarify the potential of substances and drugs that potentially act via other 5-HT receptors, DA receptors, and sigma receptors, other serotonin receptors including CB1, NOP, and other receptors and transporters (DAT, NET, SERT) and other mechanisms. Drugs acting in both the 5-HT and glutamate systems, particularly 5-HT2A agonists and open-channel NMDAR antagonists, glutamate receptors including AMPAR, and / or S-nitrosylation activity at the NMDAR receptor are of particular importance. The modulation of neuroplasticity, anti-inflammatory effects and neuroprotective and trophic effects on the retina, olfactory and inner ear, including supporting cells including retinal pigment cells and cells of the nervous system including neurons, astrocytes, oligodendrocytes and Schwann cells, are potential mechanisms and targets of the therapeutic action of the neuroplastic substances and drugs detailed throughout this application. The therapeutic effects listed above are particularly obtained with neuroplastic drugs acting primarily as 5-HT2A receptor agonists administered repeatedly, continuously or intermittently over a period of days or months, or chronically.

[0058] Indoleamines and phenethylamines administered in doses that cause psychedelic symptoms in a single session, particularly psilocybin, are currently under clinical investigation for a number of psychiatric disorders and symptoms. Depression, anxiety, PTST, existential anxiety, and addiction are some of the psychiatric disorders and symptoms that may be improved by psychedelic drugs [Kvam TM, Stewart LH, Andreassen OA, Psychedelic drugs in the treatment of anxiety, depression and addiction, Tidsskr Nor Laegeforen., November 12, 2018;138(18)].

[0059] Despite the fact that the scientific psychiatric community's interest in 5-HT2A agonists for the treatment of psychiatric indications has been renewed, the recreational misuse of these substances and drugs presents a significant barrier to their development as pharmaceuticals. Strong concerns about public safety and regulation remain regarding the use of substances with the potential to induce psychedelic effects, including their use for the treatment of disease, and these substances and drugs remain illegal in most countries. In the United States and many other countries, natural and synthetic psychedelic substances, including plants and fungi, are highly liable to misuse and are classified as Schedule I substances with no accepted medical use.The relative safety and low potential for addiction of these substances have been emphasized in recent scientific publications (Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, Thomas CD, Hetzel SJ, Henriquez KM, Ribaudo AS, Hutson PR, Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults, Clin Pharmacokinet, December 2017;56(12):1543-1554; Studerus E, Kometer M, Hasler F, Vollenweider FX, Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies, J Psychopharmacol., November 2011;25(11):1434-52; Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE, The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act, Neuropharmacology, November 2018;142:143-166). However, despite their low potential for addiction, concerns remain regarding the potential for misuse, and due to the strong and multifaceted sociocultural and legal barriers (which vary widely by country), the development of psychedelic substances for the treatment of disease has remained problematic to date, and more research is needed to more fully define the role of these substances as therapeutic agents. Furthermore, the current general and scientific understanding to date teaches that psychotomimetic effects and / or the overall "psychedelic experience" are essential to the potential therapeutic activity of these substances.

[0060] The importance of psychedelic experiences as therapeutic tools may hold promise for several psychiatric indications and subsets of patients. However, the inventors here define 5-HT2A agonists, which are administered repeatedly, chronically, or intermittently over several days or months and whose effects on neuroplasticity in the absence of psychopathology / psychedelic effects are defined here as 5-HT neuroneuroplastogens. The dosage, posology, and formulation of 5-HT2A agonists, as well as the potential non-psychopathogenic effects of novel compounds with neuroneuroplastic effects disclosed in this application, specifically synthetically modified serotonin agonists (SMSN), may be useful for the treatment of nervous system diseases and pathologies, including special sense deficits such as ophthalmological, olfactory, and inner ear pathologies, as well as numerous neurological, psychiatric, ophthalmological, and metabolic pathologies and diseases, for the treatment of age-related and aging-related deficits, for the improvement of cognition (nootropic effects) and social skills, motor skills, and for the improvement of vision, smell, taste, hearing, and balance, including the improvement of vision in subjects with insufficient vision for their potential or preferences.

[0061] In addition to disclosing that at least one mechanism for inducing neuroplasticity (regulation of the BDNF and mToR-dependent pathways) is shared by NMDAR antagonists, Fogaca et al., 2019 (dextromethadone) and 5-HT2A agonists, Ly et al., 2018 (5-HT2A agonists), the inventors conducted an extensive review of the literature and found the following reports that represent possible interactions and overlapping effects between 5-HT2A agonists and NMDAR open channel blockers. The following reports, together with the inventors' observations and experimental results (including Example 3), support this application.

[0062] First, several 5-HT2A agonists have been found to inhibit NMDA receptor activity (Arvanov VL, Liang X, Russo A, Wang RY, LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex, European Journal of Neuroscience, Vol. 11, pp. 3064-3072, 1999; Berger ML, Palangsuntikul R, Rebernik P, Wolschann P, Berner H, Tryptamines at NMDA, 5-HT1A, and 5-HT2A Receptors: A Comparative Binding and Modeling Study, Current Medicinal Chemistry, 2012, 19, 3044-3057). When combined with the disclosures and experimental findings of the present inventors, the results by Arvanov et al. suggest that complementary and synergistic effects at two pharmacological targets can potentially enhance biological responses such as neuroplasticity and thus can affect the treatment outcomes of a number of diseases and pathologies.

[0063] Second, the study by Ceglia et al. (Ceglia I, Carli M, Baviera M, Renoldi G, Calcagno E, The 5-HT2A receptor antagonist M100,907 prevents extracellular glutamate rising in response to NMDA receptor blockade in the mPFC, Journal of Neurochemistry, 2004, 91, 189-199) suggests that the 5-HT2A antagonist blocks the effect of NMDAR blockade, which can suggest that 5-HT2A receptor activation may be required for the action of NMDAR antagonists. This finding also potentially supports the inventors' findings and disclosures regarding allosteric interactions and perhaps the synergistic effect between NMDA antagonists and serotonin agonists.

[0064] Third, the 1998 report by Farber et al. (Farber NB, M.D., Hanslick J, Kirby C, McWilliams L, Olney JW, Serotonergic agent that activate 5-HT2A receptors prevent NMDA antagonist neurotoxicity, Neuropsychopharmacology, 1998, 18(1)) suggests the potential protective effect of a 5-HT2A agonist against the toxicity induced by the high-affinity NMDAR antagonist MK-801. This finding, together with the inventors' disclosure, suggests potential safety advantages regarding the combined administration of an agent with 5-HT agonist activity and an agent with NMDAR antagonist activity.

[0065] Fourth, the study by Zhong et al. (Zhong P, Yuen EY, Zhen Yan, Modulation of Neuronal Excitability by Serotonin-NMDA Interactions in Prefrontal Cortex, Mol Cell Neurosci., June 2008; 38(2):290-299) suggested that the effect of 5-HT2A receptor agonists on neuronal membrane depolarization is dependent on the NMDA receptor, suggesting a co-dependence of these receptors for at least a portion of their effects.

[0066] Fifth, metabotropic glutamate receptors interact with 5-HT2A receptors to form a functional complex in the cerebral cortex (Gonzalez-Maeso J, Ang RL, Yuen T et al., Identification of a serotonin / glutamate receptor complex implicated in psychosis, Nature, 2008; 452(7183):93-97, doi:10.1038 / nature06612).

[0067] Based on the shared observations suggesting an indirect interaction between serotonin receptors and the NMDAR pathway by the authors cited above, the inventors hypothesized and then experimentally demonstrated a direct effect of 5-HT2A on NMDAR regulation, namely the induction by 5-HT2A agonists of the synthesis of NMDAR subunits in ARPE-19 cells. This novel finding and other experimental results detailed in Examples 1-3 below represent the potential efficacy of 5-HT2A agonists not only when administered as a single pulsed high dose for the treatment of depression and other psychiatric indications, as hypothesized by several researchers (Phase 2 trials are in progress), but also when administered chronically, continuously or intermittently as a neuroplasticogen (at a dose without psychedelic / psychotomimetic effects) for the treatment of diseases and conditions such as those disclosed in International Application PCT / US2018 / 016159 and this application, where modulation of NMDAR is potentially therapeutically useful.

[0068] Furthermore, the inventors disclose that a novel drug having both 5-HT2A agonist activity and NMDAR antagonist activity can provide further efficacy and safety compared to a combination of two agents. Accordingly, the inventors designed a first group of serotoninergic agonists with 5-HT2A affinity, including novel molecular features capable of conferring additional regulatory activity on NMDAR. In this context, in particular, the inventors designed novel 5-HT agonist derivatives characterized by the introduction of a nitrate ester group and planned to test the effects of these novel molecules for their affinity to block NMDAR subtypes in addition to their agonist effects on the 5-HT2A receptor. The hypothesized mechanism of NMDAR antagonism of these novel compounds is the regulation of NMDA receptor activity by S-nitrosylation of the sulfhydryl group of cysteine residues at the N-terminus (or extracellular domain) of NMDAR while maintaining the serotoninergic activity of the parent compound. The inventors are currently testing these novel agents for serotoninergic activity in both selected 5-HT receptor families and subtypes and NMDAR and their subtypes. These novel compounds are also being tested for excitotoxicity, their ability to prevent inflammatory cell damage, and neurotrophic effects.

[0069] Table 1A (below) includes novel derivatives with novel improved pharmacokinetic (PK) and / or pharmacodynamic (PD) parameters, in particular deuterated derivatives that modulate PK and / or PD, fluoro derivatives that modulate lipophilicity / cell membrane permeability and thus PK and PD properties, nitro derivatives that modulate PK and PD parameters and potentially provide additional neuroprotective effects including additional NMDAR modulation, and combinations thereof including deuterated fluoro-nitro derivatives, and variants of psilocybin, psilocin, DMT, DOI, and LSD (5-HT2A agonists).

[0070] [Table 1]

[0071] Formula I in Table 1A (Table 1) represents a structural analog of psilocin, norpsilocin, psilocybin, baeocystin, norbaeocystin, or N,N-dimethyltryptamine, wherein (1) R 1 and R 2 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, (independently or ring-closed with nitrogen) C 3 ~C 8 cycloalkyl, (independently or ring-closed with nitrogen) C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate, (2) R 3 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (3) R 4 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, any of which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamide, alkylamide, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino, and (4) R 5 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8represents 1 to 3 substituents selected from the group consisting of cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, (5)R 6 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, any of which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 6 is halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, -OP(O)(OH) 2 、-OC(O)R 7 、-OSO 2 OH、-OC(O)NHR 7 、-OC(O)NR 7 R 8 or - selected from the group consisting of SONH, (6)n is 1 to 5.

[0072] Formula II in Table 1A represents a compound containing a structural analog of 2,5-dimethoxy-4-iodoamphetamine, wherein (1) A is C 1 ~C 6 alkylene, C 2 ~C 6 alkenylene, or C 2 ~C 6 alkynylene, (2) R 1 and R 2 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, (independently or closed in a ring with nitrogen) C 3 ~C 8 cycloalkyl, (independently or closed in a ring with nitrogen) C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, (3) R 3 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8is cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, (4)R 4 and R 5 are independently, hydrogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 4 and R 5 are each independently selected from the group consisting of alkyl ester, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitrate, (5)R 6 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 Represents 1 to 3 substituents selected from the group consisting of cycloalkenyl, aryl or heterocyclyl, and may be substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions.

[0073] Formula III in Table 1A (Table 1) represents a structural analog of diethylamide of lysergic acid, wherein (1) R 1 and R 2 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, (either independent or forming a closed ring with nitrogen) C 3 ~C 8 cycloalkyl, (either independent or forming a closed ring with nitrogen) C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate at one or more positions, and (2) R 3 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 3 is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (3) R 4 and R 7 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, th ioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (4) R 5 and R 6 are independently hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 8 is cycloalkenyl, aryl or heterocyclyl and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 5 and R 6 in each occurrence is independently selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (5) R 8 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 represents 1 to 3 substituents selected from the group consisting of cycloalkenyl, aryl or heterocyclyl and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate.

[0074] Formula IV in Table 1A (Table 1) represents a structural analog of ibogaine, wherein (1) R 1 is deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, (2) R 2 is hydrogen, deuterium, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or R 2is selected from the group consisting of halogen, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, and (3) R 3 is hydrogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8 cycloalkenyl, aryl or heterocyclyl, and may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate or R 3 is selected from the group consisting of alkyl ester, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitrate, and (4) R 4 is hydrogen, deuterium, halogen, C 1 ~C 8 alkyl, C 2 ~C 8 alkenyl, C 2 ~C 8 alkynyl, C 3 ~C 8 cycloalkyl, C 3 ~C 8represents 1 to 3 substituents selected from the group consisting of cycloalkenyl, aryl or heterocyclyl, which may be substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate.

[0075] Another aspect of the present invention is a molecule disclosed in Table 1A (Table 1) for the treatment of diseases and conditions in mammals having NMDAR, which is used according to the following method for preventing and treating diseases and conditions in a patient or subject, or improving a function, the method comprising repeatedly administering a substance in Table 1A (Table 1) or a substance in Table 1B (Table 2) (hereinafter) in a dose, dosage, posology, and / or formulation that results in a clinical effect comparable to the clinical effect brought about by a clinically meaningful psychedelic / psychoactive effect (neuroplasticity dose), with a human plasma psilocin Cmax of 4 ng / ml or less and / or a human 5-HT2A CNS receptor occupancy of 50% or less, preferably resulting in a PD effect comparable to the PD effect brought about by a human plasma psilocin Cmax of 2 ng / ml or less and / or a 5-HT2A human CNS receptor occupancy of 40% or less, preferably resulting in a PD effect comparable to the PD effect brought about by a human plasma psilocin Cmax of 1 ng / ml or less and / or a 5-HT2A human CNS receptor occupancy of 30% or less, and / or resulting in a PD effect comparable to the PD effect brought about by a human plasma psilocin Tmax exceeding 60 minutes, preferably exceeding 120 minutes, preferably exceeding 180 minutes.

[0076] This method is carried out under conditions where the administration of the substance can regulate NMDAR and their subunits in addition to the regulation of 5-HT2A receptors, the administration of the substance can provide excitotoxicity protection, the administration of the substance can regulate neurogenesis, the administration of the substance is carried out under conditions effective for the substance to bring about a neuroplastic effect including the regulation of neural plasticity, the administration of the substance is safe and well-tolerated, particularly without clinically significant psychedelic and / or psychotomimetic effects, the administration of the substance is repeated administration over several days or months, or chronic administration, the administration of the substance is intermittent administration, carried out every other day, every two days, or every week or two weeks, or every month, and / or blister packaging or other suitable packaging is used to promote compliance when intermittent (not daily) administration is used.

[0077] Another aspect of the present invention is a method for preventing and treating diseases and conditions or improving functions in a patient or subject, comprising the step of repeatedly administering a 5-HT2A agonist substance in a dose, dosage, posology, and / or formulation that results in a clinical effect comparable to the clinical effect brought about by a human plasma psilocybin Cmax of 4 ng / ml or less and / or a human 5-HT2A CNS receptor occupancy of 50% or less, without clinically significant psychedelic / psychotomimetic effects (neuroplastic dose), preferably resulting in a PD effect comparable to the PD effect brought about by a human plasma psilocybin Cmax of 2 ng / ml or less and / or a 5-HT2A human CNS receptor occupancy of 40% or less, preferably resulting in a PD effect comparable to the PD effect brought about by a human plasma psilocybin Cmax of 1 ng / ml or less and / or a 5-HT2A human CNS receptor occupancy of 30% or less, and / or resulting in a PD effect comparable to the PD effect brought about by a human plasma psilocybin Tmax exceeding 60 minutes, preferably exceeding 120 minutes, preferably exceeding 180 minutes.

[0078] This method is carried out under conditions where administration of a substance can regulate NMDAR and their subunits in addition to the regulation of 5-HT2A receptors, where administration of the substance can provide excitotoxic protection, where administration of the substance can regulate neurogenesis, where administration of the substance is carried out under conditions effective for the substance to bring about a neuroplastic effect including the regulation of neural plasticity, where administration of the substance is safe and well-tolerated, with no clinically significant psychedelic and / or psychotomimetic effects in particular, where administration of the substance is repeated administration over several days or months, or chronic administration, where administration of the substance is intermittent administration, carried out every other day, every two days, or every week or two weeks, or once a month, and / or blister packaging or other suitable packaging is used to promote compliance when intermittent (not daily) administration is used.

[0079] Another aspect can include a method for preventing and treating diseases and conditions in a subject, including a step of administering a 5-HT2A agonist derivative, including carbamate derivatives, fluoro derivatives, and nitro derivatives, and their deuterated forms including deuterated carbamate derivatives, deuterated fluoro derivatives, nitro derivatives and deuterated fluoro-nitro derivatives, including the substances listed in Table 1A (Table 1) and Table 1B (Table 2).

[0080] Any of the methods comprises the steps of treating metabolic syndrome and its complications; treating impaired glucose tolerance, diabetes and their complications; treating NAFL, NAFLD, NASH and their complications; treating obesity and its complications; treating visual impairment and vision loss including macular degeneration and retinopathy; treating neurological diseases including neurodevelopmental and neurodegenerative diseases in which modulation of neuroplasticity may be beneficial, including neurological diseases, symptoms and signs that can respond to neuroplastic drugs and SMSN: Alzheimer's disease; mild cognitive impairment associated with aging; dementia; vascular dementia; dementia with Lewy bodies; mild cognitive impairment associated with chronic diseases and their treatment including chemotherapy, immunotherapy, and radiotherapy; Parkinson's disease, and Parkinson's disease-related disorders including Parkinson's dementia, not limited to this; cognitive impairment; disorders associated with the accumulation of beta-amyloid protein (including but not limited to cerebral amyloid angiopathy, posterior cortical atrophy); frontotemporal dementia and its variants, frontal lobe dementia, primary progressive aphasia (semantic dementia and progressive non-fluent aphasia), corticobasal degeneration, supranuclear palsy, not limited to this, disorders associated with the accumulation or disruption of tau protein and its metabolites; epilepsy; NS injury; NS infection; NS inflammation including inflammation due to autoimmune disorders including NMDAR encephalitis, and cellular pathology due to toxins (including microbial toxins, heavy metals, and pesticides, etc.); stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases such as glaucoma, diabetic retinopathy and age-related macular degeneration; amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders [including anorexia nervosa ("AN"), bulimia nervosa ("BN"), and binge eating disorder ("BED")]; trichotillomania, excoriation (dermotillomania), nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, which can be treated or prevented by neuroplastic substances and drugs Symptoms or signs of nervous system disorders: Decrease, impairment, or abnormality of cognitive ability, including executive function, attention, cognitive speed, memory, language function (speech, comprehension, reading, and writing), sense of space and time, practice, ability to perform activities, ability to recognize faces or objects, concentration, and agility; Akathisia, bradykinesia, tics, myoclonus, dyskinesia associated with Huntington's disease, levodopa-induced dyskinesia, and neuroleptic-induced dyskinesia, including dyskinesia, dystonia, tremors including essential tremor, and restless legs syndrome, including abnormal movements; Sleep-related symptoms, insomnia, sleep pattern disorders; Psychosis; Delirium; Excitement; Headache; Motor paralysis, spasticity, endurance disorders; Visual and visual field defects, olfactory, gustatory, auditory, and balance sense disorders, including sensory disorders; Autonomic neuropathy; And ataxia, balance or coordination disorders, tinnitus, neuro-otological and eye movement disorders, delirium, headache, tremors, hallucinations, and alcohol withdrawal neurological symptoms including hypertension, processes; Disorders of the integration disorder spectrum and other psychotic disorders, bipolar disorder and related disorders, depressive disorders, anxiety disorders, obsessive-compulsive disorder and related disorders, trauma-related disorders and stressor-related disorder groups, dissociative disorders, somatic symptoms and related disorders, eating behavior disorders and eating disorders, excretory disorders, sleep-wake disorders, sexual dysfunction, gender dysphoria, disruptive, impulse control, and conduct disorders, substance-related disorders and addictive disorders, neurocognitive disorders, personality disorders, and paraphilia disorders, including the process of treating psychiatric diseases; The process of treating systemic inflammatory conditions and autoimmune diseases; The process of treating aging, senescence, and related deficiencies, including osteoporosis; The process of treating dry eye syndrome; The process of treating restless legs syndrome.

[0081] In any of these methods, the function can be selected from vision, hearing, balance sense, smell, and taste.

[0082] In any of these methods, the substance can be psilocybin, psilocin, norpsilocin, baeocystin, norbaeocystin, or a mixture thereof, and / or the substance is a release-regulating preparation of psilocybin, psilocin, norpsilocin, baeocystin, norbaeocystin, or a mixture thereof. In some embodiments, the drug is a combination of at least two drugs, the first drug is selected from 5-HT2A agonists including psilocybin or psilocin or norpsilocin or baeocystin or norbaeocystin in a dose of 0.01 to 24 mg, and the second drug is selected from open-channel low-affinity non-competitive NMDAR antagonists including dextromethorphan, dextromethadone, ketamine and its isomers, memantine, amantadine, noribogaine in a dose of 0.01 to 50 mg, and the administration of the combined substance provides a synergistic effect and / or improved safety compared to the administration of either substance alone.

[0083] Furthermore, any of the methods can be carried out in combination with magnesium and / or zinc and / or lithium and their salts, and the administration of the combined substance provides a synergistic effect and / or improved safety compared to the administration of either substance alone.

[0084] The method includes the step of orally administering psilocybin and / or psilocin and / or baeocystin contained in fungi and / or its extract daily.

[0085] In any of the methods, the substance can be coated with an emetic to reduce the possibility of substance abuse.

[0086] Also, the substance is administered orally, orally, sublingually, rectally, intravaginally, intranasally, by aerosol, transdermally, transmucosally, parenterally (e.g., intravenous, intradermal, subcutaneous, and intramuscular injection), epidurally, intrathecally, intraauricularly, intravitreally, or topically including skin or ophthalmic creams, lotions, gels, and ointments, and eye drops.

