Novel compositions and pharmaceutical compositions

Abstract

To provide novel compositions and pharmaceutical compositions.SOLUTION: Pharmaceutical formulations of novel indole compounds and psilocybin analogs are manufactured, provided in novel oral, transdermal and nasal pharmaceutical compositions for use to treat neurological, mood or abuse diseases and disorders. The present invention relates to: novel indole compounds, the administration of psilocybin and psilocybin chemical analogues, and novel indole chemical compounds; and pharmaceutical compositions, methods of preparing the pharmaceutical compositions, and methods of treating neurological diseases or disorders using the analogues and novel compounds.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 021,866, filed May 8, 2020; U.S. Provisional Patent Application No. 63 / 106,516, filed October 28, 2020; and U.S. Provisional Patent Application No. 63 / 134,805, filed January 7, 2021.

[0002] Field of the Disclosure The present invention relates to novel indole compounds, the administration of psilocybin, psilocybin chemical analogs, and novel indole chemical compounds; and to pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treating neurological diseases or disorders using the above - mentioned analogs and novel compounds.

Background Art

[0003] Background of the Invention Psychoactive drugs are compounds that affect behavior, mood, thinking, or perception. Psychoactive drugs include antipsychotics, anxiolytics, stimulants, reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, and mood stabilizers. Some of these compounds have historically been used for off - label psychoactive activities and are currently the subject of active clinical efficacy investigations. In addition to potential therapeutic efficacy, these drugs must be investigated for all relevant pharmaceutical properties, including minimum and maximum dosing thresholds and the most effective delivery systems.

[0004] Indole compounds represent a diverse class of compounds with broad biomedical potential across many targets, including cancer, cardiovascular, gastrointestinal, and a wide range of neurological disorders. In in vivo biosynthesis, the amino acid tryptophan precursor of serotonin has been an optimal scaffold for many drugs containing the heterocyclic indole skeleton. Serotonin (5-HT) supports many important bodily functions, including mood, sleep, appetite, gut motility, and sexual health. The serotonergic system consists of a class of G-protein-coupled receptors, 5-HT1 - 5-HT7 and their subtypes (1A, 2A, 2B, etc.), which modulate the range of these biological pathways.

[0005] Most serotonergic targeted therapeutics are antidepressants, either as selective reuptake inhibitors (collectively: SSRIs), direct 5-HT regulators (atypical), or in combination with norepinephrine inhibitors (SNRIs). Although not fully understood, the general mechanism of action of approved therapeutics relies on increasing the concentrations of the monoamines, 5-HT and norepinephrine, in postsynaptic receptors to restore synaptic balance. However, these medications generally lack efficacy (only 20 - 30% more effective than placebo), have significant side effects, and onset is delayed by weeks to months.

[0006] The sigma-1 receptor (σ receptor) is an intracellular receptor expressed in specific regions of the brain. Modulation and agonism of sigma-1 (σ1) have been shown to have positive effects on motility, mood disorders, increased brain-derived neurotrophic factor (BDNF), neuron growth, and neurogenesis. Various classes of psychotropic drugs, including antipsychotics, antidepressants, selective serotonin reuptake inhibitors (SSRI), and motor neuron drugs, bind to the (σ1) receptor. Binding of SSRI to the σ1 receptor may mediate the serotonin-independent actions of this class of drugs. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous σ1 receptor modulator.

[0007] Psilocybin is an indole alkaloid produced by over 200 species of mushrooms and a naturally occurring psychoactive prodrug. Psilocybin is a prodrug that is dephosphorylated in vivo by oral administration to produce the active compound, psilocin. Both psilocybin and psilocin are indole compounds and are known to be potent 5-HT agonists and can cross the blood-brain barrier. The therapeutic implications of psilocybin have been widely demonstrated by active clinical research targeting depression, anxiety, migraine, addiction, dementia, Alzheimer's disease, eating disorders, obsessive-compulsive disorder, and palliative care.