[0087] It is known that fluorine can enhance the lipophilicity of a molecule, increase its partitioning into a membrane, and promote hydrophobic interactions with target receptors. In the case of psychedelic drugs, ring fluorination decreases the psychedelic effect while maintaining 5-HT2A affinity. This suggests that the activity at this receptor, while necessary, may not be sufficient for the psychedelic effect (Blair JB1, Kurrasch-Orbaugh D, Marona-Lewicka D, Cumbay MG, Watts VJ, Barker EL, Nichols DE, Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines, J Med Chem., November 30, 2000;43(24):4701-4710). The neuroplastic and neuroprotective effects can be maintained despite the decrease in the psychedelic effect, and thus, in view of the disclosure of the present inventors, some fluoro derivatives may be particularly important for the inventors' neuroplasticogen treatment program, whereas, as disclosed in more detail above, the psychedelic / psychotomimetic effects are rather undesirable side effects compared to the therapeutic effects. Therefore, novel designed drugs characterized by 5-HT2A affinity and the decrease in the psychedelic effect obtained by ring fluorination may be particularly desirable for the therapeutic indications disclosed in the present application, particularly for the conditions and diseases in which modulation of NMDAR and / or neuroplastic effects may be beneficial.

[0088] Furthermore, if it is found that the nitro derivative of the psychedelic drug is itself effective against a particular disease, this therapeutic effect may, as in the case of nitro-memantine, result from S-nitrosylation of overactive NMDARs with NO-induced channel closure (Tomohiro Nakamura and Stuart A. Lipton, Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases, Trends in Pharmacological Sciences, January 2016, Vol. 37, No. 1), or for entirely different reasons, including differential regulation of 5-HT receptor subtypes or other receptors, as revealed in the present application (Stamler et al., U.S. Patent No. 5,593,876; Inturrisi, CE, NMDA receptors, nitric oxide and opioid tolerance, Regulatory Peptides, 1994, Vol. 54, No. 1).

[0089] Furthermore, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are normal components of cellular metabolism, but overproduction of these types of radicals can cause cells to lose control over them, leading to redox imbalance and the formation of oxidative stress. Nitro derivatives of psychedelic drugs with potential neuroplastic and neuroprotective effects can control these reactive radicals and prevent or reduce cell damage by this or other mechanisms. Merely enhancing the affinity for the 5-HT2A receptor is not necessarily therapeutically advantageous for the indications disclosed in this application. LSD is a very potent psychedelic drug (the effective dose for inducing the psychedelic effect is measured in micrograms), but it cannot provide improved neuroprotection compared to other neuroplastic molecules administered at comparable doses without the psychedelic / psychotomimetic effect. Very high potency may rather lead to concerns about safety, as in the case of LSD. On the other hand, changes in the molecular structure that determine the PK and PD functions of selected neuroplastics may prove to be advantageous for the selected disease, and thus, among the various possible structural variants, the synthesis of deuterated compounds (including deuterated fluoro-nitro derivatives), including fluoro derivatives and nitro derivatives, and combinations of these variants, can give rise to potentially effective new molecules useful for the treatment of the indications disclosed in this application.

[0090] Finally, the inventors hypothesize that the 5-HT2A receptor and NMDAR are in proximity within the postsynaptic megacomplex. This proximity can determine allosteric interactions, and thus activation of 5-HT2A by some agonists at this receptor can also regulate, e.g., inhibit (close), the open NMDAR channel, and vice versa, and NMDAR blockers can also interact with the 5-HT2A receptor [(Furthermore, some NMDAR blockers also inhibit the SERT and NET pathways (Codd et al., 1995), and more importantly, the NMDAR antagonist dextromethorphan confers affinity for the 5-HT-2A receptor in the nanomolar concentration range (Rickli et al., 2017)]. The inventors are currently testing these interactions in an electrophysiological model to determine the relationships within the receptor NMDAR subtype and 5-HT receptor subtype affinities, and affinities for other selected receptors including the dopamine receptor, σ1 receptor, histamine receptor, of various molecules among both of these pharmaceutical classes (NMDAR antagonists and 5-HT2A agonists including novel designer drugs) 5-HT1A; 5-HT1B; 5-HT1D; 5-HT2A; 5-HT2B; 5-HT2C; 5-HT5; 5-HT6; 5-HT7; D1; D2L; D3; D4; D5; SERT; NET; MOP; DOP; KOP; H1σ1; NMDAR2A, 2B, 2C, 2D subtypes). The inventors are also testing the affinity of nitro derivatives that can be agonists at the 5-HT2A receptor, and determining the NMDA block by interacting with the extracellular domain outside the open channel, as described above for nitro derivatives.

[0091] Particularly important derivatives of 5-HT2A agonists include psilocybin, psilocin carbamate, psilocin, norpsilocin, DMT, DMO, LSD, baeocystin, norbaeocystin, noribogaine derivatives; fluoro-derivatives (F) including fluoro-psilocybin; nitro-derivatives (NO) including nitro-psilocybin; fluoro-nitro-derivatives including fluoro-nitro-psilocybin; deuterated fluoro-derivatives (F) including fluoro-psilocybin, deuterated nitro-derivatives (NO) including nitro-psilocybin, and deuterated fluoro-nitro-derivatives including fluoro-nitro-psilocybin, and deuterated 5-HT2A agonist derivatives modified as above for psilocybin.

[0092] The same derivatives of psilocybin listed above disclose psilocin, norpsilocin, DMT, DMO, LSD, baeocystin, norbaeocystin, noribogaine and their carbamate derivatives. See also Table 1A (Table 1).

[0093] In the present disclosure, the inventors define a "prodrug" or "pro-drug" as a compound having a moiety that can be chemically or enzymatically hydrolyzed in vivo to release an active compound. Examples of prodrugs and their uses are well known in the art (see, for example, Rautio et al. (2018), Nature Reviews Drug Discovery, 17, pp. 559-587). Prodrugs can be prepared in situ during the final isolation and purification of the compound or by reacting the purified compound separately with a suitable derivatizing agent. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched alkyl ester moieties (e.g., propionate esters), alkenyl esters, dialkylaminoalkyl esters (e.g., dimethylaminoethyl esters), acylaminoalkyl esters (e.g., acetyloxymethyl esters), acyloxyalkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (e.g., phenyl esters), arylalkyl esters (e.g., benzyl esters), aryl and arylalkyl esters, amides, alkylamides, dialkylamides, and hydroxyamides, alkyl carbamates, dialkyl carbamates, each of which may be substituted at one or more positions with deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamide, alkylamide, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate. Preferred prodrug moieties of the present invention are N-monosubstituted amino acid carbamates (e.g., L-isoleucyl, L-leucyl, L-alanyl, β-alanyl, L-valinyl, etc.).

[0094] The present invention can include a compound of any of the formulas in Table 1A (Table 1), its salts, and prodrugs thereof.

[0095] Psilocybin (PSY) is thought to act as a prodrug of the corresponding psilocin (PSI in vivo (Jacob III, P.; Shulgin, A.T., NIDA Research Monograph 146 (Hallucinogens, an Update), 2000, Eds. Lin, G.C.; Glennon, R.A., p. 74)). PSY is dephosphorylated to active PSI by alkaline phosphatase. Furthermore, PSI rapidly chemically degrades in the presence of air, heat, and / or light. This is because the free 4-hydroxy group is present on the tryptamine scaffold and is susceptible to oxidation. On the other hand, PSY is much more stable than PSI because of the presence of a phosphate ester that protects the 4-OH group from both chemical and metabolic degradation. Therefore, the prodrug approach has been found to be a successful tool for the utilization of PSI pharmacological activity.

[0096] The present invention also relates to novel PSI carbamate prodrugs (4-carbamoylindoles) and derivatives thereof that are also substituted at the 5-, 6-, and / or 7-positions reversibly protected as carbamic acid esters in which the 4-hydroxyl moiety is linked to the N-terminus of a natural amino acid. Lipophilic amino acid carbamate prodrugs of phenolic compounds have been shown to enhance absorption, reduce metabolism, and in particular lead to sustained release of low concentrations of the active compound in brain tissue for up to 24 hours, potently improving bioavailability (see, for example, Azzolini et al., (2017), Eur J Pharm Biopharm, 115, 149-158). Sustained release at low concentrations of the active compound represents the advantage of safe pharmacological use of PSI (and derivatives) by avoiding the psychedelic / psychotomimetic effects after administration of PSY (and derivatives) while maintaining the ability to promote both structural and functional plasticity in brain tissue.

[0097] For further explanation, the concept of prodrug corresponds to the target effect, for example, the agonist action at the 5-HT2A receptor. However, as hypothesized for the drugs classified as 5-HT2A agonists and their derivatives listed in Table 1A (Table 1), in the case of different target effects (e.g., NMDAR regulation) at different hypothesized sites (e.g., the pore channel of NMDAR), the prodrug of the 5-HT2A receptor can also function as a drug for pore channel block, as suggested by the docking results of the inventors for psilocybin and the carbamate "prodrug" (see Table 1B (Table 2) below).

[0098]

Table 2A

[0099]

Table 2B

[0100]

Table 2C

[0101]

Table 2D

[0102]

Table 2E

[0103]

Table 2F

[0104]

Table 2G

[0105]

Table 2H

[0106]

Table 2I

[0107]

Table 2J

[0108] A moderately high dose that produces plasma psilocin Cmax levels of 4.8 - 12.3 ng / ml [e.g., typical effects of the psychedelic substance with 12 - 20 mg (0.178 - 0.254 mg / Kg) of psilocybin (Hasler F, Bourquin D, Brenneisen R, Bar T, Vollenweider FX, Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man, Pharm Acta Helv., 1997;72(3):175 - 184. doi:10.1016 / s0031-6865(97)00014-9) include increased intensity and instability of emotional responses, as well as alterations in visual, auditory, and tactile perceptual processes. Another study by Hasler et al. in 2004 (Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX, Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study, Psychopharmacology (Berl), 2004;172(2):145 - 156. doi:10.1007 / s00213-003-1640-6) examining the effects of various doses of psilocybin found that a threshold dose of 0.045 mg / kg defined as "very low dose" (the high dose in this study was nearly 10 times higher at 0.315 mg / kg) was clearly evaluated as psychoactive by most of the study subjects. Drowsiness and increased sensitivity and intensification of the existing mood state were the most prominent effects with this "very low dose" of psilocybin.Findings by Hasler et al. in 1994 and 2004 state that they rule out the potential use of 5-HT2A agonists for non-psychiatric diseases and symptoms, and also state that when psychedelic and psychotomimetic effects are contraindicated or not necessary for therapeutic activity, they rule out the potential use of 5-HT2A agonists for psychiatric diseases and symptoms. Furthermore, findings by Hasler of increased intensity and instability of emotional responses using "very low doses" and findings of the study by Polito on microdosing cited above state that they rule out potential neuropsychiatric therapeutic effects, including ruling out a positive effect on cognitive ability (nootropic effect) or a positive effect on enhancement of special senses including vision. Indeed, the generation of alterations in visual, auditory, and tactile processes is stated to rule out the use of these substances for the treatment of ophthalmological diseases and the possibility of improving vision in general or other special senses including hearing loss and tinnitus. Also, in a subset of psychiatric patients, including patients suffering from diseases and symptoms currently under clinical investigation (depression, addiction, post-traumatic stress disorder, anxiety), the current administration methods of 5-HT agonists, particularly psilocybin, include single sessions with high psychedelic doses and can be more harmful than beneficial for treatment. As disclosed by the inventors herein, these psychiatric patients can rather potentially benefit from low non-psychedelic repeated doses (neuroplasticogen doses, posology and formulation). The potentially effective dose (0.01 mg / Kg) tested in the inventors' experimental model corresponds to less than 1 / 4 of the "very low dose" (0.045 mg / Kg) defined by Hasler (see details of the following experiments).

[0109] The manifestation of mental abnormalities / psychedelic effects of psychedelic substances appears to be mediated mainly by serotonin receptors, particularly the 5-HT2A receptor, although not exclusively, based on experimental studies using moderately selective 5-HT2A antagonists (e.g., ketanserin, which blocks the psychedelic effect), selective agonists (e.g., lorcaserin, which is selective for 5-HT2C and has no psychedelic effect), and also based on the correlation between the relative potency of the psychedelic effects of various drugs and 5-HT2A affinity (Ki: 3.5; 107; 127 for LSD, psilocin, DMT). Apart from their affinity for the 5-HT2A receptor, most psychedelic substances show moderate to high affinity for several other receptors, including other serotonin receptors, as well as dopamine and histamine receptors (Halberstadt AL, Geyer MA, Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens, Neuropharmacology, September 2011; 61(3): 364 - 381). The effects that bring about changes in the mind, including the effects on sensory alterations induced by psychedelic substances, appear to correlate with 5-HT2A receptor affinity, but the actions at other receptors, including 5-HT1 and / or dopamine receptors, are likely to contribute to these effects, and other factors related to PK properties are also important (Blair JB, Kurrasch-Orbaugh D, Marona-Lewicka D, Cumbay MG, Watts VJ, Barker EL, Nichols DE, Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines, J Med Chem., November 30, 2000; 43(24): 4701 - 4710). Based on the inventors' novel experimental studies detailed below and a thorough re-examination of the available data from the literature, the inventors disclose a novel mechanism of neuroplasticity induced by 5-HT2A agonists.5-HT2A agonist-induced neuroplasticity may be associated with the regulation of NMDAR subunit synthesis via an allosteric interaction-mediated NMDAR blocking effect. This effect can be induced and maintained by the acute downregulation of the 5-HT2A receptor, which is the basis of the known acute tolerance that occurs upon administration of high (psychedelic) doses of 5-HT2A agonists. Thus, chronic downregulation of the 5-HT2A receptor, determined by chronic dosing (multiple administrations given over several days or months), can underlie the neuroplasticity effects mediated by NMDAR regulation and may potentially be useful in the treatment of a number of pathologies and disorders.

[0110] The potential neurological, metabolic, and ophthalmic therapeutic effects described below are mediated, at least in part, by other mechanisms, including actions at receptors other than 5-HT2A and mechanisms that may follow binding to the 5-HT2A receptor, including mechanisms that have already been elucidated, and can be determined by actions that are present or differentially present at doses that potentially benefit the treatment of a number of diseases and pathologies where psychedelic / psychedelic effects are harmful side effects and do not produce psychedelic / psychedelic effects. Furthermore, other properties also determine psychedelic effects such as onset and offset receptor times, and thus may have a neuroplastic effect even at higher doses without a psychedelic effect, thus providing potential parameters important in improving the clinical effectiveness of newly designed SMSNs that widen the therapeutic time window of novel non-psychedelic 5-HT2A agonist drugs.

[0111] Findings regarding the potential modulation of neuroplasticity by indoleamines and other psychedelic drugs are becoming better understood (Ly et al., 2018), but the potential therapeutic value of these substances and drugs beyond psychiatric disorders, and the concept that the modulation of neuroplasticity and the potential for neuroprotective effects can be achieved without psychedelic / psychotomimetic effects, are beyond the focus of current research which remains centered on administering 5-HT2A agonists at doses that cause strong psychedelic / psychotomimetic effects for the treatment of psychiatric disorders in isolated treatment sessions. In short, the psychedelic experience and its strong psychotomimetic effects are still considered by non-experts, users, and the scientific community to be essential for psychiatric treatment effects. Due to the strong sociocultural burden of these substances and the current scientific perspective centered on psychedelic treatment for psychiatric disorders, primarily depression, these substances are defined as narrowly as psychedelic drugs, or in the case of most psychoplastogens (Ly et al., 2018), are defined using their potentially therapeutic effects limited to the field of psychiatry, with reference to their ability to induce potentially therapeutic psychedelic experiences, but it is not recognized that therapeutic effects can exist at "neuroplasticogen doses" chronically administered as shown by the inventors' new research and can be useful in treatment outside the scope of the field of psychiatry for metabolic, ophthalmological, and neurological diseases and conditions. Therefore, the inventors disclose here that 5-HT2A agonist drugs without psychedelic effects (e.g., psilocybin 0.1 - 4 mg) have neuroplasticogenic effects and can potentially be useful for the treatment of a number of diseases and conditions including, but not limited to, the psychiatric disorders disclosed throughout this application.

[0112] Rather, the importance of repeated administration of a drug with a neuroplasticogen dose having an effect on neuroplasticity over a certain period of time is well recognized for NMDAR antagonists that may treat neurological diseases. The inventors have reexamined the available publications on dexmedetomidine, an open channel NMDAR blocker, in several published studies and published patent applications, taking into account the inventors' observations, results, and disclosures. In a single ascending dose study (SAD) testing doses of 5 - 200 mg, only the lowest test dose of 5 mg of dexmedetomidine induced an orienting signal (International Application PCT / US2018 / 016159). In this study, the MTD was set at 150 mg (nausea and vomiting), and thus the orienting dose was presumably 1 / 30 of the MTD. In a multiple ascending dose study (MAD) testing doses of 25, 50, and 75 mg over 14 days, only the lower dose (25 mg per day) produced a statistically significant increase in plasma BDNF (De Martin et al., 2018).

[0113] In recent studies, the cognitive effects of psilocybin 10, 20, 30 mg and dextromethorphan 400 mg were compared. This study found dose-dependent negative effects of psilocybin on psychomotor function, working memory, episodic memory, associative learning, and visual cognition, and stated that it excluded the present disclosure. The effects of 400 mg dextromethorphan on psychomotor function, visual cognition, and associative learning were in the range of the effects of moderate to high doses (20 - 30 mg / 70 kg) of psilocybin. This was the first study on the dose effects of psilocybin and dextromethorphan on a large battery of neurocognitive assessments. The effect of psilocybin on working memory was greater than that of DXM. The effects of DXM on balance, episodic memory, response inhibition, and executive control were greater than those of all psilocybin doses (Barrett FS, Carbonaro TM, Hurwitz E, Johnson MW, Griffiths RR, Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: effects on cognition, Psychopharmacology (Berl), October 2018; 235(10):2915 - 2927). Notably, the test dose of dextromethorphan, 400 mg, is much higher than the doses used in approved formulations with neurological therapeutic effects (the FDA-approved dose of dextromethorphan for mood regulation disorder is 20 mg, and even when explaining the metabolic block provided by quinidine, it is a much lower dose compared to the 400 mg used in the above study).

[0114] Based on the above observations regarding dextromethadone, an NMDAR open-channel blocker (International Application PCT / US2018 / 016159; De Martin et al., 2018) and the dose-dependent cognitive effects observed in Barrett's 2018 study regarding dextromethorphan and psilocybin, the inventors disclose that not only are the effects of 5-HT agonists and NMDAR antagonists similar in their potential to induce neuroplasticity as seen in in vitro and in vivo studies, but also that the clinically advantageous therapeutic effects of these drugs exist only at low “neuroplasticogen doses” and are not necessarily present at higher doses, that there is an upper limit to the therapeutic dose, and that the psychedelic effect can represent an upper limit to the therapeutic effect for at least the disorders and the majority of patients for which non-psychedelic neuroplasticogens can be beneficial. The dose of the NMDAR antagonist and the dose of the 5-HT2A agonist are high enough to cause psychedelic, dissociative, psychotomimetic symptoms and the types of neurocognitive disorders described by Barrett et al., 2018, and the therapeutic effects of these substances for some or all of the indications disclosed herein will likely be impaired. The same is true for ketamine, which is an anesthetic at high doses and an FDA-approved antidepressant (esketamine) at lower doses.

[0115] However, based on the inventors' observations and findings, the inventors disclose that at lower doses (doses about 1 / 10 to 1 / 20 of the psychedelic dose) without the side effects of the psychedelic experience, both classes of drugs, 5-HT2A agonists and NMDAR open-channel blockers, produce a neuroplasticogenic effect along with a potential therapeutic effect for a number of diseases and conditions. The psychedelic experiences and psychotomimetic symptoms induced by these drugs are, from the current scientific perspective, essential for the therapeutic effect, particularly for some psychiatric disorders, and are thus side effects that can be avoided by administering the lower doses daily, every other day, every two days, weekly, biweekly or monthly, or in a long-term daily schedule for the majority of the indications disclosed in this application.

[0116] For further illustration, the neuroplasticogen effect sufficient to produce a clinically meaningful effect for a number of diseases is induced by 5-HT agonists at doses much lower than those used in current use by non-experts, including traditional tribal users, recreational users, and therapists, and those used in ongoing clinical trials for psychiatric disorders, including clinical trials at major US university centers.

[0117] Finally, the effect on neuroplasticity, rather than the "psychedelic experience," forms the basis of the main potential therapeutic actions of neuroplasticogens, including effects on the special senses, effects on aging, potential therapeutic effects for nervous system disorders and pathologies, metabolic disorders, ophthalmological disorders, and including some of the effects on psychiatric disorders that can represent harmful side effects without the need for a psychedelic effect. The inventors cannot rule out that for some patients, the psychedelic experience may be therapeutically useful (clinical trials are ongoing), but the inventors disclose that there is a large group of psychiatric patients for whom neuroplasticogens (non-psychedelic repeated doses of 5-HT agonists) may be beneficial, but the psychedelic experience is harmful, and thus for these patients, instead of the currently used doses of 8 - 50 mg administered in an isolated single session, much lower and safer doses of drugs, such as 0.1 mg - 4 mg of psilocybin or psilocybin equivalents, are required and are administered periodically for several days or months (continuously or intermittently) or chronically. Furthermore, at lower neuroplasticogen doses, the agonist effect at the 5-HT2A receptor is not clinically meaningful, especially when defined by its ability to induce a psychedelic / psychotomimetic effect. As shown in the experiments of Example 3 of the inventors, the neuroplasticogen effect of these drugs classified as 5-HT2A agonists can be associated with the modulation of the action at NMDAR.

[0118] By the same token, NMDAR antagonists are supported, but for these drugs, the concept is already understood by the scientific community, and the approved therapeutic doses of dextromethorphan are far below the doses that cause dissociative symptoms, and the doses of dextromethadone under clinical investigation do not cause psychotomimetic effects (International Application PCT / US2018 / 016159; Relmada.com).

[0119] Furthermore, the inventors hypothesize that at least some of the neuroplasticity effects may not be induced by direct agonist interactions with the 5-HT2A receptor and subsequent downstream cascades, but rather by other mechanisms including downregulation / regulation of the expression of 5-HT receptors, including the 5-HT2A receptor, following exposure to 5-HT agonists, as well as potential effects associated with other receptors such as NMDAR and AMPA receptors and DA and histamine and σ1 and opioid receptors. Thus, some of the neuroplasticity effects, including effects potentially useful for the treatment of a number of diseases and conditions, may be best achieved by repeated administration of low doses of drugs without psychotomimetic / psychotomimetic effects rather than by single high-dose administrations with psychotomimetic / psychotomimetic effects.

[0120] In 2018, Ly et al. studied the acute effects of high doses of several compounds with 5-HT2A agonist activity in vitro and in vivo (however, Ly et al. did not specifically study psilocin / psilocybin in 2018, did not study NMDAR antagonists, and did not disclose the possible effects of drugs classified as 5-HT2A agonists at NMDAR). The 2018 study by Ly et al. was designed to evaluate the mechanisms underlying the clinical findings of the effects of high doses of selected drugs that produce psychedelic and psychotomimetic effects in patients with psychiatric disorders, particularly the effects of these drugs in patients with depression and anxiety. The 2018 findings by Ly et al. support their hypothesis. High doses of psychedelic drugs (doses predicted to produce psychedelic and psychotomimetic effects in humans) potentially promote functional neuroplasticity in prefrontal cortex neurons, and this effect potentially leads to the antidepressant and anxiolytic effects seen in patients currently under investigation in Phase 2 clinical trials. The inventors conducted different subsets of experiments, detailed below, to study different hypotheses. Chronic administration of low neuroplasticogen doses of drugs and modulators classified as 5-HT2A agonists produces neuroplasticogen effects by modulating NMDAR, and thus can potentially be useful for the treatment of improved function, including disease and pathology as well as vision.

[0121] The current DEA scheduling (Schedule I) of 5-HT2A agonist drugs may change as the therapeutic indications and scope of effects become more fully defined by ongoing clinical studies for psychiatric use, but for one, due to concerns about abuse driven by sociocultural forces, these drugs will still remain unattractive for pharmaceutical development (Sellers EM, Romach MK, Leiderman DB, Studies with psychedelic drugs in human volunteers, Neuropharmacology, November 2018;142:116-134). Currently, researchers of psychedelic drugs for the treatment of psychiatric disorders have only considered their use at high doses (psychedelic) in single sessions in supervised settings. This requirement for inpatients and / or supervised administration can reduce the potential for abuse because the drug is generally administered directly by a therapist in a supervised setting and the risk of diversion is reduced.

[0122] The relative safety and low potential for abuse of these substances have been emphasized in recent scientific publications (Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE, The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act, Neuropharmacology, November 2018;142:143-166). However, the potential for abuse of pharmaceutical 5-HT2A agonists is real, and the possibility of generally non-severe but harmful effects when these drugs are taken for recreational purposes is supported by sufficient data. Approximately 6,000 cases of mushroom-containing psilocybin have been reported to US poison centers between January 1, 2000 and December 31, 2016 (Leonard JB, Anderson B, Klein-Schwartz W, Does getting high hurt? Characterization of cases of LSD and psilocybin-containing mushroom exposures to national poison centers between 2000 and 2016, J Psychopharmacol., December 2018;32(12):1286-1294). Therefore, the potential for abuse of 5-HT agonists with neuroplastic effects raises questions about safety, especially when these drugs with neuroplastic effects are for long-term outpatient treatment in a setting where they are relatively unmonitored. Recreational users seeking a psychedelic experience may potentially abuse the drug by self-administering several tablets at once, rather than at a prescribed non-psychedelic / psychotomimetic dose.

[0123] To minimize the potential for abuse of these substances, the inventors disclose a formulation strategy that introduces anti-abuse features that have the potential to reduce their potential for abuse even when administered in an outpatient setting.

[0124] Accordingly, the inventors disclose a combination of a neuroplasticogen with an emetic, including an emetic embedded in the coating of a capsule or tablet, an emetic acting on the CTZ of the medulla oblongata, and / or a gastrointestinal irritant. The inventors disclose a misuse prevention preparation comprising a combination of a neuroplasticogen, which may cause a psychedelic effect when misused (for example, ingesting 10 times the prescribed dose of a neuroplasticogen may potentially induce a psychedelic effect), and a low dose of an emetic. The emetic dose has no effect when the drug is taken as prescribed (for example, 1 or 2 tablets at a time), but the emetic dose becomes effective when the subject attempts to misuse the drug with the intention of inducing a psychedelic effect (for example, taking 5 - 10 tablets at a time may potentially induce a psychedelic effect) and ingests a larger dose (multiple tablets at a time, for example, more than 3 tablets). Notably, even when there is no induction of vomiting, which can only occur when a higher dose (for example, 10 times or more the prescribed dose) is ingested, when misuse is limited to 3 - 5 times the prescribed dose, a nausea effect that is not severe but still preventive may occur, and these preventive effects may be sufficient to limit future misuse (even a weak psychedelic experience sought by potential drug abusers may be significantly weakened by the accompanying nausea).

[0125] In the same vein, the inventors also disclose other forms of abuse deterrent drugs and methods that can be combined with MR 5-HT neuroplastogens, including when formulated as long-acting and / or sustained-release pharmaceutical compositions, and when combined with emetics. (1) Incorporation of additives that gel upon mixing with water, alcohol, or other commonly used solvents; (2) Incorporation of physical barriers that resist fragmentation, dissolution, melting, or chemical extraction; (3) Formulation of very strong tablets that are extremely difficult to break or adulterate; (4) Chemical engineering prodrugs that require in vivo enzymatic cleavage to exert a pharmacological effect (e.g., amide bonds formed between a drug molecule and a single amino acid such as lysine or a small (up to 15 amino acids) oligopeptide, ester bonds formed between a hydroxyl group on the drug and a carboxyl group on the carrier, complex formation with ion exchange resins, complex formation with metal cations, complex formation with fatty acids); (5) Incorporation of another aversive component in addition to or in place of an emetic: (e.g., flushing agents [niacin], diuretics, laxatives, or stimulants [capsaicin]; nasal irritants, emetics, bitter agents, and foaming agents, and / or (6) Co-formulation with sequestering antagonists or aversive agents that are released upon adulteration of the product.

[0126] Modified Release (MR) formulations For some patients / diseases and conditions, non-psychedelic / psychotomimetic doses of IR psilocybin (e.g., 2 - 4 mg or less) may be beneficial, but a subset of patients or selected diseases and conditions may require slightly higher doses of psilocybin or other 5H-2a agonists (e.g., besosisin MR) for optimal neuroplastogen action. However, for these patients, the psychedelic / psychotomimetic effects are harmful. In fact, the majority of patients, particularly those who can benefit most from neuroplastogens (patients with neurodevelopmental and neurodegenerative disorders, elderly patients, all patients with any form of cognitive impairment including mild cognitive impairment, and many patients with psychiatric disorders as defined by DSM5, etc.) are likely to be more susceptible to the effects of experiencing harmful psychedelic and psychotomimetic side effects when higher doses than 2 - 4 mg of IR psilocybin are administered.

[0127] Interindividual variability in the experience of psychedelic / psychotomimetic effects is well-documented. Both pharmacologic intersubject PK variability factors and non-pharmacologic variability factors play important roles in intersubject susceptibility to the psychedelic / psychotomimetic side effects of neuroplastogens. Thus, the psychedelic / psychotomimetic effects of 5-HT2A agonists are directly related to the administered dose [Studerus E, Kometer M, Hasler F, Vollenweider FX, Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies, J Psychopharmacol., November 2011;25(11):1434-52; Studerus E, Gamma A, Kometer M, Vollenweider FX, Prediction of Psilocybin Response in Healthy Volunteers, PLoS ONE, 2012;7], and plasma levels that also correlate with 5H2A receptor occupancy [Madsen, M.K, Burmester, D, Stenbaek, D.S, Psilocybin occupancy of brain serotonin 2A receptors correlates with psilocin levels and subjective experience: a (11C) Cimbi-36 PET study in humans, European Neuropsychopharmacology, 2019, 29], yet some patients cannot tolerate even potentially effective IR psilocybin doses, which are very low (e.g., less than 1 mg of psilocybin or psilocybin equivalents), without incurring cognitive side effects, including psychedelic / psychotomimetic side effects.MR formulations of appropriately designed 5-HT2A agonists that can target specific PK parameters (Cmax, AUC, Tmax) and PD effects (receptor occupancy and psychedelic / psychotomimetic effects or their absence) detailed below may rather be effective for these patients.

[0128] In addition to dose, and the individual PK and psychiatric variables, differences in pharmacokinetic parameters caused by the route of administration of psilocybin also play an important role in the psychedelic / psychotomimetic effects. Compared with oral psilocybin 10 - 20 mg (similar Cmax: 8.2 ± 2.8 ng / ml; longer Tmax: 105 ± 37 minutes), the high Cmax (12.9 ± 5.6 ng / ml) and short Tmax (1.9 ± 1 minute) of 1 mg of IV psilocybin induced similar psychedelic effects despite the much smaller AUC of the IV-administered drug (240 ± 55 vs 1963 ± 659) (Hasler F, Bourquin D, Brenneisen R, Bar T, Vollenweider FX, Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man, Pharm Acta Helv., June 1997; 72(3):175 - 84). Cmax and Tmax are likely to be enhanced (Cmax) and shortened (Tmax), as with IV administration, when the drug is inhaled intranasally rather than taken orally. Dose and route, PK parameters and other variables related to subsets of patients and / or selected diseases and conditions are of importance, and with controlled-release formulations (oral or transdermal), by maintaining lower Cmax, longer Tmax and greater or equal AUC compared to an IR 5-HT2A agonist, it is possible to administer higher daily doses without the side effects of the psychedelic / psychotomimetic effects, and thus optimize PK parameters (and PD effects) for neuroplastic effects without cognitive side effects rather than for the psychedelic effects.

[0129] As discussed above, patients who can benefit most from neuroplastic drugs, such as patients with neurodevelopmental and neurodegenerative disorders, elderly patients, and even patients with mild cognitive impairment, are patients with lower tolerance and higher risk of psychedelic and psychiatric manifestation effects. Therefore, the inventors disclose the use of 5-HT2A agonist release modulating formulations (e.g., psilocybin MR and beosistrin MR) that optimize PK parameters compared to 5-HT2A IR at the same dose (lower Cmax, later Tmax, increased T1 / 2 and equivalent or larger AUC). This release modulating formulation allows for the administration of psilocybin at a dose higher than the dose at which tolerance is observed for IR formulations, thus avoiding psychedelic / psychiatric manifestation effects. For example, in the case of IR formulations, it enables the administration of psilocybin at a maximum dose of 32 mg, which is a dose that causes psychedelic / psychiatric manifestation effects in the majority of patients. Also, in selected clinical settings (e.g., dementia) or in highly sensitive individual patients, very low doses, such as 0.5 mg of psilocybin, are possible only with MR formulations and not with IR formulations. The paper by Madsen et al. cited above shows the correlation between psychedelic / psychiatric manifestation symptoms and psilocin plasma levels and 5-HT2A receptor occupancy. In this study, an oral dose of 3 mg of IR psilocybin (the lowest dose tested in this study) determined a psychedelic / psychiatric manifestation effect, a psilocin Cmax of 2.4 ng / ml, and a 5-HT2A receptor occupancy of 42.9%. The intensity of the psychedelic / psychiatric manifestation symptoms was mild compared to higher test doses that resulted in stronger psychedelic / psychiatric manifestation effects, higher Cmax (up to 19.3), and higher receptor occupancy (up to 72.4%). Notably, the subject with the highest receptor occupancy (72.4%) was not the subject with the highest psilocin plasma level. This suggests additional potential inter-individual variable factors other than Cmax when determining receptor occupancy (e.g., drug CNS permeability, receptor variable factors including receptor affinity state).Moreover, especially as technology advances and test costs decline, the evaluation of receptor occupancy can help predict the tolerability of the neuroplastic dose of 5-HT2A agonists without psychedelic / psychotomimetic side effects [for example, a receptor occupancy of 40% or less (or 50% or less or 30% or less) can be expected to have good tolerability for the test neuroplastic dose]. Therefore, 5-HT2A receptor occupancy testing can assist clinicians in prescribing neuroplastic doses suitable for individual patients.

[0130] Finally, combinations of 5-HT2A agonists and NMDA antagonists, including the combination of psilocybin and dextromethorphan, can provide synergistic benefits while reducing the potential for psychedelic / psychotomimetic and other side effects, as discussed throughout this application, for PK and / or PD effects, including receptor regulation and receptor occupancy.

[0131] It is known that the various subtypes of NMDAR change throughout life. NMDAR2B is more dominant in the earlier developmental ages and is replaced by NMDAR2A in the later stages of development. NMDAR2B appears to have a longer "on" time, and thus this receptor subtype is associated with an improvement in long-term potentiation (LTP), and some periods of life (young age) are characterized by the promotion of learning, such as language learning. This natural transition of NMDAR subtypes (2B→2A) can potentially be physiologically regulated by the action of endogenous agonists (e.g., DMT) at the 5-HT2A receptor. Low-dose 5-HT2A agonists can result in enhanced neuroplastic regulatory effects, as seen in our in vitro experiments in ARPE-19 cells.

[0132] The inventors cannot rule out that psychedelic symptoms may be useful in the treatment of selected diseases, as hypothesized by some researchers, or may be useful in the treatment of selected psychiatric symptoms or selected patients (clinical trials are underway to answer this question), but the current view that the psychedelic / psychopathological effects in non-experts and the scientific community are always necessary for the potential therapeutic activity of 5-HT2A agonists is verified by the inventors' observations, experimental results and disclosures.

[0133] Accordingly, the inventors disclose that a neuroplastic agent comprising a 5-HT agonist, including 5-HT agonists having potential regulatory activity against NMDARs and their subtypes as defined above, will not produce psychedelic / psychopathological / dissociative effects and will not produce negative neurocognitive side effects when a neurocognitive function test is performed, particularly after the drug has had its regulatory CNS plasticity effect for a period of time (chronic administration), and may actually produce an orienting effect potentially at a dose that produces such an effect. In this context, the inventors have verified in both in vitro and in vivo the changes in NMDAR receptor expression and 5-HT receptor expression induced by neuroplastic drugs, including their subtypes and their subunits.

[0134] Based on the experimental results of the present inventors described in the following examples, the present inventors disclose that 5-HT agonists selected including those having activity at the 5-HT2A receptor, including psilocybin, can regulate endogenous receptors including the 5-HT2A receptor and / or NMDAR in the same manner as endogenous neurotransmitters including DMT. The direct action of 5-HT2A agonists at the 5-HT2A receptor, and the direct or indirect action at the NMDAR disclosed in the present application, and / or the action on the down-regulation of serotonin receptors caused by exogenous 5-HT2A neuroplasticin potentially regulate the expression of NMDAR (increase in mRNA and subunit proteins shown in the experiments of the present inventors), and in particular drugs of this pharmacological class can regulate the expression of NMDAR, specifically protein transcription, and the synthesis of subunits forming NMDAR subtypes NR1-2A, NR1-2B, NR1-2C, NR1-2D including NR1-2A-2B and other triheteromeric combinations.

[0135] It is known that the 2B subtype of NMDAR is more prominent during early development and is thought to play an important role in the learning ability of the developing brain. During development, the NMDAR subtype 2B is gradually replaced by subtype 2A, and eventually subtype 2A predominates in the adult brain. Therefore, neuroplasticity by modulating NMDAR subtypes may potentially reproduce the levels of neuroplasticity seen during early development, and thus support and promote new neural circuits and / or nerve repair, and thus may potentially be useful in the treatment of a number of diseases and conditions, particularly those affecting sensory pathways and memory and learning (learning is not limited to memory and cognition, but also determines motor skills, social skills and emotional functions). Finally, neuroplastic agents of the 5-HT2A agonist class can improve the outcome of rehabilitation programs, including neurorehabilitation programs focused on cognitive aspects, language, vision, and rehabilitation programs focused on physical therapy, including rehabilitation programs for substance use disorders. The improvement of rehabilitation outcome is achieved by enhancing and modulating the neuroplasticity and neural circuits involved in learning.

[0136] Furthermore, based on the in vitro, in vivo and clinical results of the inventors, there may be a subset of patients suffering from psychiatric disorders for whom psychedelic experiences may be beneficial (as there are psychiatric patients for whom ECT is beneficial), but the inventors disclose that other patients, including subsets of psychiatric patients, are likely to benefit from treatment involving continuous ongoing treatment with non-psychedelic neuroplastic agents administered at low doses, including release-modulating formulations and intermittent doses.

[0137] Treatment with non-psychedelic doses of neuroplastic agents is likely to determine additional benefits when associated with psychotherapy and neurorehabilitation programs.

[0138] Finally, ketamine, a neuroplasticogen of the NMDAR antagonist pharmacological class, is FDA-approved for depression at doses that demarcate the psychedelic / psychotomimetic-expressing dose or the psychedelic / psychotomimetic-expressing window (dissociative symptoms), and the fact that psilocybin is in clinical trials at psychedelic doses suggests that there may be a subset of patients for whom higher psychedelic / psychotomimetic-expressing doses are beneficial, or that these patients may benefit from (or in fact may benefit even more from) much lower non-psychedelic doses and formulations of the same drugs administered over the long term when tested in appropriately designed clinical trials.

[0139] Furthermore, both magnesium and zinc are modulators in NMDAR. Magnesium is an NMDAR blocker, and thus, due to the reasons and results disclosed above, the combination of magnesium and a 5-HT2A agonist may be synergistic. Zinc is an NMDAR modulator, and thus, due to the reasons and results disclosed above, the combination of zinc with or without magnesium and including a 5-HT2A agonist may be synergistic. Magnesium supplementation has been shown to have the potential to improve hypertension, insulin sensitivity, hyperglycemia, type 2 diabetes, left ventricular hypertrophy, and dyslipidemia; furthermore, magnesium can treat certain types of seizures (e.g., seizures that occur as part of eclampsia) and can be used for arrhythmias such as torsades de pointes [Houston M, The role of magnesium in hypertension and cardiovascular disease, J Clin Hypertens (Greenwich), November 2011;13(11):843-847]; [Rosanoff A, Magnesium and hypertension, Clin Calcium., February 2005;15(2):255-260]. The combination of a 5-HT2A agonist with magnesium and / or zinc and their salts can potentially be synergistic for the treatment of diseases and conditions where modulation of neuroplasticity may be beneficial, resulting in drugs with improved efficacy as well as improved safety. In the case of blister packaging for intermittent dosing, magnesium and / or zinc can be used instead of an inactive dose on a "treatment-free" day (e.g., every other day).

[0140] Chronic administration of NMDA causes mitochondrial dysfunction in rats [Kim, H.K. et al., Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment, J Psychiatr Res., May 2016;76:59-65]. Therefore, when lithium is combined with an NMDAR antagonist, the safety can be enhanced compared to the NMDAR antagonist alone. According to Leslie et al. in 1993, the combination of a 5-HT2A agonist and lithium can enhance the potential antidepressant effect of the 5-HT2A agonist (Leslie RA, Moorman JM, Grahame-Smith DG, Lithium enhances 5-HT2A receptor-mediated c-fos expression in rat cerebral cortex, Neuroreport, December 13, 1993;5(3):241-4). Summarizing the inventors' new evidence regarding the potential neuroplasticity effect of a non-psychedelic dose of a 5-HT2A agonist, the increase in c-fos expression induced by lithium seen by Leslie et al. can also suggest the possibility of a synergistic effect not only for the antidepressant effect but also for the neuromodulatory effect (neuroplasticity effect).

[0141] According to the observations, findings and disclosures of the inventors, as well as ongoing and planned in vitro, in vivo, and clinical studies, the repeated or chronic repeated administration of low doses of known 5-HT2A agonists and novel drugs (SMSN), herein defined as neuroplasticogens, listed in Table 1A (Table 1) over several days or months, in subjects and patients with sensory impairments due to a number of diseases and conditions, activates serotonin, as well as various cell lines including retinal pigment cells (which thereby also affect photoreceptor activity and viability), other retinal cells, and specialized olfactory, auditory, and balance cells, and specific neuron populations including neurons and astrocytes (including astrocytes such as Müller cells like those of the retina), and other receptors including 5-HT2A receptors on neurons involved in the visual pathway including retinal ganglion cells and cortical neurons including hippocampal neurons, resulting in trophic functions, regulating and generating new and / or stronger synaptic activity and new connections, thereby improving the functions of the special senses, improving memory and learning, and improving neurological functions including visual function, other sensory functions, and cognitive functions in subjects with neurological disorders due to a number of diseases and conditions including neurological, psychiatric, and metabolic diseases and deficits due to aging including aging. In particular, the trophic and protective effects in retinal pigment epithelial cells and astrocytes are particularly important for their roles in opening and closing the blood-retinal barrier and the BBB, and thus supplying nutrients, neurotransmitters, and other critical molecules to CNS neurons and receptors that are part of the visual and other sensory pathways including photoreceptors, as well as their roles as scavengers and other important roles in neuroplasticity.

[0142] Due to the neuroplasticity effects, including the trophic effects on those cells, and anti-inflammatory effects, the effects of 5-HT2A agonist substances and SMSN can not only last longer than their clearance from the body, but also, under certain circumstances, the positive effects can be more obvious and can only become obvious after the substance is substantially excreted. This can be particularly appropriate for some visual and cognitive improvements, especially when the doses of NMDAR antagonists and / or 5-HT2A agonist drugs and / or their combinations are sufficient to cause CNS symptoms such as the onset of mental disorders or psychedelic symptoms.