[0008] Magic mushrooms is a general term for a group of over 200 naturally occurring mushrooms that contain psilocybin and active psilocybin chemical analogs and combinations thereof. Similarly, other naturally occurring psychedelic indole compounds include N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT), lysergamide (e.g., LSD), and ibogaine. The fruiting bodies as well as extracts containing these natural products have been orally ingested for their psychoactive effects. Accurate dose-response activity has been difficult to quantify due to the variability of individual responses, the difficulty of measuring the potency of natural organisms and extracts, and the different inherent potencies and ratios of different analogs and combinations thereof. This is exacerbated only by serotonin receptor activity as well as the interaction of the sigma-1 (σ1) receptor, particularly for compounds such as DMT. Specifically, for neurodegenerative diseases and cognitive function, agonists of the σ1 receptor (e.g., DMT) have been shown to enhance brain plasticity, which is important in memory and learning.

[0009] ​Psilocybin and its known analogs have been synthesized and bioengineered. In the mid-20th century, Sandoz Pharmaceuticals briefly sold an oral formulation of psilocybin for use as an adjunctive therapy in psychotherapy. The product was quickly removed from the market because individual responses to the dosage form were unpredictable. As of 2020, the US Drug Enforcement Administration classifies psilocybin as a Schedule 1 drug, which has a high potential for abuse, no approved medical uses, and no recognized safety for use under medical supervision.

[0010] The administration and evaluation of the pharmaceutical efficacy of these compounds have proven difficult. One reason is that the plasma concentration-time curve is highly variable. Additionally, psilocybin and especially DMT undergo first-pass metabolism in oral dosage forms, thereby reducing the availability of the pharmaceutical active ingredient before it enters the systemic circulation. There are also wide individual differences in the renal excretion of the compounds. Furthermore, pH and monoamine oxidase (MAO) enzymatic cleavage of the pharmaceutical active ingredient psilocin from psilocybin after oral delivery can also be determinants of pharmacodynamics. As a result, research on optimal dosages for treating various neurological disorders has not been rigorously pursued.

[0011] The 2016 Johns Hopkins study reported that relatively high doses, such as a dosing regimen of 0.2 mg / kg correlated with a plasma concentration of 4 - 8 ng / mL, are required to induce psychedelic effects. The in vivo half-life of psilocin is approximately 50 minutes, resulting in a psychedelic experience that lasts 4 - 6 hours, during which trained experts monitor subjects in a clinical setting. Psychotherapy is conducted before and after the psychedelic dose to prepare the patient and integrate the experiential results into personal responses to improve depressive thoughts and behaviors, and the drug acts only as a holistic tool. However, inpatient treatment is, of course, costly for the patient and time-consuming for healthcare providers due to the increased risk of adverse events while the patient is under the influence of the psychedelic drug.

[0012] Furthermore, positive psychological effects were seen with increasing doses, but as the doses increased, so did the negative side effects of anxiety, negative imagery, nausea, and headaches. Thus, professional monitoring of patients is necessary before, during, and after psychedelic sessions. Recently, microdosing has been used to administer psychedelic substances in very small, subperceptible amounts. Psychedelic substances that have been microdosed include LSD (lysergic acid diethylamide), cannabis, and psilocybin analogs. Reports of microdosing substances such as DMT and 5-MeO-DMT are scarce, as their lack of bioavailability and short half-life make their administration difficult. Microdosing has been reported to have beneficial therapeutic effects that improve mood, intellectual focus, energy levels, and creativity without disabling hallucinogenic effects.

[0013] Microdosing of psychedelic substances greatly reduces the psychoactive effects, and indirectly (anecdotally), the dose is usually 1 / 10th the psychedelic dose. th ) Depression and Many clinical studies of psychedelics to alleviate depression and PTSD exclude participants with a history of cardiac disease, psychiatric illness, and schizophrenia, as the strong psychoactive effects may exacerbate these conditions, but microdosing can alleviate these issues. Psychedelic-free treatments eliminate the need for administration of drugs in clinical settings, allowing for more traditional, flexible, and affordable drug regimens. Reports of microdosing have noted improved cognitive benefits, such as productivity, creativity, and abstract thinking; the combined evidence suggests that psychedelics reduce neuroinflammation and increase neuroplasticity and neuronal connectivity may lead to effective treatments for dementia, Alzheimer's disease, and other neurocognitive disorders.

[0014] The transdermal and nasal administration of pharmaceutical active ingredients has many advantages when used for psychostimulants. In particular, thyroxine is a product of the conversion of psilocin, a prodrug that is converted to thyroxine in the digestive tract. By avoiding the gastrointestinal tract via transdermal application of thyroxine, problems due to absorption and food interactions can be avoided. Since the therapeutic effect of orally administered DMT can only be achieved by co-administration of MAOI, the transdermal system provides a new delivery method with reduced metabolism and improved pharmacokinetic / pharmacodynamic (PK / PD) properties. Other advantages of transdermal administration include avoiding first-pass metabolism; providing treatment for multiple days with a single application, thereby improving patient compliance; and extending the activity of drugs with short half-lives due to the reservoir of the drug present in the delivery system and its controlled release characteristics.