[0143] Research by Banganz (Baganz, N.L. and Blakely, R.D., A dialogue between the immune system and brain, spoken in the language of serotonin, ACS Chem. Neurosci., 4, 48-63 (2013)) and Arreola (Arreola, R. et al., Immunomodulatory effects mediated by serotonin, J Immunol Res., 2015, 354957 (2015)) regarding inflammation and serotonin, as well as research by Flanagan and Nichols (Flanagan TW, Nichols CD, Psychedelics as anti-inflammatory agents, Int Rev Psychiatry., August 13, 2018: 1-13), all coincide with the inventors' clinical observations and experimental results as well as the inventors' findings and disclosures. It is the agonist action at the serotonin receptor of psychedelic drugs, mainly the 5-HT2A receptor, but also the action at other receptors including non-serotonin receptors, that can reduce inflammation including TNF-α-mediated inflammation. Based on the inventors' experimental results, these anti-inflammatory effects potentially play a role in improving neurological functions including vision, or in preventing neurological deficits including visual deficits in CNS diseases where inflammation potentially plays a role in neurodegenerative and neurodevelopmental diseases including diseases in which inflammation in the visual pathway (anywhere from retinal pigment cells to cortical structures) is involved, as well as neurological and ophthalmological deficits associated with aging and cellular senescence. Regulation of systemic indicators of inflammation can also improve psychiatric symptoms and syndromes including depression associated with systemic inflammation.

[0144] The results of recent studies by Madsen et al. [Madsen, M.K., Burmester, D., Stenbaek, D.S., Psilocybin occupancy of brain serotonin 2A receptors correlates with psilocin levels and subjective experience: a (11C) Cimbi-36 PET study in humans, European Neuropsychopharmacology, 2019, 29] suggest that the psychedelic effect of psilocybin correlates with dose and, thus, in line with the observations and disclosures of the present inventors, that lower doses do not produce psychotomimetic / psychedelic effects. Further, also in line with the clinical observations, experimental results and disclosures of the present inventors regarding safety and potential therapeutic indications, other side effects of psychedelic substances such as psychotomimetic effects, headache, fatigue and increased blood pressure are dose-dependent (MW Johnson, Sewell AR, Griffiths RR, Psilocybin dose-dependently causes delayed, transient headaches in healthy volunteers, Drug and Alcohol Dependence, 2011, 123, 1; Studerus E, Kometer M, Hasler F, Vollenweider FX, Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies, J Psychopharmacol., November 2011; 25(11):1434-52), and it is confirmed that relatively lower doses of psychedelic substances are not only safe but also well-tolerated and are likely to have no psychotomimetic and other side effects.On the one hand, the anti-inflammatory effect appears to be active at very low doses (Nichols DE et al., 2016, Psychedelics as medicines; an emerging new paradigm), and thus supports both the inventors' new observations and the inventors' new experimental data in patients, and accordingly supports the development of psychedelic drugs as pharmaceuticals in non-psychedelic doses and non-psychedelic formulations not only for the psychiatric indications disclosed throughout this application, but also for neurological and ophthalmological and metabolic indications.

[0145] In a 2011 study by Studerus et al. (Studerus E, Kometer M, Hasler F, Vollenweider FX, Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies, J Psychopharmacol., November 2011; 25(11):1434-1452), the inventors recognized an improvement in the symptom of "lower limb akathisia" in two patients treated with psilocybin (see Table 2 of the 2011 paper by Studerus et al.). The inventors also recognized a similar improvement in one of the inventors' patients (CF). Although this observation was limited to three patients, when combined with the inventors' new data on the NMDAR antagonistic effects of the selected 5-HT agonists and the effects of these drugs on the glutamatergic pathway and excitotoxicity, it means that three patients who probably suffered from restless legs syndrome improved after treatment with 5-HT-agonists, suggesting a possible therapeutic activity of 5-HT2A agonists in restless legs syndrome (RLS). A hyperglutamatergic state has been hypothesized as a mechanism of RLS.

[0146] The clinical observations, experimental results and disclosures of the inventors teach that relatively low doses of 5-HT agonist substances administered over several days or months, or even chronically, continuously or intermittently, may be safe and well-tolerated and may have no clinically significant side effects, including psychedelic effects and other typical psychedelic effects, as well as cognitive side effects. Thus, when appropriately administered, Neuroplastogen and SMSN may be safe and effective in the management of the diseases and conditions enumerated throughout this application and in improving metabolic disorders, including vision and cognition, a number of neuropsychiatric diseases and conditions, and metabolic syndrome. To date, the psychedelic effects of 5-HT2A agonists have not been seen as side effects but have been seen as inherent in the potential therapeutic advantages of 5-HT2A agonist drugs (centered on psychiatric diseases). In the disclosure of the inventors, the neuroplasticity and improvement of diseases and conditions seen at lower appropriate doses and formulations are therapeutic effects, while the psychedelic effects are side effects caused by overdose. The psychedelic effects can be completely minimized or avoided by using non-psychedelic doses and formulations of these substances administered repeatedly over a period of time and / or by adding structural molecular modifications to known 5-HT2A agonists (see Table 1A), resulting in SMSN with improved PK and PD parameters.

[0147] Based on the inventors' disclosures, observations, and experimental results, doses of IR psilocybin of 4 mg or less (or other 5-HT2A agonists and NMDAR antagonists at psychedelic-efficacy-equivalent doses) may be sufficient to modulate neuroplasticity that can potentially treat a number of the disorders and pathologies listed in this application. Indeed, according to the inventors' observations and results, the neuroplasticogen effect may potentially be more prominent when lower concentrations are maintained over a period of time rather than when higher concentrations are administered in a single session [see also the cited BDNF results of the Phase 1 trial of dexamethasone (De Martin et al., 2018) where an increase in BDNF reached statistical significance only in the 25 mg group and not in the 50 mg or 75 mg groups]. However, for selected diseases and / or selected patient subgroups or individuals, higher doses of neuroplasticogen drugs may be required to effect the appropriate modulation of neuroplasticity to improve a particular disease or pathology. In such patients, modulation of the release of 5-HT2A agonists or administration of long-acting or sustained-release formulations may be appropriate, as detailed below. The psychedelic effect is known to be associated with dose, plasma levels, and receptor occupancy.Higher doses correspond to higher blood levels, higher receptor occupancy, and more prominent psychedelic symptoms [Madsen, M.K, Burmester, D, Stenbaek, D.S, Psilocybin occupancy of brain serotonin 2A receptors correlates with psilocin levels and subjective experience: a (11C) Cimbi-36 PET study in humans, European Neuropsychopharmacology, 2019, 29; (Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller D, Thomas CD, Hetzel SJ, Henriquez KM, Ribaudo AS, Hutson PR, Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults, Clin Pharmacokinet, December 2017;56 (12):1543-1554]. The neuroplasticity effect is potentially driven not by the drug's direct binding to the 5-HT2A receptor alone, but rather by additional and consequential mechanisms. The neuroplasticity effect demonstrated by our in vitro, in vivo, and clinical observations is actually enhanced by lower doses / concentrations compared to higher doses (e.g., psychedelic / psychotomimetic doses), and thus can exist at non-psychedelic / psychotomimetic doses. Release modulation, long-acting, and / or sustained-release formulations of neuroplastic drugs allow for the administration of relatively higher amounts of the drug while also avoiding the psychedelic and / or psychotomimetic side effects (psychedelic effects caused by high Cmax and short Tmax) caused by the peak of the drug blood level.Accordingly, the inventors disclose formulations for the long-term action and / or sustained release of neuroplastogens, including long-acting oral or transdermal formulations and / or sustained release formulations of psilocybin and / or beosystin at a maximum dose of 30 mg per 24 hours (or the equivalent dose of other 5-HT2A agonists and NMDAR antagonists having psychedelic / psychotomimetic efficacy and thus no such effects). The release-modulated long-acting / sustained release formulations are designed to maintain plasma levels of psilocybin (or the psychedelic-efficacy-equivalent plasma levels of other 5-HT2A agonists and / or NMDAR antagonists) below the 4 - 6 ng / ml window that causes the psychedelic / psychotomimetic effects of psilocybin, and thus do not determine plasma levels sufficient for psychedelic effects.

[0148] Finally, the release-modulated long-acting and / or sustained release preparations can be indicated for administration of higher doses of 5-HT agonists in the case of the diseases and conditions selected from those listed above and / or in the case of selected subjects, for example subjects who may be more sensitive than average to the psychedelic / psychotomimetic effects of these drugs, thus enabling effective treatment by extending the treatable time range of these drugs.

[0149] The same rationale underlying the potential therapeutic role of psychedelic substances in ophthalmological disorders applies to other pathological conditions of other sensory organs and pathways, including auditory / vestibular - otological disorders, and olfactory / smell disorders, and / or gustatory / taste deficiencies, and some sexual disorders, particularly those associated with aging, such as tactile disorders. For these substances and drugs, it may be possible to potentially safely improve or prevent or delay the sensory loss (visual, auditory, vestibular, olfactory, gustatory, and somatosensory) associated with aging.

[0150] The inventors further disclose that the neuroplastic effects of these drugs involve non-neuronal cells such as retinal pigment cells, as well as astrocytes and neurons outside the prefrontal cortex, and thus, as detailed in the inventors' clinical observations, experiments and disclosures, can bring about effects and potential therapeutic effects on a number of neurological and ophthalmological syndromes (beyond psychiatric disorders) not only by promoting neurite growth, but also through neuroprotective and anti-inflammatory mechanisms, including excitotoxic protection. In particular, the inventors' disclosures reveal that these effects of 5-HT agonists are not limited to neurons, but involve other cells such as retinal pigment epithelial cells, and potentially hepatocytes and pancreatic cells shown and represented in the inventors' novel experiments (see Examples 1-3). Furthermore, the inventors emphasize the potential role of these cells as it has been revealed that astrocytes express 5-HT2A receptors when corroborating the inventors' disclosures [Xu T1, Pandey SC, Cellular localization of serotonin(2A) (5-HT2A) receptors in the rat brain, Brain Res Bull, April 2000;51(6):499-505]. As described above, the effects of psychedelic drugs on astrocytes and retinal pigment cells are particularly important for their role in opening and closing the blood-retinal barrier and the BBB, and thus supplying nutrients, neurotransmitters and other critical molecules to CNS neurons and photoreceptors, which are part of the visual pathway, as well as their role as scavengers and other important roles in neuroplasticity.

[0151] Current scientific understanding of the cognitive functions of psychedelic effects states that the use of psychedelic drugs to improve cognitive functions is excluded (Bayne T, Carter O, Dimensions of consciousness and the psychedelic state, Neurosci Conscious, 2018; 2018(1)): "Findings can be broadly divided into three categories (sensory perception, cognitive function, and the experience of unity), revealing that some aspects of consciousness are improved or enhanced in the psychedelic state, but many of the functional abilities associated with consciousness are severely impaired."

[0152] Finally, since the mechanism of regulating neuroplasticity by psychedelic substances can be driven by experience, the inventors disclose the importance of the timing of administration of these substances and drugs (known 5-HT2A agonists and modified novel molecules detailed in Table 1A) together with specific activities (including activities of daily life and specific mental activities, and specific neurorehabilitation programs including visual rehabilitation programs). This coupling of drugs and activities can provide additional advantages for their use as neurological and ophthalmological treatments, including neurological and ophthalmological rehabilitation treatments of these drugs. Therefore, the timing of neuroplasticogen treatment may be important to achieve a progressive decrease in plasma and tissue levels of the drug at relatively high levels during specific activities that can potentially result in enhanced neuroplasticity during physiological sleep (at very low or ineffective drug concentrations) and in the evening hours. This argument indicates the administration of 5-HT2A serotonin agonist substances in such a way as to achieve higher serum levels during the day and lower levels during sleep, also during specific neurorehabilitation sessions. In the subjects reported by the inventors, the administration of psilocybin-containing substances was timed in intensive visual tests, and the inventors hypothesize that this timing can have a potentially beneficial effect on positive outcomes on the fifth day, substantially after all clearance of the psychedelic substance (48 hours after the last dose).

[0153] Based on immunohistochemical and morphological results suggesting the neuroplasticity effects of 5-HT2A agonists administered repeatedly at low doses, the inventors disclose that substances acting at the 5-HT2A receptor and other CNS receptors, and SMSN, may be useful not only in treating psychiatric disorders and symptoms, including all forms of depression, all forms of anxiety, PTSD, addictive behaviors, and addiction to drugs, but also in potentially preventing these disorders and symptoms when administered prior to the onset of a psychiatric disorder or symptom in anticipation of life stressors, or during or immediately after a stress event. By promoting neuroplasticity and by other mechanisms such as modulating the 5-HT2A receptor, NMDAR, SERT, and NET pathways, and BDNF, 5-HT2A agonists and SMSN can increase resilience to psychiatric disorders and symptoms during periods of suffering from mental stressors or when mental stressors are anticipated, and thus may be useful in preventing psychiatric disorders and symptoms triggered by a number of causes, including social stress, grief, illness, personal loss, spousal and family-related stress, financial stress, war, natural disasters, and human disasters. This disclosure is supported by the experimental results by Brachman on ketamine (Brachman RA, McGowan JC, Perusini JN et al., Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior, Biol Psychiatry, 2015;79(9):776-786). Ketamine is an NMDAR antagonist that potentially shares neuroplasticity effects with selected 5-HT2A agonists.

[0154] In the United States, the prevalence of metabolic syndrome has increased in all sociodemographic strata from 1988 to 2012. By 2012, more than one-third of all US adults met the metabolic syndrome definitions and criteria jointly agreed upon by several international agencies (Moore JX, Chaudhary N, Akinyemiju T, Metabolic Syndrome Prevalence by Race / Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988 - 2012, Prev Chronic Dis., 2017;14:160287, DOI: http: / / dx.doi.org / 10.5888 / pcd14.160287). Metabolic syndrome is associated with cardiovascular disease, obesity, arthritis, NAFL, NASH, MDD, schizophrenia, dementia, and cancer. The results of the present inventors suggest that a neuroplastic 5-HT2A agonist, such as a low chronic dose of psilocybin, can improve one or more features of metabolic syndrome, either as a single treatment or in combination with a low-dose NMDAR antagonist. Based on the experimental findings of the present inventors, 5-HT2A neuroplastic drugs represent strong therapeutic potential not only as appetite suppressants and anti-obesity drugs but also as potentially disease-modifying therapeutics with molecular-level actions and effects on hepatocytes (decrease in steatosis), Langerhans cells (decrease in blood glucose peak), and immune cells (decrease in inflammatory markers) for the treatment of metabolic syndrome.

[0155] Metabolic disorders that can be treated or prevented by neuroplastic substances and drugs include metabolic syndrome, obesity, hyperglycemia, type 2 diabetes, hypertension, coronary artery disease including myocardial infarction and unstable angina, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hypogonadism, testosterone deficiency, hypothalamic-pituitary axis disorders, BDNF deficiency including WAGR syndrome, 11p deletion, and 11p inversion, and Prader-Willi, Smith-Magenis, and ROHHAD syndromes.

[0156] In 2015, a total of 1.02 million people were blind and approximately 3.22 million had visual impairment (best corrected visual acuity in the better-seeing eye) in the United States. By 2050, the number of these conditions is projected to double to approximately 2.01 million blind and 6.95 million with visual impairment (Varma R, Vajaranant TS, Burkemper B, Wu S, Torres M, Hsu C, Choudhury F, McKean-Cowdin R, Visual Impairment and Blindness in Adults in the United States: Demographic and Geographic Variations From 2015 to 2050, JAMA Ophthalmol., July 1, 2016;134(7):802-809).

[0157] Currently available pharmaceuticals are inadequate for treating eye diseases and conditions associated with visual impairment. There has been little innovation in this area for the past decade. There is still a need for better treatments for visual impairment associated with retinal diseases, particularly age-related visual impairment.

[0158] Vision or eyesight (adjective form: visual / ocular) is the ability of the eye to focus on and detect an image of visible light on the photoreceptors of the retina of each eye, which generates electrical nerve impulses for changing color, hue, and brightness. There are two types of photoreceptors: rods and cones. Rods have very high light sensitivity but do not distinguish colors. Cones distinguish colors but have low sensitivity to dim light. Stereopsis, a depth perception that uses both eyes, is generally a cognitive (i.e., post-perceptual) function of the brain's visual cortex, in which shapes and objects in an image are recognized and interpreted based on previously learned information (visual memory).

[0159] People who are blind due to deterioration or damage to the visual cortex but still have functioning eyes can actually have some level of vision and reaction to visual stimuli, but conscious perception is not possible. This is called blindsight. People with blindsight are not aware that they are reacting to a normal visual information source and rather unconsciously adapt their actions to the stimuli.

[0160] Neuroplastogens may play a role in improving vision affected by diseases and injuries at all levels of vision loss, including partial or complete cortical blind patients, by preventing retinal lesions, restoring some vision, or at least maintaining "blindsight" at all levels of the visual pathway from the retina to the cortical area. The multifactorial decline in vision associated with aging can also be slowed or improved by neuroplastogenic substances. Improvements in vision by neuroplastogens include improvements in visual acuity, contrast sensitivity, color vision, visual field, and stereopsis.

[0161] Retinal neurodegenerative, neurodevelopmental, and inflammatory diseases such as glaucoma, diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, optic neuritis, and LHON, as well as refractive disorders, are included among the diseases that can potentially be improved by neuroplastogenic substances, including SMSN. Ophthalmic diseases that can respond to neuroplastogenic drugs and SMSN, and their symptoms and signs, include all of the disorders cited above.

[0162] In neurodegenerative diseases of the retina such as glaucoma, diabetic retinopathy, and age-related macular degeneration, glutamate is released during metabolic stress, initiating dysfunction and death of neurons including ion channel-type NMDA receptors in retinal ganglion cells and certain types of amacrine cells. The main causes of cell death following NMDA receptor activation are influx of calcium into cells, generation of free radicals associated with the formation of advanced glycation end products (AGE) and / or advanced lipoxidation end products (ALE), and mitochondrial respiratory chain abnormalities. Macular edema represents the end stage of multiple pathophysiological pathways in numerous vascular, inflammatory, metabolic, and other diseases. Novel therapeutic agents such as neuroprotective agents like nerve growth factor and NMDA antagonists can inhibit neuronal cell death in the retina (Wolfensberger TJ, Macular Edema - Rationale for Therapy, Dev Ophthalmol., 2017;58:74 - 86). Similar NMDA-induced neuronal damage can occur in glaucoma and optic neuritis. Memantine, an NMDA antagonist, has been shown to potentially benefit glaucoma in experimental studies (Celiker H et al., Neuroprotective Effects of Memantine in the Retina of Glaucomatous Rats: An Electron Microscopic Study, J Ophthalmic Vis Res., April - June 2016;11(2):174 - 82). The authors concluded that starting at the early stage of the glaucoma process, memantine can help preserve the ultrastructure of the retina and thus prevent neuronal injury in experimentally induced glaucoma. Memantine did not improve vision but was also found to be effective in reducing thinning of the retinal nerve fiber layer (RNFL) in patients with optic neuritis (Esfahani MR et al., Memantine for axonal loss of optic neuritis, Graefes Arch Clin Exp Ophthalmol., June 2012;250(6):863 - 9).

[0163] The context-free observations by Honygllo et al. regarding the distribution of psilocin in the human body after ingestion of psilocybin mushrooms further support the present inventors' disclosure regarding potential ophthalmological therapeutic activity herein. After ingestion of psilocybin mushrooms, psilocin in peripheral and cardiac blood was quantified at 60 and 67 ng / mL, respectively, and psilocin in urine (2230 ng / mL), bile (3102 ng / mL), and vitreous humor (57 ng / mL) was quantified (Honyiglo, E, Franchi A, Cartiser: Unpredictable Behavior Under the Influence of "Magic Mushrooms": A Case Report and Review of the Literature, Journal of Forensic Sciences, December / 2018). These equivalent levels of psilocin in blood and vitreous humor seen in this report, when combined with the present inventors' novel clinical observations and experimental results, suggest that the retina can be exposed to psilocin at levels equivalent to those reaching the systemic circulation after systemic ingestion of a 5-HT agonist. These relatively high levels in vitreous humor have a biological effect on retinal pigment cells (see Example 3, which are homologous to the ARPE-19 cells used in the present inventors' experiments) and other retinal cells and are thus potentially sufficient to modulate and improve important connections and cellular activities within the visual pathway starting from the retina. This finding supports the present inventors' clinical observations and confirms their experimental findings and disclosure. Since the vitreous psilocin concentration is comparable to the concentration seen in blood, the visual effects of psilocin observed in the present inventors' clinical observations (see Example 1) can also be associated with retinal exposure by local vitreous diffusion, not only by exposure through the blood-retinal barrier or across the BBB for more central NS structures. Thus, the long-lasting positive effects on vision seen in the present inventors' subjects can be associated with the modulation of neuroplasticity through different mechanisms, including weakening inflammation anywhere in the nervous system pathway, including the retina and visual pathway, including the cells that make up the retinal pigment cells within the retina and up to the cortical regions.

[0164] Substances that prevent excitotoxic events (excitotoxicity) are potentially considered neuroprotective. From experimental studies, several drugs have been shown to reduce or prevent the death of retinal neurons lacking nutrients. These agents generally block the NMDA receptor, prevent the action of glutamate, or halt the subsequent pathophysiological cycles that lead to cell death (Schmidt KG et al., Neurodegenerative diseases of the retina and potential for protection and recovery, Curr Neuropharmacol., June 2008;6(2):164-178). Glutamate-induced optic nerve atrophy toxicity has also been shown to be associated with changes in BDNF expression (Ito Y et al., Degenerative alterations in the visual pathway after NMDA-induced retinal damage in mice, Brain Res., May 30, 2008;1212:89-101). Excitotoxic injury has been hypothesized as a concurrent etiological factor in Leber hereditary optic neuropathy (Howell N, Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve, 1988, Vis Res, 38:1495-1504. Sala G, Antioxidants Partially Restore Glutamate Transport Defect in Leber Hereditary Optic Neuropathy Cybrids, Journal of Neuroscience Research, 2008, 86:3331-3337). Changes in glutamate metabolism have been described in various retinitis pigmentosa models.The glutamate-mediated excitotoxic mechanism has been found to be a factor causing rod photoreceptor death in a retinal degeneration mouse model (Delyfer MN et al., Evidence for glutamate-mediated excitotoxic mechanisms during photoreceptor degeneration in the rd1 mouse retina, Mol Vis., September 1, 2005; 11:688-96). The applicant's new findings regarding the regulatory effect of 5-HT2A agonists on NMDAR open up a new perspective for their potential use in preventing excitotoxic nerve damage.