[0015] Systemic delivery of pharmaceutical components by administration to the nasal mucosa can be advantageous. Nasal delivery enables avoidance of intestinal metabolism and first-pass metabolism. Furthermore, nasal delivery of systemic drugs can bypass the blood-brain barrier and enter the brain via the olfactory and trigeminal pathways, which can be advantageous for pharmaceutical administration of central nervous system diseases. A further advantage of nasal administration is rapid systemic absorption via the nasal mucosa. Combining this with a compound with a short half-life such as DMT can have significant clinical advantages over longer-acting psychedelics.

[0016] Oral delivery of drugs is often preferred over various other drug administration routes due to ease of ingestion, pain avoidance, good patient compliance, and dispensing history. However, many problems such as low solubility of drugs in an aqueous environment, taste, drug stability with pharmaceutical excipients, various dissolution rates, unknown gastrointestinal absorption problems, and food effects are still associated with oral delivery. Oral pharmaceutical formulations are recognized as a scientific endeavor that requires specific knowledge and innovative design in the general field.

[0017] Recent studies on psilocybin and its psilocybin analogs and combinations thereof have been reported to be effective in models of substance use disorders and small-scale clinical trials including post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression and anxiety, opioid intoxication, alcohol intoxication, nicotine intoxication, cannabinoid intoxication, headache, central nervous system inflammation, dementia, and disorders of cognition and memory. These promising experimental reports using psilocybin and its analogs have demonstrated the urgent need to determine the most advantageous dosage and dosing period; improved pharmacokinetic (PK) profile, pharmacodynamic (PD) profile, or safety profile; evaluation of the benefits of long-term or maintenance treatment; development of treatment regimens that maximize the biological effectiveness for treating the disease; and formulations that enable the use of these compounds in other potential advantageous benefits. Furthermore, there is a need for the development of novel, safe and effective exogenous serotoninergic and / or sigma-1 modulators for treating neurological, mood and substance use disorders or diseases. Summary of the Invention Means for Solving the Problems

[0018] Overview Provided herein are novel indole compounds having biological effectiveness and increased clinical safety.

[0019] These compounds include the compound of structure (1) or a pharmaceutically acceptable salt or solvate thereof: Structure (1)

Chemical formula

[0020] A further aspect of the present invention is a compound according to the above structure (1) selected from the group consisting of: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] and any salt form thereof.

[0021] In another aspect of the present invention, a compound of structure (2) or a pharmaceutically acceptable salt or solvate thereof: Structure (2) [Chemical formula] In the formula, R1 is selected from the group consisting of H, F, Cl, Br, I, or CF3; R2 is or CH3; R3 and R4 are each independently, optionally, selected from the group consisting of H, CH3, C2H5, (H3C)2CH, or H2C=CH-CH2; R5 is selected from the group consisting of OCH3, OCOCH3, O-phosphate, O-polyethylene glycol (PEG), O-(CH2)2(COOH)2 (succinate), O-(CH2)2(COOH) (hemisuccinate), and CH2SO2NHCH3 (sulfonamide); when R1 is H, R5 is CH2SO2NHCH3.

[0022] Specific compounds of structure (2) are 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine. Other specific compounds of structure (2) that are of particular interest are 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, and 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide.

[0023] Another aspect of the present invention is a compound of structure (3) or a pharmaceutically acceptable salt or solvate thereof: Structure (3) [Chemical formula] In the formula, R1 is selected from the group consisting of F, Cl, Br, I or CF3; R2 is CH3; R3 and R4 are each independently, optionally, selected from the group consisting of H, CH3, C2H5, (H3C)2CH, or H2C=CH-CH2, and is a compound or a pharmaceutically acceptable salt or solvate thereof.

[0024] Specific compounds of structure (3) are 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinyl ethenamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine.