[0165] The dose of psilocybin of the neuroplasticogen (see Example 1), which has been shown to potentially improve visual parameters without causing psychotropic effects in human subjects, can potentially treat and / or prevent the exacerbation of many neurological and ophthalmological pathologies. Altered neuronal plasticity or the regulation of neuroplasticity plays a role, and it can be treated and prevented by systemic administration, local administration via eye drops, and / or intravitreal depot preparations, including diseases of the retina, optic nerve, and visual pathway, including diseases in which BDNF controls neuronal plasticity. The inventors have discovered that the sclerotia of psilocybe atlantis improve visual parameters. 5-HT2A agonists stimulate neuroplasticity via the BDNF and mToR pathways (Ly et al., 2018). The effect of BDNF on nerve cells in the eye, including retinal ganglion cells, can prevent or treat retinal and ocular neurodegenerative and inflammatory diseases.

[0166] Currently available pharmaceuticals are insufficient for the treatment of nervous system disorders, their symptoms, and / or their signs. There has been little innovation in this area in the past decade. Better treatments are still sought.

[0167] Neuroplastic drugs and neurological diseases that can respond to SMSN, as well as their symptoms and signs, include Alzheimer's disease; mild cognitive impairment due to aging; senile cognitive impairment; vascular cognitive impairment; Lewy body dementia; mild cognitive impairment associated with aging and mild cognitive impairment associated with the treatment of chronic diseases including chemotherapy, immunotherapy, and radiotherapy, Parkinson's disease, and Parkinson's disease-related disorders including Parkinson's dementia; cognitive impairment; disorders associated with the accumulation of beta-amyloid protein (including but not limited to cerebral amyloid angiopathy, posterior cortical atrophy); frontotemporal dementia and its variants, frontal lobe dementia, primary progressive aphasia (semantic dementia and progressive non-fluent aphasia), corticobasal degeneration, supranuclear palsy; disorders associated with the accumulation or destruction of tau protein and its metabolites; epilepsy; NS trauma; NS infections; inflammation due to autoimmune disorders including NMDAR encephalitis, and cell pathology due to toxins (including microbial toxins, heavy metals, and pesticides, etc.); NS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases such as glaucoma, diabetic retinopathy, and age-related macular degeneration; amyotrophic lateral sclerosis; tardive dyskinesia; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders [including anorexia nervosa ("AN"), bulimia nervosa ("BN"), and binge eating disorder ("BED")], trichotillomania, dermatillomania, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology.

[0168] Symptoms or signs of nervous system disorders that can be treated or prevented by neuroplastic substances and drugs include cognitive decline, dysfunction, or abnormalities, including executive function, attention, cognitive speed, memory, language functions (speech, comprehension, reading, and writing), sense of space and time, practice, ability to perform activities, ability to recognize faces or objects, concentration, and agility; akathisia, bradykinesia, tics, myoclonus, dyskinesia associated with Huntington's disease, levodopa-induced dyskinesia, and neuroleptic-induced dyskinesia, including dyskinesia, dystonia, tremors including essential tremors, and restless leg syndrome, including abnormal movements; parasomnias, insomnia, sleep pattern disorders; psychosis; delirium; excitability; headache; motor paralysis, spasticity, endurance disorders; visual and visual field defects, olfactory, gustatory, auditory, and balance sense disorders, and sensory disorders including abnormal sensations; autonomic neuropathy; and ataxia, balance or coordination disorders, tinnitus, neuro-otological and oculomotor disorders, delirium, headache, tremors, hallucinations, and neurological symptoms of alcohol withdrawal including hypertension.

[0169] Psychiatric disorders and symptoms that can be improved by neuroplastin include those listed in DSM5 and ICD11, and further include schizophrenia spectrum disorders and other psychotic disorders, bipolar disorder and related disorders, depressive disorders, anxiety disorders, obsessive-compulsive disorder and related disorders, trauma-related disorders and stress-related disorder groups, dissociative disorders, somatic symptoms and related disorders, eating and feeding disorders, elimination disorders, sleep-wake disorders, sexual dysfunction, gender dysphoria, disruptive, impulse control, and conduct disorders, substance-related disorders and addictive disorders, neurocognitive disorders, personality disorders, paraphilia disorders, and other disorders.

[0170] Age-related disorders and deficits that can be treated or prevented by neuroplastic substances and drugs include disorders associated with physiology or accelerated aging (including aging accelerated by harmful factors including medical treatments including cancer treatment), the symptoms and signs of which include cognitive impairment, sarcopenia, osteoporosis, sexual dysfunction, skin aging, hair loss and / or graying, endurance disorders, sensory disorders including hearing, balance, smell, taste, and / or visual disorders; fatigue.

[0171] Hearing Hearing (or audition) is the sense of perceiving sound. The mechanical receptors in the inner ear convert motion-vibration into nerve electrical pulses. Since sound is vibration traveling through a medium, the detection of these vibrations, i.e., hearing, is a mechanical sense as these vibrations are mechanically conducted from the eardrum through a series of small bones to the hair-like fibers in the inner ear that detect the mechanical motion of fibers within a range of approximately 20 to 20,000 hertz with substantial variation among individuals. High-frequency hearing declines with increasing age. The inability to hear is called deafness or hearing impairment. Sound can also be detected as vibrations conducted through contact and through the body.

[0172] Neuroplastogen may play a role in the improvement of hearing affected by diseases, their treatments, and injuries at all levels of the auditory pathway from the inner ear hair cells to the cortical region, as well as in the deceleration or improvement of age-associated hearing loss.

[0173] Neuroplastogen for the improvement of hearing and balance or for the reduction of tinnitus can be administered locally via iontophoresis to increase inner ear penetration in the form of ear drops, via transtympanic injection including in the form of inner ear depot, or can be administered systemically.

[0174] Taste and Flavor Taste (or gustation) refers to the ability to detect the taste of substances such as food, some minerals, and poisons. Taste is often confused with the "sensation" of flavor, which is a combination of the perception of taste and smell.

[0175] Flavor depends on smell, texture, and temperature, as well as taste. Humans receive taste through sensory organs called taste receptors or taste buds concentrated on the upper surface of the tongue. There are five basic tastes: sweet, bitter, sour, salty, and umami. Other tastes such as calcium and free fatty acids may also be basic tastes but are not yet widely recognized. The absence of taste is called ageusia.

[0176] Neuroplastogen may play a role in improving the deficits in taste and flavor perception affected by diseases, disease treatments, and other injuries at all levels of the taste pathway from taste buds to the cortical region. The decline in taste perception associated with aging can also be slowed or improved by neuroplastogen.

[0177] Smell Smell (smell or olfaction) is a chemical sense like taste. Different from taste, there are hundreds of olfactory receptors (388 by one source), each binding to specific molecular characteristics. Odor molecules have various characteristics and thus excite specific receptors more or less strongly. This combination of excitatory signals from different receptors constitutes what the inventors perceive as the smell of the molecule.

[0178] In the brain, smell is processed by the olfactory system. Olfactory receptor neurons in the nose are different from most other neurons in that they die and regenerate regularly. The absence of smell is called anosmia. Some neurons in the nose are specialized to detect pheromones. The loss of smell is a precursor symptom of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

[0179] Neuroplastogen may play a role in improving the deficits in smell affected by diseases, their treatments, and injuries at any and all levels of the olfactory pathway from olfactory receptors to the cortical region. The decline in smell perception associated with aging can also be slowed or improved by neuroplastogen. The prevention of anosmia or the improvement of hyposmia by neuroplastic drugs can, in addition to improving the quality of life of patients, be useful for the treatment of selected neurological diseases and conditions, including neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0180] Neuroplastogen for improving the sense of smell can be administered locally, including in the form of an intranasal spray, an aerosol to increase penetration via iontophoresis, in the form of an intranasal depot, or can be administered systemically.

[0181] Tactile sensation Tactile sensation, somatic sensation, or mechanoreception generally occurs in the skin, including the hair follicles, but also in the tongue, pharynx, cornea, and mucous membranes, and is the perception caused by the activation of nerve receptors. Various pressure receptors respond to fluctuations in pressure (strong, brushing, sustained, etc.). Itching tactile sensations caused by insect stings or allergies involve special itch-specific neurons in the skin and spinal cord. The loss or impairment of the ability to feel that something is touching is called tactile anesthesia. Abnormal sensations are skin tingling, prickling, or numbness sensations that can be caused by nerve damage and can be permanent or temporary.

[0182] Neuroplastogen may play a role in improving tactile deficits affected by diseases, medical treatments, and injuries at all levels of the somatosensory pathway from nerve receptors in the skin, including hair follicles, tongue, pharynx, cornea, and mucous membranes, to the cortical areas. The decline in tactile perception associated with aging can also be slowed or improved by neuroplastogen.

[0183] Balance and acceleration, vestibular system sensation Balance, sense of balance, or vestibular sense is the sense that enables an organism to perceive body movements, directions, and accelerations and to achieve and maintain postural equilibrium and balance. The organ of the sense of balance is the vestibular labyrinth system found in the inner ear. In technical terms, this organ is responsible for two senses, angular acceleration and linear acceleration (which also senses gravity), and is also known as the sense of balance.

[0184] The vestibular nerve conducts information from sensory receptors in three enlarged parts that sense the movement of the fluid in the semicircular canals caused by three-dimensional rotation of the head. The vestibular nerve also conducts information from the utricle and saccule, which contain hair-like sensory receptors that are bent by the mass of otoliths (small crystals of calcium carbonate) that provide the inertia necessary to detect the direction of head rotation, linear acceleration, and gravity.

[0185] Neuroplastogen may play a role in improving the balance deficit affected by diseases and injuries at all levels of the somatosensory pathway from the nerve receptors in the inner ear to the cortical areas. The decline in the sense of balance associated with aging can also be slowed down or improved by neuroplastogen.

[0186] Proprioceptive sensation Proprioceptive sensation, which is a sense of movement, provides information about the movement and relative position of body parts to the parietal cortex of the brain. Neuroplastogen may play a role in improving the deficit of proprioceptive sensation affected by diseases, their treatments, and injuries at all levels of the somatosensory pathway from the receptors to the cortical areas. The decline in proprioceptive sensation associated with aging can also be slowed down or improved by neuroplastogen.

[0187] Sexual stimulation and sexual function Sexual stimulation is any stimulus (including physical contact) that can lead to, enhance, maintain sexual arousal, and lead to orgasm. Different from general tactile sensation, sexual stimulation is strongly associated with the body's hormonal activity and chemical triggers. Sexual arousal may occur without physical stimulation, but usually, physical sexual stimulation and the stimulation of Krause-Finger corpuscles found in the body's erogenous zones are required to achieve orgasm.

[0188] Neuroplastogen may play a role in improving sexual dysfunction affected by diseases and injuries at all levels of the sexual stimulation pathway from the nerve receptors in the skin (including hair follicles), tongue, pharynx, and mucous membranes to the cortical areas. The decline in sexual function and bladder control associated with aging or oncological treatments including radiotherapy and chemotherapy can also be slowed down or improved by neuroplastogen.

[0189] Furthermore, by enhancing and / or restoring the senses of smell, vision, hearing, and touch, neuroplastogen can also enhance sexual desire and sexual function affected by diseases and aging.

[0190] Time perception Time perception refers to how the flow of time is perceived and experienced. The sense of time is not associated with a specific sensory system, but research by psychologists and neuroscientists indicates that the human brain, which consists of a highly distributed system including the cerebral cortex, cerebellum, and basal ganglia, has a system that governs time perception. The suprachiasmatic nucleus, a specific component, is responsible for the circadian (or daily) rhythm, and other cell clusters appear to be able to manage time in a shorter range (ultradian). One or more dopaminergic pathways in the central nervous system seem to have a strong regulatory influence on mental time measurement, particularly interval timing.

[0191] Psychoactive drugs are known for their potential to deeply affect the sense of time. When this sense is disrupted by CNS diseases or injuries, including visual impairments, neuroplastogens may play a role in restoring physiological time measurement. Age-related impairments in time measurement may also be slowed down or improved by neuroplastogens.

[0192] Sense of agency Sense of agency refers to the awareness of having selected a particular action. Some neurological diseases or injuries may lead to the loss of this sense, thereby causing a person to feel like a machine or even leading to the delusion of being controlled by some external source. The exact opposite can also occur, where there are people who experience everything in their environment as if they had determined that it would happen. When this sense is disrupted by CNS diseases or injuries, neuroplastogens may play a role in restoring this sense. Age-related impairments in the sense of agency may also be slowed down or improved by neuroplastogens.

[0193] Sense of familiarity Episodic memory is sometimes divided by neuroscientists into two functions: sense of familiarity and recollection. A strong sense of familiarity can occur without any recollection, for example, in the case of déjà vu. The temporal lobe, particularly the perirhinal cortex, responds separately to newly sensed stimuli rather than to things one feels familiar with. The firing rate in the perirhinal cortex is associated with the sense of familiarity in humans and other mammals.

[0194] When this sensation is disrupted by CNS diseases or injuries and / or eye diseases or injuries, neuroplastogen may play a role in restoring this sensation. The impairment of the sense of familiarity associated with aging can also be slowed down or improved by neuroplastogen.

[0195] Additional literature supports the experimental results disclosed in this application.

[0196] According to recent studies, these two compound classes of NMDAR antagonists (De Martin et al., 2018; Fogaca et al., 2019) and 5-HT2A agonists (Ly et al., 2018) share the ability to promote neuroplasticity, induce trophic effects, and can have anti-inflammatory effects, and some of these effects can be mediated through the regulation of BDNF, while other mechanisms can potentially play a role. Therefore, selected molecules from both classes can present neuroprotection and cytoprotection that can be useful for the treatment of a number of clinical disorders. Furthermore, due to the potential interactions between these two receptor classes disclosed throughout the present application, including receptor cross-induction (protein synthesis) and regulation (allosteric or in-channel blocking effects), as well as allosteric interactions and the induction of selected protein subunits selective for some receptor subtypes, with potentially co-operative mechanisms of action that are different at the NMDAR and 5-HT2A receptors respectively, these two drug classes of NMDAR antagonists and 5-HT2A agonists can potentially act synergistically, i.e., their effects are additive and can be advantageous for selected patients and / or diseases. Moreover, when administered together, these drugs can be safer than either drug administered alone. For example, their co-administration can be effective for the treatment of some diseases and conditions at much lower doses compared to treatment with single agents from each class administered alone.Furthermore, some of the neuroplasticity-modulating effects of NMDA pore blockers such as ketamine, dextromethorphan, and dextromethorphan can be mediated via 5-HT receptors to which these drugs have affinity [inhibition of NET and SERT or agonist effects at 5-HT receptors] [Kapur S, Seeman P, NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors - implications for models of schizophrenia, Mol Psychiatry, 2002;7(8):837-44; Codd et al., Serotonin and Norepinephrine activity of centrally acting analgesics: Structural determinants and role in antinociception, IPET 1995; 274 (3)1263-1269; Rickli et al., 2017].

[0197] Both serotonin agonists and NMDAR antagonists potentially determine neuroplastic effects, probably through the regulation of BDNF (Ly et al., 2018 and De Martin et al., 2018; Fogaca et al., 2019). The inventors disclose that a potential synergistic effect exists among these two different classes of drugs, but both classes of drugs and selected drugs within each of the two classes can potentially have different target clinical indications.

[0198] The 2013 study by Catlow et al. (Catlow B, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J, Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning, Exp Brain Res., August 2013; 228(4): 481-491) showed that psilocybin reduced hippocampal neurogenesis at high doses, while noting an opposing trend towards increased hippocampal neurogenesis at lower doses. This observation further supports the findings and disclosures of the present inventors, emphasizing the importance of dosing when aiming for neuromodulatory effects, particularly with respect to the potential therapeutic effects of lower doses of 5-HT2A agonists chronically administered for the regulation of plasticity, neurogenesis, and neuroprotection, as revealed by the experiments of the present inventors (particularly Example 3). The 2018 study by Ly et al. (Ly C, Greb AC, Cameron LP et al., Psychedelics Promote Structural and Functional Neural Plasticity, Cell Rep., 2018; 23(11): 3170-3182) confirmed the potential of psychedelic drugs to promote neural plasticity, BDNF, TrkB, and mToRC 1A mechanism based on the activation of the 5-HT2A receptor by a dependency mechanism is suggested. This paper focuses on the potential neuronal plasticity effects on specific neuronal populations (prefrontal neurons) known to be affected in depression and other psychiatric syndromes (PTSD, anxiety, addiction) by psychedelic drugs acutely administered at high concentrations (24 hours), and thus suggests a hypothesis for a better understanding of the potential use and effects of high doses of psychedelic drugs in the treatment of depression. This study supports the currently investigated single high-dose (psychedelic experience) treatment approach, in combination with psychotherapy / counseling, for the use of 5-HT2A agonists in the treatment of depression and other psychiatric symptoms and syndromes (addiction, anxiety, PTSD). The studies by the inventors rather support the hypothesis of the safety and efficacy of neuroplasticogen doses administered chronically, continuously or intermittently.

Example

[0199] (Example 1) The following clinical observations were made in subjects who self-administered sclerotia of Psilocibe atlantis (magictruffles.com) in the Netherlands. Psilocibe atlantis is a species that contains psilocybin, psilocin, baeocystin, and norbaeocystin (Guzman G, Hanlin RT, White C, Another new bluing species of Psilocybe from Georgia, U.S.A., Mycotaxon, 2003; 86: 179-183).

[0200] Notably, the sale and use of sclerotia of psychedelic mushrooms are legal in the Netherlands, and the manufacturers of the specific brands and sclerotia species self-administered by the subjects described instructed an intake of 15 grams as a "psychedelic dose" [the amount ingested by the first subject CF (1.5 grams) was 1 / 10 of the suggested "psychedelic dose", and the amounts ingested by the other two subjects GG and PM (3 grams) were 1 / 5 of the suggested "psychedelic dose"].

[0201] The inventors state that they are 85-year-old with a medical history of mild myopia (-2 diopters, RE and LE) corrected by intraocular lens implantation during cataract surgery (at 82 years old), and report improved vision (improvement in vision when objects are distant, specifically improved detection of distant objects) after occasionally ingesting low-dose (non-psychoactive) psilocybe fungi.

[0202] In response to patient requests, without ingesting mushrooms, drugs or other substances, including prescription drugs, vitamins and supplements, at least 3 months later, the inventors conducted visual tests and psychometric tests (baseline day 0) on day 3, and 2 hours after oral ingestion of 1.5 grams of Psilocybe atlantis sclerotia daily for 3 days (acute effect) (day 3), and on day 4, 24 hours after the last administration of Psilocybe atlantis sclerotia (day 4).

[0203] [Table 3]

[0204] These results suggest a persistent visual improvement (up to 24 hours) after repeated administration (for 3 days) of a very low dose of psilocybin containing sclerotia (repeated administration of 1.5 grams of Psilocybe atlantis sclerotia daily for 3 days).

[0205] The inventors describe two subjects as follows. The first subject GG is a 56-year-old healthy male. The next subject PM is a 57-year-old healthy male with moderate myopia (-9 diopters) since childhood, well corrected with contact lenses. Neither subject had ingested drugs, including prescription drugs, food supplements or vitamin supplements, for at least 3 months prior to baseline evaluation.

[0206] Visual parameters before (day 0, baseline) and after (day 4, 24 hours after ingestion of the third and last dose) ingestion of 3 grams of Psilocybe atlantica sclerotia per day for 3 days. Spatial contrast sensitivity was measured by randomly scrambled Snellen letters of contrast that decreased according to a logarithmic scale of 0.15 for a constant visual acuity of 0.3.

[0207]

Table 4

[0208]

Table 5

[0209] The inventors performed the Farnsworth-Munsell 100 Hue Color Vision Test 100 and generated TES values. TES is an automatically generated value that calculates the number of tiles placed incorrectly and adjusts that value for uniform analysis. The average TES score ranges from 30 to 40 in a series of tests, and scores above 70 can indicate a marker for color vision abnormalities. Since the TES score is directly related to the number of tiles identified incorrectly, lower scores indicate a significant increase in color vision accuracy. https: / / www.colormunki.com / game / huetest_kiosk

[0210]

Table 6

[0211] To obtain a measure of the global behavior of visual performance, the inventors evaluated visual field testing by the Humphrey computerized visual field measurement program 30-2, which provides a widely accepted standardized static measurement of photopic vision over a consistent and reproducible illumination background, and determined the visual field index (% unit) and mean defect (dB unit), which are classical metrics provided by the system.

[0212]

Table 7

[0213] Since the highest concentration of photoreceptors is concentrated in the macula, the central (macula and perimacular) visual field test by the Humphrey computerized visual field measurement program 10-2 was evaluated by considering the average defect (unit: dB).

[0214]

Table 8

[0215] The sensitivity (unit: dB) of the fixation point corresponding to the position of the usually sharpest visual performance was also tested with a Humphrey perimeter (data, unit: dB).

[0216]

Table 9

[0217] For both subjects, on the 3rd day, 2 hours after administration, pupillometry (dark adaptation, mesopic vision, and light adaptation (photonic)) was performed.

[0218]

Table 10

[0219] The present inventors performed a 5-dimensional Altered State of Consciousness Rating Scale on the baseline (day 0), and on the 1st and 4th days after administration. The results in the summary of the following results.

[0220] Summary of Results: Compared to the baseline on day 0, when 3 grams of Psilocybe atlantis sclerotia were administered daily for 3 days and on day 4, 24 hours after the last administration, the inventors detected improvements in the measured values of contrast sensitivity, visual acuity, and color vision in both test subjects compared to the day 0 baseline. Visual field indices also showed improvements in both subjects. A mild increase in mydriatic tension was observed in both subjects on day 3, 2 hours after administration, compared to the day 0 baseline (pupillometry). The 5-dimensional altered state of consciousness assessment scale in both subjects showed a normal state of consciousness in all test areas at all test times (day 0, day 1, day 4), and the absence of psychedelic / psychotomimetic effects was confirmed as expected both acutely (day 1, 2 hours after administration) and 24 hours after the last administration of the daily 3-day regimen.