[0025] In this specification, pharmaceutical compositions are provided that are designed to release the pharmaceutical active ingredients described herein into the bloodstream through transdermal application of the pharmaceutical active ingredients to the skin and nasal cavity. These pharmaceutical compositions are transdermal or transnasal pharmaceutical formulations. The pharmaceutical active ingredients can be applied by means of a sprayable liquid, gel, cream, lotion, ointment, transdermal patch, etc.

[0026] In one embodiment, the transdermal pharmaceutical composition and the transnasal composition of the pharmaceutical active ingredient can be a compound as described by structures (1), (2), (3), and compounds listed in Table (1) and any ionic or salt forms thereof.

[0027] In certain embodiments, psilocybin analogs and combinations thereof include any compound that is structurally related to psilocybin and functionally mimics and / or antagonizes the action of serotonin. In another embodiment, the pharmaceutical active ingredient includes psilocybin and active analogs and combinations thereof. The active analogs of psilocybin and combinations thereof include, but are not limited to, the compounds listed in Table (2) of psilocybin analogs.

[0028]

Table 2

[0029] The present specification provides for the manufacture of transdermal or transnasal pharmaceuticals using as pharmaceutical active ingredients novel compounds described by structures (1), (2), and (3), novel compounds listed in Table (1), and psilocybin analogs of Table (2), and salts or solvates thereof for treating neurological, mood, and abuse disorders or diseases.

[0030] The transdermal and transnasal pharmaceutical compositions of the present invention provide compositions for use in medicaments for treating, managing, or preventing diseases.

[0031] In another embodiment, the pharmaceutical composition is designed for oral delivery to the human systemic circulation with rapid onset and duration.

[0032] In another embodiment, the pharmaceutical composition is designed to provide sustained release to the human systemic circulation via oral delivery, preferably in a once-daily dose.

[0033] The oral pharmaceutical compositions described herein can be designed for modified timed release of the pharmaceutical active ingredient into the human systemic circulation over an extended period. The composition may consist of a solid, semi-solid, liquid, or flexible delivery system and can be administered sublingually, buccally, or orally. The pharmaceutical active ingredient can be provided in tablets, capsules, softgels, strips, sublingual strips, cachets, solutions, suspensions.

[0034] In one embodiment, the oral pharmaceutical composition contains the pharmaceutical active ingredient of the novel compounds described by structures (1), (2), (3), the novel compounds of Table (1), and the psilocybin analogs of Table (2), or salts or solvates thereof. Combinations of psilocybin analogs and / or novel indole compounds as the pharmaceutical active ingredient of pharmaceutical formulations are also part of the present invention.

[0035] The present invention provides the described compositions for use in the treatment, management, or prevention of neurological disorders, mood disorders, or substance use disorders or diseases, which may be depression, central nervous system inflammation, addiction, headache, or dementia, or disorders of cognition and memory.

[0036] The present invention provides a combination of the compounds and analogs described herein for topical, nasal or oral application in combination with a pharmaceutically active ingredient approved by a regulatory authority for the treatment, management or prevention of neurological, mood and abuse disorders or diseases. The approved pharmaceutically active ingredient can be delivered to a patient in need thereof by any delivery system approved by a regulatory authority. In one aspect of the invention, the approved pharmaceutically active ingredient for use in combination with a novel indole or psilocybin analog is an MAOI. In another aspect of the invention, the approved pharmaceutically active ingredient is a 5-HT antagonist.

[0037] Also provided herein are novel synthetic routes for providing novel indole compounds of structures (1), (2), and (3), as well as the novel compounds of Table (1) and psilocybin analogs of Table (2). The novel syntheses of the compounds described are as described in the specific examples and as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0038]

Figure 1

[0039]

Figure 2

[0040] Detailed Description Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0041] As used in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context clearly dictates otherwise.

[0042] The terms "about" or "approximately" mean an acceptable error of a particular value as determined by one of ordinary skill in the art and depend in part on how the value is measured or determined. In certain embodiments, the terms "about" or "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms "about" or "approximately" mean 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

[0043] As used herein, unless otherwise specified, the terms "treat", "treating", and "treatment" refer to the eradication or amelioration of a disease or disorder, or one or more symptoms associated with a disease or disorder. In certain embodiments, the term refers to minimizing the spread or worsening of a disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject having such a disease or disorder. In some embodiments, the term refers to the administration of a compound or dosage form provided herein, with or without one or more additional active agents, after the onset of symptoms of a particular disease.