[0221] The above results suggest that repeated administration of low-dose (non-psychedelic / non-psychotomimetic) Psilocybe atlantis sclerotia, which results in low plasma levels of psilocybin, psilocin, and baeocystin, potentially determines clinically meaningful and persistent effects on different visual parameters. The inventors disclose that these therapeutic effects are potentially mediated by the neuroplastic effects of these molecules at various levels of the visual pathway, potentially from the retinal pigment epithelium (see ARPE-19 test results, Annex 3) to the visual cortex (see in vitro results regarding neurogenesis, Annex 2).

[0222] Therefore, based on the inventors' observational study, the following conclusions were reached. a) Repeated daily administration of a neuroplastic dose of a 5-HT2A agonist substance is potentially safe and effective for visual improvement; b) Repeated daily administration of a neuroplastic dose of a 5-HT2A agonist substance is potentially safe and effective for the treatment of ophthalmological diseases and conditions associated with visual impairment; c) The 5-HT2A agonists at a neuroplasticogen dose can be useful for treatment as a single substance (e.g., psilocybin or psilocin or baeocystin), or as a mixture of molecules, such as the mixture contained in the Psilocybe atlantis fungus: including the mixture of other molecules contained in the sclerotia of Psilocybe atlantis, can be useful for treatment as psilocybin and / or psilocin and / or baeocystin and their mixtures; d) The clinically meaningful measurable potential therapeutic effect of the 5-HT2A agonists at a chronic neuroplasticogen dose lasts longer than the effect predicted from receptor occupancy, represents a potential effect on the regulation of neuroplasticity, rather than an effect based on immediate receptor occupancy; e) The clinically meaningful measurable effect of the 5-HT2A agonists at a chronic neuroplasticogen dose lasts longer than the effect predicted from receptor occupancy, represents the potential therapeutic effect of the 5-HT2A agonists at a chronic intermittent neuroplasticogen dose [*Drugs that act directly on the pathway, including neurotransmitters and their transporter pathways, such as benzodiazepines, opioids, etc. (furthermore SSRIs), produce their effects by interacting with specific receptors, and their effects end when the drug is discontinued, or even rebound. The persistence of the effects observed in the case of chronic neuroplasticogen dose administration of the 5-HT2A agonist substances of the present inventors represents a potential effect regulated through other mechanisms (e.g., neuroplasticity mechanisms or biological pathways) that lasts longer than receptor occupancy].

[0223] In the case of drugs with a very short half-life in humans, as with many 5-HT2A drugs, high doses (psychedelic doses) can lead to rapid down-regulation of the 5-HT2A receptor and a decrease in effect (e.g., a decrease in the psychedelic effect) upon repeated administration. However, low (non-psychedelic doses) chronic administration can maintain efficacy because receptor down-regulation is minimal or non-existent due to 1) low receptor occupancy, 2) rapid clearance of the drug, and 3) effects on NMDAR (see Example 3 below). The above mechanism can suggest a reverse U-shaped curve when 5-HT2A agonists are used as neuroplasticogens (to regulate neuroplasticity in the absence of psychedelic / psychotogenic effects). The dose at the top of the reverse U-shaped curve (the neuroplasticogen dose) is more effective than a very extreme dose on the ascending slope of the reverse U-shaped curve and also more effective than higher doses on the descending slope of the reverse U-shaped curve.

[0224] These observations show that clinically measurable effects on visual parameters can be obtained using a 5-HT2A agonist substance at repeated neuroplasticogen doses (non-psychedelic / non-psychotogenic) at doses that do not cause psychedelic / psychotogenic symptoms, with the plasma levels of the substance being much lower than those generally required for psychedelic / psychotogenic effects.

[0225] (Example 2) In vivo studies Scientific literature available in both clinical settings (safety and efficacy studies) and experimental settings (in vitro and in vivo experimental settings, including the 2018 study by Ly et al.) has, to date, focused on acute pulse treatments using "large" doses of drugs that were predicted and intended to produce clinically meaningful psychedelic / psychotomimetic effects (Johnson M, Richards W, Griffiths R, Human hallucinogen research: guidelines for safety, J Psychopharmacol., August 2008; 22(6):603-20). Similar techniques (pulse exposure to high concentrations) have been conducted in pilot experiments (Ly et al., 2018), thus supporting the use of psychedelic doses of 5-HT2A agonists.

[0226] To evaluate whether chronic repeated low-dose (non-psychedelic / psychotomimetic) administration of 5-HT2A agonists can potentially modulate neuroplasticity and / or modulate neuroinflammation, and to evaluate whether these effects are potentially cytoprotective and whether these effects can potentially result in clinically meaningful therapeutic effects, the inventors conducted a series of preclinical in vivo experiments. These studies were specifically designed to evaluate the potential therapeutic effects of the neuroplastic chronic dosing of 5-HT2A agonists.

[0227] 1. Effects of Psilocybin on Western Diet-Fed Rats Hypothesis: Chronic low-dose treatment with psilocybin counteracts the negative effects on the metabolic parameters of a Western diet (WD).

[0228] Background: The modern Western lifestyle is characterized by the consumption of a high-calorie diet rich in fat and simple carbohydrates. This diet is associated with obesity, type 2 diabetes (T2D) and the metabolic syndrome (Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C, Pinget M, Jeandidier N, Maillard E, Marchioni E, Sigrist S, Dal S, High-fructose and high-fat diet-induced disorders in rats: Impact on diabetes risk, hepatic and vascular complications, Nutrition & Metabolism, 2016, 13:15). These metabolic disorders have been associated with other diseases, such as non-alcoholic fatty liver disease (NAFLD), but also with pathological conditions characterized by low-grade inflammatory states, which may lead to severe immune and neuropsychiatric dysfunctions (Castanon N, Lasselin J, Capuron L, Neuropsychiatric Comorbidity in Obesity: Role of Inflammatory Processes, Frontiers in Endocrinology, 2014, 5:74).

[0229] In the liver, lipid accumulation can be caused by increased delivery or de novo lipogenesis of fatty acids and / or decreased lipid secretion or oxidation, resulting in reduced lipid clearance (Musso G, Cassader M, Gambino R, Non-alcoholic steatohepatitis: Emerging molecular targets and therapeutic strategies, Nature Review Drug Discovery, 2016, 15:249-274). Accumulation of fatty acids in the liver leads to the development of NAFLD, which represents one of the most common causes of chronic liver disease and one of the main causes of liver-related morbidity and mortality worldwide, and is strongly associated with the development of obesity, type 2 diabetes, and metabolic syndrome, as described above (Byrne CD, Targher, G, NAFLD: A multisystem disease, Journal of Hepatology, 2015, 62:S47-S64). The relative contributions of the various pathways described above to the development of NAFLD are only partially known, but several preclinical and clinical studies have revealed that de novo lipogenesis plays a central role in the development of NAFLD (Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ, Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease, Gastroenterology, 2014, 146:726-735). To date, the prevalence of NAFLD and its complication, non-alcoholic steatohepatitis (NASH), has been increasing worldwide, but treatment options are currently unavailable (Alkhouri N, Lawitz E, Noureddin M, Looking Into the Crystal Ball: Predicting the Future Challenges of Fibrotic NASH Treatment, Hepatology Communications, 2019, 3:605-613).

[0230] Method: Thirty male Sprague-Dawley rats (200 ± 50 g) were housed at a temperature of 21°C, three rats per cage, and the 12-hour light and 12-hour dark cycles were repeated alternately. After the acclimation period, they were randomized into two groups. The control group (N = 10) continued with the standard diet (SD, Altromin, Italy), and the Western diet (WD) group (N = 20) was switched to a high-fat diet (HFD) (60% kcal from fat, Altromin, Italy) with 30% (w / v) fructose added to the drinking water. The combination of HFD and 30% fructose in the drinking water is a so-called WD model. After 26 weeks, the WD-fed rats were randomly divided into two subgroups (N = 10) and treated daily for 15 days with either an aqueous vehicle or psilocybin (0.05 mg / kg body weight) by forced oral administration into the stomach.

[0231] All procedures involving animals were conducted in accordance with the institutional guidelines in compliance with national and international policies and regulations (Council Directive of the European Economic Community 86 / 609, OJ L 358, 1, December 12, 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publication No. 85-23, 1985). The study design was approved by the Ethics Committee of the University of Padua and the Italian Ministry of Health regarding the management and use of experimental animals.

[0232] Results: Oral glucose tolerance test On the day before sacrifice, an oral glucose tolerance test was performed to evaluate the blood glucose response after oral administration of glucose (2 g / kg body weight). Referring to FIGS. 1A and 1B, in the WD + vehicle group, the oral glucose tolerance test induced a significant increase in blood glucose peak 15 minutes after forced oral administration of glucose compared to the SD group, but the curve of the WD + psilocybin rats was comparable to that of the SD group. Accordingly, after the oral glucose tolerance test, the increase in blood glucose peak caused by WD was offset by day 15 by forced oral administration of psilocybin at 0.05 mg / kg body weight to the stomach compared to forced oral administration of vehicle to the stomach.

[0233] Body weight and liver weight Next, referring to FIGS. 2A - 2C, at the time of sacrifice, the inventors observed an increase in body weight and liver weight in the WD + vehicle rats compared to the SD - fed rats and the WD + psilocybin rats. Notably, treatment with 0.05 mg / kg of psilocybin for 15 days was able to offset this WD - induced increase in body weight and liver weight.

[0234] Liver tissue image and liver inflammation To evaluate the state of the liver, the inventors performed histological analysis of liver tissue by hematoxylin - eosin staining of paraffin - embedded liver sections. In the histological diagnosis, the SD - fed rats showed a normal liver structure (FIG. 3A), while in the WD - fed rats, lipid accumulation leading to hepatic steatosis was observed, and the lipid accumulation could be observed in 15% (median) of hepatocytes (FIG. 3B, white lipid vesicles, see also Table 2 (Table 11) below), but in the WD rats treated with psilocybin, a dramatic reduction in steatosis could be observed (FIG. 3C, Table 2 (Table 11)).

[0235]

Table 11

[0236] The gene expressions of three kinds of interleukins involved in the inflammatory pathway in rat liver were measured by qRT-PCR. The results are shown in FIGS. 4A to 4C. The gene expression of the pro-inflammatory interleukin IL-6 was significantly increased by WD administration, indicating an increase in liver inflammation, but the psilocybin treatment could counteract this effect and return it to the physiological IL-6 level. As for the anti-inflammatory interleukin IL-10, its gene expression increased in WD-fed rats and significantly decreased in psilocybin-treated rats, but did not reach the normal level. Furthermore, the gene expression of CCL2, a chemokine involved in liver inflammation and the recruitment of immune cells, was increased by WD compared to SD. A tendency to decrease was observed in psilocybin-treated animals compared to untreated WD-fed rats, but the psilocybin treatment did not significantly affect this increase.

[0237] Reactive oxygen species Since the production of reactive oxygen species (ROS) has been associated with hepatic oxidative and metabolic stress, such as hepatic lipid deposition, the inventors evaluated ROS production in rat liver by the 2',7'-dichlorofluorescin diacetate (DCFDA) method. The results are shown in FIG. 5, indicating that hepatic ROS production was significantly increased by WD + vehicle administration, but WD + psilocybin treatment could return it to the physiological ROS level.

[0238] Hepatic lipid metabolism To confirm the histological data indicating the presence of hepatic steatosis, the inventors measured the expressions of two genes involved in lipid metabolism, namely GPAT4 and SREPB2, by qRT-PCR. Referring to FIGS. 6A and 6B, the gene expressions of both GPAT4 and SREPB2 were significantly increased by WD + vehicle administration, but the WD + psilocybin treatment could cause a significant decrease in their expressions, even though this decrease did not return them to their physiological levels. This indicates that psilocybin can lead to a reduction in hepatic steatosis by reducing lipid accumulation and de novo lipogenesis in hepatocytes.

[0239] Behavioral test In order to determine whether chronic administration of low-dose psilocybin changes behavior in WD-fed rats, the inventors conducted a locomotor activity test (LMA) before and after psilocybin treatment (see FIGS. 7A-7C). This test has the goal of evaluating the spontaneous motor activity in experimental animals. This test is conducted in a gray arena (open field) exposed to light of controlled intensity (24 and 30 lux), avoiding the zones of light and shadow within the perimeter of the field where the experiment is being conducted. Along the base of the open field, four standard-sized squares were drawn that were large enough to be clearly visible even during the dark period and for the animals to be able to stay inside them with their entire body length. Prior to the LMA test, a 1-hour acclimation was conducted, and at the end, the rats were placed inside the open field within one of the pre-designed squares. Subsequently, the movement and behavior were recorded for 10 minutes in response to the environment.

[0240] In the LMA test, three basic aspects were evaluated. 1. The number of crossings, i.e., the number of times the animal crosses from one square to another by passing both legs over the lines that define the squares. This value gives an indication of the distance the animal moves during the test and its spontaneous motor activity; 2. The number of rears, i.e., the number of times the animal stands up on its two hind legs. This value is proportional to the anxiety experienced; 3. The grooming time, i.e., the time spent by the animal while cleaning itself, which is another value indicating the anxiety experienced during the test.

[0241] As far as the number of crossings is concerned, the inventors observed a decreasing trend similar to that obtained using SD-fed rats in psilocybin-treated animals. This is probably because the test was repeated after two weeks, but this effect could not be observed in WD-fed rats. The inventors also observed a significant increase in grooming time only in psilocybin-treated rats.

[0242] Notably, no psychedelic behavioral effects were clearly observed from chronic (15 days) administration of psilocybin at a low dose of 0.05 mg / Kg.

[0243] Inflammatory cytokine To determine whether the observed liver inflammation was correlated with a systemic increase in inflammatory markers, the inventors measured the plasma levels of two cytokines (IL-6 and TNF-α) involved in the inflammatory process using an ELISA kit (RayBiotech) according to the manufacturer's instructions.

[0244] As shown in FIGS. 8A and 8B, administration of psilocybin dramatically decreased the plasma concentration of TNF-α in both standard diet-fed rats (p < 0.05) and Western diet-fed rats (p < 0.01). Due to high inter-individual variability, a significant difference could not be detected between different groups at the plasma level of IL-6, but a similar trend as that observed for the TNF-α level was observed.

[0245] 2. Effects on neurogenesis Hypothesis: Chronic low-dose treatment with psilocybin counteracts the negative effect of a Western diet (WD) on neurogenesis.

[0246] Background: Neurogenesis persists in two niches of the adult brain, the dentate gyrus of the hippocampus and the subventricular zone (SVZ) along the outer wall of the lateral ventricle (Lepousez G, Nissant A, Lledo PM Adult neurogenesis and the future of the rejuvenating brain circuits, Neuron, 2015; 86: 387-401; Lledo PM, Alonso M, Grubb MS Adult neurogenesis and functional plasticity in neuronal circuits, Nature reviews Neuroscience, 2006; 7: 179-193).

[0247] Neurogenesis represents a mechanism of neuronal plasticity and can be affected by several factors (Redolfi N, Galla L, Maset A, Murru L, Savoia E, Zamparo I, Gritti A, Billuart P, Passafaro M, Lodovichi C, Oligophrenin-1 regulates number, morphology and synaptic properties of adult-born inhibitory interneurons in the olfactory bulb, Human Molecular Genetics 2016; 25:5198-5211. Rochefort C, Gheusi G, Vincent JD, Lledo PM, Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory, The Journal of neuroscience:the official journal of the Society for Neuroscience 2002; 22:2679-2689. Lepousez G, Nissant A, Lledo PM, Adult neurogenesis and the future of the rejuvenating brain circuits. Neuron, 2015; 86:387-401. Lledo PM, Saghatelyan A, Integrating new neurons into the adult olfactory bulb:joining the network, life-death decisions, and the effects of sensory experience, Trends in Neurosciences, 2005; 28:248-254).

[0248] Recent studies have reported that obesity accelerates the aging process, suppresses neurogenesis, and potentially leads to neuro-psychiatric effects. The effect seems to be specific to the SVZ, as it does not appear to affect the generation of new neurons in the hippocampus (Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Kruger P, Fielder E, Victorelli S, Ruswhandi RA, Giorgadze N, Pirtskhalava T, Podgorni O, Enikolopov G, Johnson KO, Xu M, Inman C, Palmer AK, Schafer M, Weigl M, Ikeno Y, Burns TC, Passos JF, von Zglinicki T, Kirkland JL, Jurk D, Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis, Cell Metabolism, 2019, 29:1233).

[0249] Method: To perform immunohistochemical examination, rats were euthanized, then perfused with 0.9% saline, and then with 4% paraformaldehyde (PFA) in 1× phosphate-buffered saline (PBS) (n tot = 8 rats, n = 2 for each condition). Rat brains were rapidly dissected and then post-fixed with 4% PFA for 48 hours. Brains were embedded in 2.5% agarose (Sigma-Aldrich) and then sectioned into sagittal sections (40 μm thick) with a vibratome (Vibratome VT1000S, Leica). Sagittal brain sections containing the subventricular zone were treated with a blocking solution of 10% normal goat serum (Jackson ImmunoResearch) in 1× PBS for 1 hour and then stained overnight with rabbit anti-Ki67 monoclonal antibody (Abcam, AB 16667) (1:200). The primary antibody was applied for 2 hours at room temperature using Alexa Fluor 488-conjugated goat anti-rabbit (1:500, Jackson ImmunoResearch) and visualized. Brain sections were mounted with Aqua-Poly / Mount (Polysciences). Images of sagittal sections containing the subventricular zone were acquired with a confocal microscope (Zeiss LSM 700) equipped with an EC Plan-Neofluar 20X / 0.50 M27 objective (Zeiss). Ki67-positive cells were counted along the outer wall of the lateral ventricle of sagittal sections of rat brains using ImageJ software (RRID: nif-000030467).

[0250] Results Referring to Fig. 8, the inventors found that neurogenesis was significantly reduced in WD-fed rats compared to SD-fed rats (WD-fed rats, new cells n = 2722 ± 225; SD-fed rats, new cells n = 4601 ± 17; WD rats vs. SD rats, unpaired t-test, p = 0.01). By performing forced oral administration of psilocybin at 0.05 mg / Kg to the stomach for 15 days, the number of newly generated cells in WD-fed rats (psilocybin-treated rats, new cells n = 3404 ± 199) could be partially preserved compared to vehicle-treated WD-fed rats.

[0251] Conclusion From the results, it was shown that its low-dose chronic treatment with low-dose psilocybin administered to WD-fed rats had a positive effect on various metabolic parameters including blood glucose control, lipid accumulation in the liver, body weight, and inflammatory markers. From the results, it was also confirmed that WD significantly reduced the number of newly generated cells in the SVZ. Furthermore, chronic treatment with low-dose psilocybin was able to partially rescue the number of newly generated neurons in the SVZ of WD-fed rats and did not cause signs of anxiety or psychedelic behavioral effects in the rats. The following further conclusions were also reached. a) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of diseases and conditions; b) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of diseases and conditions associated with neurogenic disorders; c) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of diseases and conditions related to learning disabilities, including academic underachievement, underachievement in motor skills, underachievement in social skills, and patterns of emotional dysfunction (based on b); d) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of psychiatric disorders, including those defined by DSM5 and ICD11 (based on b); e) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of neurological diseases and conditions, including neurodevelopmental and neurodegenerative diseases (based on b); f) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of diseases and conditions related to glucose intolerance, including type 2 diabetes; g) Chronic administration of a neuroplasticogenic dose of a 5-HT2A agonist is potentially safe and effective for the treatment of diseases and conditions related to obesity, including its complications; h) Chronic administration of a 5-HT2A agonist at a neuroplasticogen dose is potentially safe and effective for the treatment of diseases and conditions associated with NAFLD and NASH; i) Chronic administration of a 5-HT2A agonist at a neuroplasticogen dose is potentially safe and effective for the treatment of diseases and conditions associated with hepatitis-related conditions including NASH; j) Chronic administration of a 5-HT2A agonist at a neuroplasticogen dose is potentially safe and effective for the treatment of diseases and conditions associated with systemic inflammatory conditions.

[0252] The human equivalent dose (HED) for the rat dose (0.05 mg / Kg) used in the study of Example 2 is 0.0094 mg / Kg (Nair AB, Jacob S, A simple practice guide for dose conversion between animals and human, J Basic Clin Pharm., 2016; 7(2): 27-31), which is approximately 0.66 mg of psilocybin for a 70 Kg human, well below even the lower dose shown to be psychedelic: 0.045 mg / Kg, approximately 3.2 mg for a 70 kg human (Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX, Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study, Psychopharmacology (Berl), 2004; 172(2): 145-156, doi:10.1007 / s00213-003-1640-6).

[0253] In the 1977 experiment by Davis et al., seven groups of 10 rats each were intraperitoneally injected with saline or psilocybin at 0.25, 0.50, 0.75, 1.0, 2.0, 4.0, or 8.0 mg / Kg, and then the startle reflex was measured. At doses of 0.75 - 2.0 mg / Kg, but not at lower doses, psilocybin increased the startle amplitude, while high doses (4.0 - 8.0 mg / Kg) suppressed the startle (Davis M, Walters JK, Psilocybin: biphasic dose - response effects on the acoustic startle reflex in the rat, Pharmacol Biochem Behav., 1977;6(4):427 - 431). In the 2014 study by Rambousek et al., subcutaneous administration of psilocin significantly impaired acquisition in the Carousel - type maze at both doses (1 and 4 mg / Kg) (Rambousek L, Palenicek T, Vales K, Stuchlik A, The effect of psilocin on memory acquisition, retrieval, and consolidation in the rat, Front Behav Neurosci., 2014;8:180). In both of these studies (Davis et al., 1977 and Rambousek et al., 2014), the doses administered to the rats were much higher than the chronic low - dose psilocybin of 0.05 mg / Kg tested daily for 15 days in the present inventors' study. The much lower dose of 0.05 mg / Kg by the present inventors did not significantly change rat behavior, except for the increase in grooming time detailed in the behavior section of Example 2. The increase in grooming time in rodents was associated with anxiety in the case of rats, but in the absence of other anxiety - related behaviors, the increase in grooming time may also be related to the release from stimuli that induce anxiety (Nazareth Veloso AW, Filgueiras GB, Lorenzo P, and Estanislau C, Psychology & Neuroscience, 2016, 9, 1, 91 - 104).In the case of the research by the present inventors, this release could be brought about by low-dose psilocybin treatment.

[0254] Sengupta P, The Laboratory Rat: Relating Its Age With Human's, Int J Prev Med., 2013;4(6):624-630. According to Sagupta P (2013), rats are at a fairly mature stage of their lifespan, and thus the preservation of neurogenesis in the WD+psilocybin group compared to the WD+vehicle group potentially suggests an activity against the aging of the nervous system promoted by Western diet.

[0255] The experiments of the present inventors detailed in Example 2 are particularly groundbreaking as they are the first in vivo experiments showing that chronic administration of a neuroplasticogen dose of a 5-HT2A agonist may potentially be useful for the treatment of diseases and conditions.

[0256] (Example 3) In vitro studies To evaluate the mechanism of the potential therapeutic effect and whether repeated chronic low-dose treatment with a 5-HT2A agonist potentially modulates neuroplasticity and / or modulates neuroinflammation, and whether these effects are potentially cytoprotective against excitotoxic and inflammatory mediators, and ultimately whether these effects can potentially result in a clinically meaningful therapeutic effect, the present inventors conducted a series of preclinical in vitro experiments. These tests were designed to evaluate the potential therapeutic effects of drugs classified particularly as repeated neuroplasticogen doses (low concentration) of 5-HT2A agonists.

[0257] 1. Effects of psilocin and psilocin carbamate on NMDAR subunits and 5-HT2 receptor subtypes in ARPE19 cells Hypothesis: The membrane of retinal pigment cells (ARPE-19 cell line) expresses NMDAR, 5-HT2A, and 5-HT2C receptors. Psilocin reduces L-glutamate-induced cytotoxicity and regulates the transcription and synthesis of selected NMDAR protein subunits.

[0258] Background: The mechanisms underlying the potential efficacy of 5-HT2A agonists administered at large "psychedelic / psychotomimetic" doses (single session) in depression have recently been associated with the BDNF and mTOR pathways and potentially with neural plasticity. Ly et al. have shown that psychedelic compounds such as LSD, DMT, DOI, etc. increase dendritic complexity, promote dendritic spine growth, and stimulate synaptogenesis. These cellular effects are similar to those produced by the rapid-acting antidepressant ketamine, highlighting the potential of psychedelic drugs for treating depression and related disorders (Ly C, Greb AC, Cameron LP et al., Psychedelics Promote Structural and Functional Neural Plasticity, Cell Rep., 2018;23(11):3170-3182). However, Ly et al. did not test psilocin / psilocybin, nor did they test low doses or low doses relative to higher doses.

[0259] Methods and Results: Expression of NMDAR and 5-HT Subtypes in ARPE-19 Cells First, the inventors evaluated the expression of three NMDAR subunits (NMDAR1, NMDAR2A, NMDAR2B) and two 5-HT2 subtypes (5-HT2A, 5-HT2C) by linking immunofluorescence to confocal microscopy. 7,500 cells / well were seeded onto 24-well plates on sterile glass coverslips. The next day, immunofluorescence analysis was performed. The following primary antibodies: anti-NMDAR1A (Abcam, ab68144), NMDAR2A (Bioss, bs-3507R-TR), NMDAR2B (Bioss, bs-0222R-TR), 5-HT2A (Bioss, bs-12049R), 5-HT2C (Bioss, 2959R), and secondary antibody goat anti-rabbit IgG (GeneTex, GTX213110-04) were used. Images of immunostained cells were acquired using a confocal microscope Zeiss LSM 800 at a magnification of 63x and are shown in FIGS. 9A - 9E. The intensity of the fluorescence signal was quantified using ImageJ software.

[0260] Effect of psilocin on glutamate-induced cytotoxicity To confirm the effect of psilocin on L-glutamate-induced cytotoxicity in ARPE-19 cells, the inventors performed a cell viability assay. In this experiment, ARPE-19 cells were seeded onto 96-well plates (7000 cells / well). They were incubated in an incubator at 37°C, 5% CO 2It was left overnight. The next day, the cells were pretreated with a solution of psilocybin. After 6 hours, all the wells (except for the control cells) were replaced with a glutamate solution dissolved in Tris-buffered control saline (CSS). After 5 minutes, the exposure solution was thoroughly washed away and replaced with standard medium according to the protocol described above (Choi DW, Viseskul V, 1988, Opioids and non-opioid enantiomers selectively attenuate N-methyl-D-aspartate neurotoxicity on cortical neurons, Eur J Pharmacol, 155, 27-35). After a 24-hour resting period, cell viability was evaluated using an ATPlite kit according to the manufacturer's instructions. The results can be seen in Figure 10, and the inventors observed that psilocybin, tested at three different concentrations (ranging from 0.025 to 0.1 μM), counteracted the observed reduction in cell viability induced by L-glutamate treatment.

[0261] Effect of psilocybin on protein expression of NMDAR subunits and 5-HT2 receptor subtypes The inventors conducted additional immunocytochemical studies to determine whether psilocybin induces the synthesis of selected proteins that form NMDAR and selected 5-HT receptor subtypes (5-HT2A and 5-HT2C).

[0262] 7,500 cells / well were seeded onto 24-well plates on sterile glass cover slips. The next day, the cells were treated with 10 μM psilocybin for 24 hours and then rescued with standard medium for 5 days, or treated continuously with 0.5 μM psilocybin for 6 days. After 6 days, immunofluorescence analysis was coupled with confocal microscopy and performed with the primary and secondary antibodies described above.

[0263] Referring to FIGS. 11A-11C, ARPE-19 cells exposed to 0.05 μM of psilocin for 6 days showed a dramatic increase in NMDAR1 and NMDAR2A subunits. The NMDAR2B subunit did not change. Conversely, ARPE-19 cells exposed to 10 μM of psilocin for 24 hours showed only a slight increase in NMDAR1 and NMDAR2A and no significant increase. The NMDAR2B subunit did not change.

[0264] Next, referring to FIGS. 11D-11F, generally, a less obvious effect on the expression of NMDAR subunits of the treatment could be observed when the cell culture medium containing psilocybin was replaced daily (for a total of 96 hours), or when the cells were treated alternately (for a total of 96 hours) with medium containing / without psilocin every 24 hours. In particular, when the incubation was carried out by alternately changing the medium containing / without psilocin every 24 hours, at 0.05 μM, an increase in NMDAR1 expression and a decrease in NMDAR2B expression could be observed. Furthermore, the effect of a 96-hour chronic treatment with psilocin carbamate on NMDAR subunits was evaluated. As shown in FIGS. 11D-11F, a reduction in NMDAR2A and NMDAR2B expression was observed.

[0265] Next, referring to FIGS. 11G-11I, the effect of co-incubation of 0.05 μM of psilocin with an excessive (30 μM) prototype NMDAR antagonist MK-801 was evaluated. In particular, as far as NMDAR1 and NMDAR2A expression was concerned, the increase reported after chronic psilocin treatment (FIGS. 11A-11C) was abolished by MK-801-mediated inhibition (FIGS. 11G-11I). Conversely, a decrease in NMDAR2B expression was observed under the same conditions. NMDAR1 expression increased significantly in the case of alternate incubation or when the psilocin-containing medium was replaced daily.

[0266] Next, referring to FIGS. 12A and 12B, conversely, psilocybin was found to have no actual effect on the expression of 5-HT2A receptors in ARPE-19 cells and tended to decrease after both acute and chronic exposure. The expression of 5-HT2C expression increased after chronic treatment with psilocybin.

[0267] Conclusion: Prevention of excitotoxicity and induction of NMDAR subunits by exposure to psilocybin in ARPE-19 cells represent regulation (down-regulation) of Ca 2+ influx. Induction of selected NMDAR subunits represents the effect on NMDAR membrane expression (the NMR1 subunit is required for NMDAR membrane expression) and represents other selective actions of 5-HT agonists on NMDAR subtypes (A-D). These actions of psilocybin potentially benefit from the prevention of excitotoxicity, including the diseases and conditions listed in this application, including ophthalmic, psychiatric, metabolic, and neurological diseases and conditions, and / or potentially benefit from NMDAR regulation and / or regulation of neuroplasticity, representing the potential therapeutic use of low-dose chronic treatment (continuous or intermittent) via NMDAR regulation using 5-HT2A receptor agonists for diseases and conditions.

[0268] The following conclusions regarding ARPE 19 cells were also reached. a) ARPE 19 cells express NMDAR (qPCR and immunofluorescence analysis); b) ARPE 19 cells express 5-HT2A receptors (qPCR and immunofluorescence analysis); c) 5-HT2A agonists are not cytotoxic to ARPE-19 cells; d) High-concentration glutamate is toxic to ARPE-19 cells; e) 5-HT2A agonists provide cell protection from excitotoxicity induced by high-dose glutamate; f) 5-HT2A agonists regulate NMDAR by regulating the mRNA of NMDAR subunits and regulating the synthesis of NMDAR subunits; g) 5-HT2A agonists regulate more effectively compared to a single high-dose (high concentration) (high pulse concentration) applied only once, at chronic and intermittent chronic neuroplastic doses (low concentration), of NMDAR subunits; h) Chronic administration of 5-HT2A agonists at neuroplastic doses and chronic administration of 5-HT2A agonists at intermittent neuroplastic doses are potentially effective in the treatment of diseases and conditions associated with NMDAR dysfunction; i) Chronic administration of 5-HT2A agonists at neuroplastic doses is potentially effective in the treatment of diseases and conditions associated with learning disabilities, including academic underachievement, underachievement in motor skills, underachievement in social skills, and mood dysfunction patterns (based on NMDAR regulation, e and f); j) Chronic administration of 5-HT2A agonists at neuroplastic doses is potentially safe and effective in the treatment of psychiatric disorders, including those defined by DSM5 and ICD11 (based on NMDAR regulation, e and f); k) Chronic administration of 5-HT2A agonists at neuroplastic doses is potentially safe and effective in the treatment of neurological diseases and conditions, including neurodevelopmental and neurodegenerative diseases (based on NMDAR regulation, e and f); l) Chronic administration of 5-HT2A agonists at neuroplastic doses is potentially effective in the treatment of ophthalmological diseases and conditions (based on effects on ARPE-19, retinal pigment epithelial cells, e and f).

[0269] Example 3 potentially suggests the therapeutic use of 5-HT receptor agonists via the regulation of NMDAR and the prevention of excitotoxicity. The finding that the synthesis of selected NMDAR subunits is regulated by 5-HT2A agonists and their protective effects against excitotoxicity is related to the potential allosteric block of open NMDAR channels by these drugs and excessive Ca 2+Reduction to physiological levels of influx, prevention of excitotoxicity, and resumption of cellular function, such as resumption of synthesis of the NR-1 subunit. The inventors have also disclosed that even before mRNA induction and synthesis occur, mobilization of the NMDAR1 subunit from the ER induced by regulation of Ca2+ influx through NMDAR can lead to cellular membrane expression of new NMDAR, as also represented in the 2018 review by Baez et al. (Baez MV, Cercato MC, Jerusalinsky DA, NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition, Neural Plast., 2018). The inventors are obtaining additional signals for allosteric regulation of the NMDAR pore (see Example 5) and are currently confirming this hypothesized mechanism of action by performing FLIPR calcium assay experiments. An increase in NMDAR in the postsynaptic cleft can also be associated with a decrease in perisynaptic / extrasynaptic NMDAR. Postsynaptic NMDAR located at the synapse has been associated with LTP and cell survival, while extrasynaptic NMDAR has been associated with excitotoxicity and apoptosis. The positive effect of the 5-HT2A agonist on cell survival and the positive effect on aging induced by UV irradiation of the combination of psilocin and dextromethorphan (see Example 6), described in Examples 3 and 4, may be due to downregulation of Ca 2+ influx. Additional experiments are being conducted to test this mechanism of enhanced cell protection and survival.

[0270] The new experiments presented with this application demonstrate excitotoxic protection by 5-HT2A agonists, confirm that NMDAR1 mRNA increases in retinal cells exposed to 5-HT2A agonists, and also show that 5-HT2A agonists induce the synthesis of the NR-2A subunit rather than the NR-2B subunit. In addition to the BDNF-dependent effects described by Ly et al. in 2018, which provide a potentially selective (NMDAR subtype-selective) "repair mechanism" involving the synthesis of selected subunits of new NMDARs and the expression of selected subtypes of new NMDARs, as well as the mechanisms of retrograde presynaptic potentiation and neurite growth effects, a potential synaptic potentiation mechanism (postsynaptic regulation of NMDARs) is represented. Together with the presynaptic neuroplasticity effects shown by Ly et al. in 2018 and the postsynaptic potentiation represented by the experiments of the inventors regarding the regulation of NMDAR subunits, they are essential for LTP, memory formation, and learning.

[0271] (Example 4) Further in vitro studies - corneal cells In vitro studies on the cytotoxic and anti-inflammatory effects of psilocybin Objective The objective of this study is to verify the following: a) The effect of psilocybin on cell viability b) The expression of NMDAR and HT2A subunits in corneal epithelial cells and keratocytes c) The anti-inflammatory effect of psilocybin on corneal epithelial cells treated with the medium of activated human monocytes (cell line U937) differentiated into macrophages d) The anti-VEGF and anti-fibrotic effects of psilocybin in keratocyte cultures exposed to the inflammatory conditioned medium of activated U937 cells

[0272] Materials and methods Cell cultures. Human corneal epithelial (HCE) cells were obtained from the American Type Culture Collection. The U937 human monocyte cell line was purchased from Thermo Scientific.

[0273] Primary corneal keratocytes were obtained after digestion of human corneas from healthy donors purchased from the Veneto Eye Bank Foundation (Venezia Mestre, Italy). The corneal epithelium was removed with a cell scraper, and the endothelium was enzymatically detached using a 0.05% trypsin / 0.02% EDTA-solution at 37 °C for 15 minutes. Subsequently, the stroma was cut into 3-4 mm strips and incubated overnight at 37 °C in Dulbecco's modified Eagle's medium (DMEM) containing type I collagenase (100 U / ml) and hyaluronidase (2 mg / ml). Then, the isolated keratocytes were seeded in monolayers and cultured at 37 °C in DMEM containing 10% FBS, 1% penicillin-streptomycin (P / S) and 1% L-glutamine (also known as complete medium) under 5% CO 2 atmosphere. The proliferated cells were trypsinized and subcultured at a 1:2 ratio. Corneal cells grew in complete DMEM medium under standard cell culture practices at 37 °C in a 5% CO 2 atmosphere. U937 human monocytes proliferated in suspension in complete RPMI 1640 medium and were diluted and subcultured twice a week at a seeding density of 10 6 cells / ml.

[0274] Psilocin cytotoxicity and viability assessment. Different concentrations of psilocin were added to corneal cells, and cytotoxicity was determined after 3 days. Cell viability was evaluated on days 1, 3, and 6 after psilocin treatment using the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Sigma, MO, USA) with a modified Denizot method. In this procedure, only live cells with functional mitochondria can oxidize MTT to a purple to red reaction product.

[0275] Linkage of immunofluorescence and confocal microscopy. 7,500 cells / well were seeded onto a 24-well plate on a sterile glass coverslip. The next day, immunofluorescence analysis was performed. The following primary antibodies were used: anti-NMDAR1A (Abcam, ab68144), 5-HT2A (Bioss, bs-12049R), 5-HT2C (Bioss, 2959R), and the secondary antibody goat anti-rabbit IgG (GeneTex, GTX213110-04). Images of the immunostained cells were acquired using a confocal microscope Zeiss LSM 800 at a magnification of 63x. The intensity of the fluorescence signal was quantified using ImageJ software.

[0276] Evaluation of anti-inflammatory and anti-fibrotic effects. Cytokine expression was analyzed in human keratinocytes and HCE cells exposed to the inflammatory conditioned medium (CM) of activated U937 cells.

[0277] U937 human monocytes were treated with 50 ng / mL of phorbol myristate acetate (PMA) for 48 hours and then exposed to 1 μL / mL of lipopolysaccharide (LPS) for 1 hour to differentiate into macrophages. The cells were then washed and cultured in complete RPMI for 24 hours to generate inflammatory CM. The CM was collected, filtered, and stored at -80°C. The differentiation of monocytes into macrophages was examined under an inverted phase contrast microscope, and the mRNA expression of the macrophage differentiation marker CD68 was analyzed by quantitative real-time PCR (qPCR). The cells were then washed and cultured in complete DMEM for 24 hours to generate CM. The CM was collected, filtered, and stored at -80°C.

[0278] Corneal cell cultures were exposed to the CM of activated U937 cells for 24 hours and then treated in the presence or absence of different concentrations of psilocybin. In human keratinocytes and HCE cells exposed to CM for 24 hours and then treated in the presence or absence of different concentrations of psilocybin, cytokine expression was analyzed using untreated cultures as controls. At 4 and 10 hours, or at 4, 10, and 24 hours, the cells were detached, mRNA was extracted, and the expression of pro-inflammatory cytokines (IL-1β, TNF-α, IL-8, IL-12, IFNγ) was analyzed. The expression of type I collagen and VEGF was analyzed for mRNA extracted from keratinocyte cell cultures. The experiment was performed 3 times.

[0279] Statistical analysis. Graphpad Prism 8 was used for statistical analysis. Student's unpaired t-test was used for comparison between groups. Data are presented as mean and standard error. For statistical significance, differences were indicated as P<0.05 (*), P<0.01 (**), P<0.001 (***).

[0280] Results Effect of psilocybin cytotoxicity and viability on HCE cells and keratinocytes. Corneal cells were cultured separately with different concentrations of psilocybin (0.1 - 100 μM), and cytotoxicity was evaluated on the 3rd day after treatment (Figures 13A and 13B). Cell viability was analyzed by MTT assay up to the 6th day, and a significantly increased viability was seen in both HCE cells and keratinocytes with psilocybin in the 0.1 - 1 μM concentration range, as shown in Figures 14A and 14B.

[0281] Expression of proteins NMDAR1, 5-HT2A, and 5-HT2C in HCE cells and keratinocytes. HCE cells express NMDAR1 and the two serotoninergic receptors 5-HT2A and 5-HT2C, while keratinocytes do not express NMDAR1 and 5-HT2C at significant levels (see Figures 15A - 15D).

[0282] Effect of psilocin on the expression of some pro-inflammatory cytokines by corneal cells grown in conditioned medium (CM) of PMA-activated U937 monocytes. Since native corneal cells have been shown to be activated during corneal stromal injury and inflammation, the inventors analyzed the expression of some pro-inflammatory cytokines in corneal cells treated with CM of activated U937 monocytes (macrophages). qPCR analysis of mRNA extracted from PMA-activated U937 cells showed a significant increase in the expression level of the macrophage differentiation marker CD68.

[0283] Exposure of corneal cells to macrophage CM was confirmed to greatly enhance pro-inflammatory cytokine expression in corneal cell cultures by the environment created by macrophages. Subsequently, to demonstrate the effect of psilocin on the production of pro-inflammatory cytokines, the molecule was added to the cells at concentrations of 0.1 or 1 μM. qPCR analysis revealed that treatment of keratinocytes with CM of PMA-activated U937 cells induced significant overexpression of IL-1β, IL-8, and IL-12 mRNA (Figures 16A - 16D). The presence of 0.1 and 1 μM psilocin induced a significant decrease in IL-1β expression at 4 hours after treatment (Figure 16A), and significant decreases in IL-8 expression (Figure 16B) and IL-12 expression (Figure 16C) at 4 and 10 hours. TNF-α expression was very low and comparable to that of cells treated with CM alone (Figure 16D). IFNγ expression was undetectable in the inventors' qPCR analysis.

[0284] VEGF I (Figure 17) and type I collagen gene expression did not change significantly in keratinocyte cultures treated with U937-activated CM and subsequently cultured for 4, 10, and 24 hours in the presence of 0.1 and 1 μM psilocin.

[0285] The gene expressions of the pro-inflammatory cytokines IL-1β, IL-8, IL-12 and TNF-α were much less obvious in HCE cells treated with the same CM of U937-activated monocytes (Figs. 18A - 18D). Furthermore, significant down-regulation of gene expression was only observed for IL-8 at 10 hours after treatment in the presence of 0.1 and 1 μM of psilosin.

[0286] Conclusion From this study, it became clear that psilosin does not have in vitro cytotoxic effects at concentrations of 0.001 - 10 μM. Moreover, psilosin induced a significant increase in in vitro corneal cell viability on the 3rd and 6th days after treatment at concentrations of 0.01, 0.1 and 1 μM. Furthermore, at concentrations of 0.1 μM and 1 μM, psilosin brings about an anti-inflammatory effect that can be useful for the treatment of anti-inflammatory treatment of eye disorders against keratinocytes and HCE cells (0.01 μM was not tested in this experiment). VEGF I (Fig. 17) and type I collagen gene expression did not change significantly in keratinocyte cultures treated with U937-activated CM, and thus could not show the anti-fibrotic effect of the molecule in this model. Alternative studies should be considered to better evaluate the anti-fibrotic effect of psilosin on corneal cells using other models of inflammation or various inflammatory stimuli. The signal transduction pathways controlled by psilosin should also be analyzed.

[0287] Moreover, based on the research of this example, the inventors concluded as follows: a) HCE cells express NMDAR and 5-HT2A receptors; keratinocytes express 5-HT2A receptors (qPCR and immunofluorescence analysis); b) 5-HT2A agonists are not cytotoxic; c) 5-HT2A agonists potentially increase cell viability at neuroplastic doses (0.01 and 0.1 μM); d) 5-HT2A agonists are potentially effective in the treatment of inflammatory conditions; e) 5-HT2A agonists are potentially effective in the treatment of dry eye diseases and dry eye syndrome.

[0288] Notably, the control of Ca 2+ influx through NMDAR can be a mechanism by which cell survival rate is increased (Liu ZY, Zhong QW, Tian CN, Ma HM, Yu JJ, Hu S, NMDA receptor-driven calcium influx promotes ischemic human cardiomyocyte apoptosis through a p38 MAPK-mediated mechanism, J Cell Biochem., 2019;120(4):4872-4882).