[0044] As used herein, unless otherwise specified, the term "substance use disorder" is a disorder or disease that affects a person's brain and behavior and results in the inability to control the use of legal or illegal drugs or medications. Prescription drugs, over-the-counter drugs, and unapproved drugs can all be drugs of abuse. Drugs and medications can also include substances such as amphetamines, opioids, cocaine, barbiturates, alcohol, marijuana, and nicotine.

[0045] As used herein, unless otherwise specified, the term "mood disorder" refers to a group of conditions characterized by underlying disturbances in a person's mood. Mood disorders can be in the group of mania (elevated mood disorder) or hypomania (depressive disorder). This classification is described in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Classification of Diseases (ICD).

[0046] As used herein, unless otherwise specified, the term "neuropathy" refers to diseases of the central and peripheral nervous systems, such as the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscles. These disorders include epilepsy, Alzheimer's disease and other dementias, stroke, migraine, cluster headache and other headache disorders including cerebrovascular diseases, multiple sclerosis, Parkinson's disease, neurological infections, brain tumors, traumatic disorders of the nervous system due to head injury, and traumatic disorders due to trauma or terrifying experiences (post-traumatic stress disorder, such as PTSD), as well as neuropathies as a result of nutritional deficiencies and substance abuse. The substances abused can be any number of addictive substances, particularly alcohol and drugs and combinations thereof. Many bacterial infections (e.g., Mycobacterial tuberculosis, Neisseria meningitides), viral infections (e.g., human immunodeficiency virus (HIV), Lyme disease, enterovirus, West Nile virus, Zika), fungal infections (e.g., Cryptococcus, Aspergillus), and parasitic infections (e.g., malaria, Chagas) can affect the nervous system. Neurological symptoms can occur due to the infection itself or due to the immune response.

[0047] As used herein, unless otherwise specified, the terms "prevent", "preventing", and "prevention" refer to the prevention of the onset, recurrence, or spread of a disease or disorder or one or more symptoms thereof. In certain embodiments, the term refers to treatment or administration with a compound dosage form provided herein, with or without one or more additional active agents, to a subject at risk of a disease or disorder provided herein, particularly prior to the onset of symptoms. These terms encompass the inhibition or alleviation of symptoms of a particular disease. In certain embodiments, subjects having a family history of a disease in particular are candidates for a prevention regimen. Additionally, subjects having a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term "prevention" may be used interchangeably with the term "preventive treatment".

[0048] As used herein, unless otherwise specified, the terms "manage", "managing", and "management" refer to preventing or delaying the progression, spread, or worsening of a disease or disorder or one or more symptoms thereof. In many cases, the beneficial effects that a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease in an attempt to prevent or minimize recurrence of the disease.

[0049] As used herein, improvement of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any alleviation, whether permanent or temporary, persistent or transient, that may result from or be related to the administration of the composition.

[0050] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with one or more other agents, provides a prophylactic benefit in the prevention of a disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic effectiveness of another prophylactic agent.

[0051] As used herein, unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. The "therapeutically effective amount" and "effective amount" of a compound mean an amount of a therapeutic agent that, alone or in combination with one or more other agents, provides a therapeutic benefit in the treatment or management of a disease or disorder. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves the overall treatment, alleviates or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effectiveness of another therapeutic agent.

[0052] As used herein, unless otherwise specified, a "pharmaceutically active ingredient (API)" is any substance or mixture of substances that is intended to be used in the manufacture of a drug (pharmaceutical) product and that becomes an active ingredient of the drug product when used in the manufacture of the drug. Such substances are intended to affect the diagnosis, cure, mitigation, treatment, or prevention of a disease or to affect the structure or function of the body.

[0053] As used herein, unless otherwise specified, the term "drug product" generally refers to the final dosage form, such as an oral, nasal, or transdermal formulation, that contains a pharmaceutically active ingredient but is not necessarily associated with inactive ingredients.

[0054] As used herein, the terms "composition", "formulation", and "dosage form" are intended to encompass compositions containing specific ingredient(s) (if shown, in the specified amounts), as well as any product directly or indirectly resulting from the combination of specific amounts of specific ingredient(s). "Pharmaceutical" or "pharmaceutically acceptable" means that any diluent(s), excipient(s), absorption enhancer(s), or carrier(s) in the composition, formulation, or dosage form is compatible with the other ingredient(s) and not harmful to its recipient. Unless otherwise indicated, the terms "composition", "formulation", and "dosage form" are used interchangeably herein.