[0289] (Example 5) Molecular modeling (Including the induction of selected NMDAR subunits (disclosed in Example 3) and the prevention of excitotoxicity induced by L-glutamate), the regulation of NMDAR by 5-HT2A agonists is excessive Ca 2+Potentially represents an allosteric interaction that downregulates the influx. This allosteric interaction can also play a role in the action of known NMDAR antagonists that also have an effect on the serotonin pathway (e.g., racemetorphan and its isomers, levometorphan and dextromethorphan, methadone and its isomers, levomethadone and dextromethadone (Codd et al., 1995), ketamine (du Jardin K.G., Liebenberg N., Muller H.K. et al., Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression, Psychopharmacology, 2016; 233, 2813-2825), and memantine (Onogi H, Ishigaki S, Nakagawasai O et al., Influence of memantine on brain monoaminergic neurotransmission parameters in mice:neurochemical and behavioral study, Biol Pharm Bull., 2009;32(5):850-855).

[0290] Conversely, the regulation of NMDAR by 5-HT2A agonists and structurally modified serotonergic neuroplastogens (SMSNs) may be due to the same mechanism hypothesized for known pore channel blockers. Thus, it may be due to the interaction in the intracellular part of the NMDAR. The inventors tested in silico the second hypothesis, the direct interaction of 5-HT2A agonists and SMSNs with the channel pore, by molecular modeling studies of selected 5-HT2A agonists and SMSNs that bind to the transmembrane region of the closed-state NMDA receptor GluN1-GluN2B tetramer subtype. The in silico NMDAR subtype constructed for the in silico test is the GluN1-GluN2B tetramer composed of two GluN1 subunits and two GluN2B subunits. Notably, the N2B subunit is essential for the formation of the supercomplex containing NMDAR. To improve the efficiency of in silico calculations, only the transmembrane region of the receptor where the putative PCP binding site is located and where the tested NMDA antagonists (dextromethorphan, ketamine, memantine), which are FDA-approved and clinically tolerated, are also likely to act, and where the inventors hypothesized that 5-HT2A agonists and their derivatives (SMSNs) could also act.

[0291] The inventors used the structure identified by Protein Data Bank (PDB) code 4TLM as a starting point for a computer study to investigate the drugs shown in Table 1A (Table 1) and positive controls (ketamine, memantine, dextromethorphan, amantadine, MK-801, PCP, all known NMDA open channel blockers with known affinities and known clinical effects and presumed to act at the PCP site of the transmembrane domain). PCP is a Schedule I drug and MK-801 is a high-affinity antagonist with severe side effects that preclude its clinical use. The other four drugs are in clinical use and are FDA-approved for various indications shown throughout this application. As seen in Table 1B (Table 2), many of the docking scores of the SMSN are in a similar range to the docking scores of well-established NMDAR channel blockers shown in Table 3 (Table 12) below.

[0292]

Table 12

[0293] Most of the test compounds show predicted affinity results (docking results, Table 1B (Table 2)) in a similar range to compounds with known NMDAR blocking action (predicted affinity -5 -7, Table 3). These computer-generated results represent potential NMDAR blocking effects in the pore channel for the 5-HT2A compounds and selected SMSN. The inventors are currently planning computer-based dynamic modeling and in vitro FLIPR calcium assays to better define and quantify the NMDAR blocking action of the Table 1A (Table 1) molecules.

[0294] These computer-generated results represent potential NMDAR blocking effects in the pore channel for the 5-HT2A compounds and selected SMSN.

[0295] (Example 6) Anti-aging effect The inventors analyzed the anti-aging effects of psilocin and d-methadone on UVB-induced aging in IMR-90, passage 20. Seeding was performed on day 1, pretreatment on day 2, UVB induction and re-treatment on day 3, SABG on day 8, and microscopy (SABG) on day 9. The anti-aging effect was observed when 10 nM of psilocin was combined with 10 nM of d-methadone, with a 34% reduction in β-Gal positive cells. Higher doses of psilocin (up to 24 μM, not shown in the experiment) and lower doses of psilocin (5 nM, according to this Example 6) did not show an anti-aging effect. The results of Example 6 can be seen in Figures 19A to 27D below, and Tables 4 (Table 13), Table 5 (Table 14), Table 6 (Table 15).

[0296] [Table 13]

[0297] [Table 14]

[0298] [Table 15]

[0299] (Example 7) Psilocin-carbamate 1. Effects of isoleucyl carbamate on young, adult, and aged mice fed a high-fructose diet Hypothesis: Low-dose chronic treatment with psilocin-carbamate (isoleucyl carbamate) has good tolerance and improves the cognitive and metabolic performance of high-fructose-treated mice of different ages.

[0300] Background: Psilocybin is thought to act as a prodrug of psilocin because it is dephosphorylated in vivo by alkaline phosphatase to the active compound psilocin (Jacob III, P., Shulgin, A.T., NIDA Research Monograph 146 (Hallucinogens, an Update), 2000, Eds. Lin, G.C.; Glennon, R.A., p. 74). Furthermore, psilocin rapidly undergoes chemical decomposition in the presence of air, heat, and / or light because of the presence of a free 4-hydroxy group that is susceptible to oxidation on the tryptamine scaffold. On the other hand, psilocybin is much more stable than psilocin because of the presence of a phosphate ester that protects the 4-OH group from both chemical and metabolic decomposition. Thus, the prodrug approach can be considered a “smart” strategy to overcome the limitations of psilocin and sustain plasma levels of psilocin after administration of the more stable psilocybin molecule.

[0301] The present inventors have now evaluated the efficacy and safety of a new psilocybin carbamate prodrug (isoleucinyl carbamate) reversibly protected as a carbamate ester in which the 4-hydroxyl moiety is linked to the N-terminus of isoleucine. Lipophilic amino acid carbamate ester prodrugs of phenolic compounds have been shown to potently improve their bioavailability by enhancing absorption after oral administration, reducing metabolism, and leading to sustained release of low concentrations of the active compound, particularly into brain tissue, for up to 24 hours (see, for example, Azzolini et al., (2017), Eur J Pharm Biopharm, 115, 149-158). Sustained release formulations of the active compound psilocybin with lower Cmax and Tmax concentrations potentially maintain the ability to promote both structural and functional plasticity in brain tissue while potentially avoiding the psychedelic / psychotomimetic effects of psilocybin and psilocin administration (depending on reaching some of the plasma concentrations disclosed in this application), representing the advantages of the safe pharmacological use of psilocybin. Accordingly, the present inventors designed, synthesized, and administered this novel drug, isoleucinyl carbamate, to young, adult, and aged mice fed a standard diet supplemented with 30% fructose in drinking water, so as to obtain information about i) the pre-toxicity profile of this psilocybin prodrug in mice of different ages; ii) preliminary signals about its potential efficacy for the treatment of diseases and pathologies.In particular, according to recent research reports, obesity and the consumption of fortified foods rich in fat and sugar accelerate the aging process and potentially lead to neuropsychiatric effects. Therefore, the effects of the administration of psilocybin-carbamate on cognitive behavior and several synaptic markers were evaluated (Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Kruger P, Fielder E, Victorelli S, Ruswhandi RA, Giorgadze N, Pirtskhalava T, Podgorni O, Enikolopov G, Johnson KO, Xu M, Inman C, Palmer AK, Schafer M, Weigl M, Ikeno Y, Burns TC, Passos JF, von Zglinicki T, Kirkland JL, Jurk D., Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis, Cell Metab, 2019; 29:1233, 2019).

[0302] Methods: Twelve male C57BL / 6 mice of different ages (young: 2 months old, adult: 5 months old, old: 18 months old) were housed at a temperature of 21°C, four per cage, and the light and dark periods of 12 hours each were repeated alternately. The mice were fed a standard diet, and 4 days before randomization, fructose (30% (w / v) in drinking water) was added to their diet. Then, the mice were randomly divided into two subgroups according to age (N = 2 animals per group), and were treated daily for 15 days with an aqueous vehicle or psilocybin-carbamate (0.05 mg / kg body weight) by forced oral administration into the stomach.

[0303] All procedures involving animals were conducted in accordance with the institutional guidelines in compliance with national and international policy regulations (Council Directive of the European Economic Community 86 / 609, OJ L 358, 1, December 12, 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publication No. 85-23, 1985). The test design was approved by the Ethics Committee of the University of Padua and the Italian Ministry of Health for the management and use of experimental animals.

[0304] Results: During the experiment, the animals were carefully monitored daily for a period not exceeding the maximum experimental endpoint. Water (30% (w / v) fructose) and food were available ad libitum. No obvious clinical symptoms were observed during the experimental period. No signs of toxicity or mortality were observed during the 14-day administration of psilocin-carbamate or vehicle by forced oral gavage into the stomach.

[0305] Body weight and liver weight Referring to FIGS. 28A and 28B, at the time of sacrifice, the inventors observed a decrease in body weight (p < 0.05) and liver weight in adult mice treated with psilocin-carbamate. Notably, the same trend could be observed in old mice, but the treatment with psilocin-carbamate had no effect on the body weight and liver weight of young mice.

[0306] Blood glucose Before the slaughter, the inventors measured the blood glucose concentration of mice after 2 hours of fasting. Figure 29 shows that young mice have higher blood glucose levels than adult and old mice, and that psilocybin-carbamate has no effect on blood glucose controls, but the inventors did not observe a statistically significant difference between the groups. In old mice treated with psilocybin-carbamate, a tendency for a decrease in blood glucose concentration was observed.

[0307] Behavioral test To determine whether chronic administration of low-dose psilocybin-carbamate alters the behavior of the test mice, the inventors conducted a locomotor activity test (LMA), a novel environment feeding suppression (NSF) test, and an olfactory habituation / dishabituation test before and after psilocybin-carbamate treatment.

[0308] The LMA has the goal of evaluating the spontaneous motor activity in experimental animals. This test is conducted in a gray arena (open field) exposed to light of controlled intensity (24 and 30 lux), avoiding the zones of light and shadow within the perimeter meter where the experiment is conducted. Along the base of the open field, four standard-sized squares were drawn that were clearly visible even during the dark period and large enough for the animals to stay inside them with their entire body length. Prior to the LMA test, a 1-hour acclimation was conducted, and at the end, the rats were placed inside the open field in one of the pre-designed squares. Then, the movement and behavior were recorded for 10 minutes in response to the environment.

[0309] Three basic aspects were evaluated. 1. The number of crossings, i.e., the number of times the animal crosses from one square to another by passing both legs through the line defining the square. This value gives an indication of the distance the animal moves during the test and its spontaneous motor activity; 2. The number of rears, i.e., the number of times the animal stands up on its two hind legs. This value is proportional to the anxiety state experienced; 3. The grooming time, i.e., the time the animal spends cleaning itself, which is another value indicating the anxiety state experienced during the test.

[0310] Referring to FIGS. 30A to 30C, as far as the number of crossings is concerned, the inventors observed a decreasing trend in both the treated and untreated mice in the post-treatment tests. This is probably due to the animals' acclimation to the tests. Regarding the rise, the same observation could be made, but the grooming was generally not affected by acclimation. Only in the old mice, a tendency for an increase in the time spent on grooming (p = 0.089) could be observed in the psilocybin-carbamate treated mice. Notably, no obvious psychedelic behavioral effects were observed by chronic (14 days) administration of low-dose 0.05 mg / Kg of psilocybin-carbamate (isoleucinyl carbamate).

[0311] To evaluate the stress and hunger levels of mice after overnight fasting, the novel environment feeding suppression (NSF) test was conducted according to the protocol described above (Blasco-Serra et al., 2017). The arena where the test was performed was illuminated with a higher light intensity in the central part and a lower light intensity in the peripheral part. In the central part of the arena, a platform consisting of a Petri dish with a paper disk and one feeding pellet was placed. After fasting for at least 12 hours, the animals were acclimated for 60 minutes before starting the experiment to get used to the new environment and minimize stress. Then, each mouse was placed in the arena and its behavior was monitored for up to 10 minutes. When the mouse finally reached the pellet and started eating, it was transferred to another standard cage with readily available feeding pellets for 5 minutes.

[0312] In this test, usually three parameters were measured: 1. The time it took for the animal to start ingesting the feeding pellet in the first cage (maximum time = 10 minutes); 2. The number of times the mouse sniffed and approached the pellet in the first cage; 3. The amount of pellets ingested by the animal in the second cage in 5 minutes. The results can be seen in FIGS. 31A to 31C.

[0313] In the olfactory habituation / dishabituation test, several odors are repeatedly presented to the mouse, with each odor presented three times for two minutes each. The investigator carefully records the sniffing time directed towards the odor as a measure of olfactory responsiveness. A typical mouse shows a decrease in response to the odor over repeated presentations (so-called habituation). The experimenter then presents a novel odor that induces an increase in sniffing behavior (dishabituation). After repeated presentation of the novel odor, the animal also shows habituation. The protocol used in this study involves the presentation of water, two non-social odors (almond and banana), and two social odors.

[0314] Referring to FIGS. 32A-32F and FIGS. 33A-33F, generally, the responses to this test were characterized by wide variability. Overall, no significant effect could be observed after the physostigmine-carbamate treatment.

[0315] 2. Effects of Physostigmine-Carbamate Treatment on NMDAR and Synaptic Markers Hypothesis: Low-dose chronic treatment with physostigmine-carbamate (isoleucinyl carbamate) modulates neuroplasticity.

[0316] Background: Some serotonergic psychedelic drugs have been shown to significantly increase neurite outgrowth and / or spine formation both in vitro and in vivo (Ly C, Greb AC, Cameron LP et al., Psychedelics Promote Structural and Functional Neural Plasticity, Cell Rep., 2018;23(11):3170-3182). These changes in neuronal structure are accompanied by an increase in the number and function of synapses.

[0317] Methods: Mice were euthanized by cervical dislocation. Immediately after sampling, fresh tissue was dissected, and four brain regions (cerebellum, lateral cortex, olfactory bulb, and the rest of the brain) were isolated, collected immediately, placed in cryovials in liquid nitrogen, and then maintained at -80°C.

[0318] Brain tissue was lysed in RIPA lysis buffer (Invitrogen) and 1% (v / v) protease and phosphatase inhibitor cocktail (Sigma). Proteins were extracted by centrifugation at 14,000 rpm for 30 minutes at 4°C. Protein concentration was determined using a bicinchoninic acid assay (BCA) kit (Catalog No. 23225, Thermo-Scientific) according to the manufacturer's instructions. Western blot analysis was performed using 30 μg per lane of nuclear or outer cortical lysate to determine NMDAR1 (primary antibody: Abcam, ab68144), PSD95 (Bioss, bs-0179R-TR), p70 (Bioss, bs-3498R-TR), and synapsin 1 (Bioss, bs-3501R-TR) protein expression. SDS-PAGE was performed on an 8% polyacrylamide gel under reducing-denaturing conditions, and proteins were transferred to a 0.45 μM nitrocellulose membrane (BioRad Laboratories). The signal intensity of immunoreactive bands was analyzed using Quantity One software (Bio-Rad Laboratories S.r.l.) and normalized to the signal intensity of the loading control GAPDH.

[0319] Results: We analyzed the protein expression of NMDAR1, PSD95, p70, and synapsin 1 in the outer cortex of young, adult, and old mice. Referring to Figure 34, NMDAR1 expression tended to increase in young and old mice after treatment with psilocybin-carbamate (isoleucyl carbamate), but tended to decrease in adult mice. It must be noted that high inter-group variability was observed.

[0320] The inventors also measured the protein expression of three synaptic proteins, PSD95, p70, and synapsin 1. Referring to FIGS. 35A to 35C, no significant difference was observed in the expression of these proteins. However, PSD95, like the NMDAR1 subunit, tended to increase in young mice and decrease in adult mice after treatment, showing different trends in young and adult mice. Conversely, synapsin 1 expression tended to increase only in adult mice after treatment. Unexpectedly, p70 could not be detected in adult mice.

[0321] Conclusion: Psilocybin-carbamate (isoleucinyl carbamate), a prodrug of psilocybin, appears to be safe and well-tolerated when administered daily for 14 days at a dose of 0.05 mg / Kg to young, adult, and old mice. Safety and tolerability were also confirmed by behavioral observation. Isoleucinyl carbamate potentially regulates synaptic proteins. These effects need to be clarified in larger experiments. Based on these preliminary results, the inventors can then plan experimental studies aimed at better characterizing the PK and PD parameters of psilocybin-carbamate and obtaining further data on its potential safety and efficacy for the treatment and prevention of diseases and conditions.

[0322] The results are consistent with the results of the LMA test, indicating that the mice were probably acclimated after the first test. Clearly, psilocybin-carbamate had no effect on performance in the NSF test. Some trends could be observed, as the decrease observed in the control group in the amount of food consumed by adult mice in the second cage in 5 minutes was counteracted by psilocybin-carbamate treatment.

[0323] In short, the in vivo effects on neurogenesis, metabolic parameters, and inflammation (as seen in Example 2, the rat study), the in vitro effects on NMDAR subunits (as seen in Example 3, the ARPE-19 study), and the in vitro effects on cell viability (as seen in Example 4, corneal cells), the clinical observations in human subjects (as seen in Example 1), and the computer-generated results (as seen in Example 5, molecular modeling), the in vitro anti-aging results (as seen in Example 6), and the mouse experiments using the psicylocarbamate of this Example 7 are supplementary to show that chronic, continuous, or intermittent administration of the 5-HT2A agonist drugs and their derivatives listed in Table 1A (Table 1) at a neuroplastic dose (non-psychedelic / non-psychotomimetic dose) has an impact on NMDAR regulation, neuroplasticity, inflammation, metabolic parameters, and cell viability, which may potentially be useful for the treatment and prevention of diseases and conditions.

[0324] Accordingly, the inventors disclose the use of the 5-HT2A agonists and their derivatives (SMSN) listed in Table 1A (Table 1) alone or in combination with an NMDAR open channel blocker, administered at a non-psychedelic / non-psychotomimetic dose, over several days or months, or chronically, continuously, or intermittently repeated, for patients who may potentially benefit from a drug that has an effect on the regulation of neuroplasticity and the regulation of NMDAR over a certain period of time for the treatment of diseases and conditions, and has good tolerance without clinically significant side effects, including psychedelic / psychotomimetic side effects.

[0325] The present invention has been disclosed by reference to the details of the preferred embodiments thereof, but it should be understood that the disclosure is not intended to be limiting in nature but rather illustrative, as modifications are contemplated by those skilled in the art within the spirit of the invention and the scope of the amended claims.

Claims

1. 1. A composition for use in a method for preventing or treating a disease or condition selected from an ophthalmological disorder and a metabolic disorder in a patient or subject, comprising a compound selected from psilocin, psilocybin, baeocystin, norbaeocystin, psilocin carbamate, derivatives thereof and mixtures thereof; the derivatives are carbamate derivatives, fluoro derivatives, nitro derivatives, or deuterated versions thereof, including deuterated carbamate derivatives, deuterated fluoro derivatives, deuterated nitro derivatives, and deuterated fluoro-nitro derivatives; composition.

2. The composition of claim 1, wherein the method comprises administering the compound at a dose that is about 1 / 10 to 1 / 20 of a psychedelic dose.

3. The composition of claim 2, wherein the administration of the compound is performed under conditions that allow modulation of NMDAR and their subunits in addition to modulation of the 5-HT2A receptor.

4. The composition of claim 2, wherein administration of the compound is capable of providing excitotoxicity protection.

5. The composition of claim 2, wherein administration of the compound is capable of modulating neurogenesis.

6. The composition of claim 2, wherein administration of the compound is under conditions effective for the compound to produce a neuroplastogenic effect, including modulation of neuroplasticity.

7. 3. The method of claim 2, wherein administration of the compound is repeated over a period of days or months, or is chronic.

8. 3. The composition of claim 2, wherein administration of the compound is intermittent, occurring every other day, every two days, or every week or every two weeks, or every month.

9. 3. The composition of claim 1 or 2, wherein the method is for treating metabolic syndrome and its complications.

10. 3. The composition of claim 1 or 2, wherein the method is for treating impaired glucose tolerance, diabetes and their complications.

11. 3. The composition of claim 1 or 2, wherein the method is for treating NAFL, NAFLD, NASH and their complications.

12. 3. The composition of claim 1 or 2, wherein the method is for treating obesity and its complications.

13. 3. The composition of claim 1 or 2, wherein the method is for treating vision impairment and vision loss, including macular degeneration and retinopathy.

14. 3. The composition of claim 1 or 2, wherein the method is for treating systemic inflammatory conditions and autoimmune disorders.

15. The composition of claim 1 or 2, wherein the method is for treating dry eye syndrome.

16. 3. The composition of claim 1 or 2, wherein the method is for treating restless legs syndrome.

17. 3. The composition of claim 1 or 2, wherein the compound is in the form of a modified release formulation.

18. 3. The composition of claim 1 or 2, wherein the method comprises the administration of a combination of at least two compounds, a first compound selected from among psilocybin or psilocin or baeocystin or norbaeocystin at a dose of 0.01 to 24 mg, and a second compound selected from among open channel low affinity uncompetitive NMDAR antagonists selected from dextromethorphan, dextromethadone, ketamine and its isomers, memantine, amantadine, noribogaine at a dose of 0.01 to 50 mg.

19. 3. The composition of claim 1 or 2, wherein the method comprises administering the compound in combination with magnesium and / or zinc and / or lithium and salts thereof.

20. 3. The composition of claim 1 or 2, wherein the method comprises a step of daily oral administration of psilocybin and / or psilocin and / or baeocystin containing fungi and / or extracts thereof.

21. 21. The composition of any one of claims 1 to 20, wherein the compound is coated with an emetic to reduce the abuse potential of the compound.

22. 22. The composition of any one of claims 1 to 21, wherein the composition is administered orally, bucally, sublingually, rectally, intravaginally, nasally, by aerosol, transdermally, transmucosally, parenterally (e.g., intravenous, intradermal, subcutaneous, and intramuscular injection), epidurally, intrathecally, intraauricularly, intraocularly, or topically, including skin or eye creams, lotions, gels, and ointments, and eye drops, including implanted depot formulations.

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