[0055] As used herein, the term "transdermal" relates to a pharmaceutical in a form that is absorbed through the skin into the bloodstream or to the delivery thereof.

[0056] As used herein, the term "nasal" relates to a pharmaceutical in a form for absorption through the nasal mucosa or to the delivery thereof. Nasal delivery can be affected by a wide range of dosage forms including, but not limited to, solutions, gels, suspensions, emulsions, liposomal formulations, and particulate formulations. for absorption through the nasal mucosa or to the delivery thereof. Nasal delivery can be affected by a wide range of dosage forms including, but not limited to, solutions, gels, suspensions, emulsions, liposomal formulations, and particulate formulations.

[0057] As used herein, "oral" relates to a pharmaceutical in a form for absorption through the oral mucosa, sublingual membrane, buccal membrane, esophageal membrane, gastric membrane, or intestinal membrane. The term "capsule" refers to an oral composition in which the API and inactive ingredients are contained as a solid, liquid, or semi-solid within an outer shell composed of gelatin, polymerized cellulose, or other suitable material. Capsules are intended to be swallowed, and the composition dissolves and releases the API for systemic absorption through the esophageal, gastric, or intestinal inner layers.

[0058] The terms "tablet" and "cachet" include oral compositions that are spherical, circular, oval, triangular, diamond, small spherical, or oblong in shape and contain API, inactive ingredients, and, optionally, a saliva stimulant, which are formed by direct compression of a powder formulation. When placed in the oral cavity, the composition dissolves and releases the API for systemic absorption via the buccal, sublingual, esophageal, gastric, or intestinal inner layers.

[0059] The term "strip" or "oral strip" includes oral compositions that are square, rectangular, triangular, circular, annular, or oblong in shape and contain API, inactive ingredients, and, optionally, a saliva stimulant that form a flexible matrix. When generally placed under the tongue and entering the oral cavity, the composition dissolves and releases the API for systemic absorption via the buccal, sublingual, esophageal, gastric, or intestinal inner layers.

[0060] As used herein, "immediate release" is defined as a formulation of a pharmaceutical active ingredient(s) that is taken orally, nasally, or transdermally and results in rapid absorption of the drug into the blood after administration. Immediate release can be measured in vitro using the FDA industry guidelines regarding dissolution and / or permeability testing, or in vivo using plasma levels.

[0061] As used herein, "modified release" or "extended release" is defined as a formulation of a pharmaceutical active ingredient(s) that is taken orally, nasally, or transdermally and releases the pharmaceutical active ingredient(s) over a period of hours or days to maintain a relatively constant plasma concentration of the drug. Such modifications can have several purposes, such as maintaining therapeutic activity over a long period, reducing toxic effects, protecting the active substance from degradation by low pH, targeting the active substance to a predetermined segment of the gastrointestinal tract for local treatment, or targeting the release of the active substance at a specified time point. Modified release is measured according to the appropriate FDA industry guidelines for modified release formulations.

[0062] As used herein, the term "subject" includes, but is not limited to, animals such as mammals including primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0063] The terms "co-administer", "in combination with", and "in combination" include administering two or more therapeutic agents simultaneously, together or sequentially within no particular time limit. In one embodiment, the agents are present intracellularly or in the body of the subject at the same time, or exert their biological or therapeutic effects at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, the first agent can be administered before (e.g., 5 minutes before, 15 minutes before, 30 minutes before, 45 minutes before, 1 hour before, 2 hours before, 4 hours before, 6 hours before, 12 hours before, 24 hours before, 48 hours before, 72 hours before, 96 hours before, 1 week before, 2 weeks before, 3 weeks before, or 4 weeks before), simultaneously with, or after (e.g., 5 minutes after, 15 minutes after, 30 minutes after, 45 minutes after, 1 hour after, 2 hours after, 4 hours after, 6 hours after, 12 hours after, 24 hours after, 48 hours after, 72 hours after, 96 hours after, 1 week after, 2 weeks after, 3 weeks after, 4 weeks after, 5 weeks after, 6 weeks after, 8 weeks after, or 12 weeks after) the administration of the second therapeutic agent.

[0064] As used herein, the term "psilocybin analog" is defined to include any compound that is structurally related to psilocybin and that functionally mimics and / or antagonizes the action of serotonin. Certain embodiments herein provide salts, co-crystals, solvates, isomers, hydrates, ions, zwitterions, complexes, prodrugs, precursors, metabolites, and / or other derivatives of psilocybin. Certain embodiments herein provide mixtures of two or more of the psilocybin analogs provided herein. As described herein, the psilocybin analogs are selected from the group consisting of the compounds listed in Table (2) and salts and solvates thereof. Certain embodiments herein provide mixtures of two or more of the psilocybin analogs provided herein.

[0065] The psilocybin analogs described herein can be synthesized using any method known to those of skill in the art. It is known that certain compounds can be provided by applying biological processes to manufactured articles, and the compounds are bioengineered.

[0066] The psilocybin analogs described herein can be provided by alcohol or acid-base extraction of the compound from natural sources containing the psychoactive compound. The extraction methods are well known to those of skill in the art.

[0067] In certain embodiments, the formulations of the invention can use psilocybin and psilocybin analogs and combinations thereof that can be obtained synthetically or by bioengineering; or extracted from naturally occurring mushrooms. As described herein, some of the manufacturing processes can be novel and others can use techniques well described in the art.

[0068] (a) A pharmaceutical dosage form, pharmaceutical preparation and composition comprising a pharmaceutically active ingredient which is a novel indole of structure (1), structure (2), structure (3) or (b), or a psilocybin analog, are provided herein. The dosage form, pharmaceutical preparation and composition release the pharmaceutically active ingredient into the bloodstream upon transdermal, nasal or oral administration. In certain embodiments, the psilocybin analog is serotonin. In certain embodiments, the psilocybin analog is 4-hydroxytryptophan. In certain embodiments, the psilocybin analog is 4-hydroxytryptofall. In certain embodiments, the psilocybin analog is 4-hydroxy-indole-3-acetaldehyde. In certain embodiments, the psilocybin analog is 4-hydroxy-indole-3-acetic acid. In certain embodiments, the psilocybin analog is norserotonin. In certain embodiments, the psilocybin analog is aeruginascin. In certain embodiments, the psilocybin analog is baeocystin. In certain embodiments, the psilocybin analog is norbaeocystin. In certain embodiments, the psilocybin analog is 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET). In certain embodiments, the psilocybin analog is 4-hydroxy-diethyltryptamine (4-OH-DET). In certain embodiments, the psilocybin analog is 4-hydroxy-N,N-dipropyltryptamine (4-OH-DPT). In certain embodiments, the psilocybin analog is 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT). In certain embodiments, the psilocybin analog is N,N-dimethyltryptamine (DMT). In certain embodiments, the psilocybin analog is indole-3-acetic acid. In certain embodiments, the psilocybin analog is N,N-dimethyltryptamine-N-oxide (DMT-NO). In certain embodiments, the psilocybin analog is lysergic acid diethylamide (LSD). In certain embodiments, the psilocybin analog is O-acetylserotonin (4-AcO-DMT). In certain embodiments, the psilocybin analog is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).In certain embodiments, the psilocybin analog is bufotenin (5-OH-DMT). In certain embodiments, the psilocybin analog is ibogaine.

[0069] In certain embodiments, an exemplary compound has a structure as shown in structure (1):

Chemical formula

[0070] In certain embodiments, the psilocybin analogs and combinations thereof provided herein include any compound that is structurally related to psilocybin and functionally mimics and / or antagonizes the action of serotonin.

[0071] In certain embodiments, exemplary psilocybin analogs and combinations thereof are the compounds provided in Table (2).

[0072] In certain embodiments, a pharmaceutical formulation and composition comprising a pharmaceutically active ingredient that is any one of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof can be used in combination with other active agents.

[0073] In certain embodiments, the pharmaceutical formulation comprises a MAOI. MAOIs are drugs of the enzyme family that catalyze the oxidation of monoamines, and certain psilocybin analogs and combinations thereof are known to be enzymatically degraded by MAOIs. MAOIs include, but are not limited to, harmala alkaloids, harmine, harman, harmaline, hydrazine, iproniazid, isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, bifemelane, moclobemide, pirindole, tropoxone, rasagiline, selegiline, safinamide, and other reversible inhibitors of monoamine oxidase A (RIMA).

[0074] Certain embodiments herein include pharmaceutical formulations and compositions comprising a pharmaceutically active ingredient that is either (a) an indole of structure (1) or (b) a psilocybin analog and combinations thereof, and optionally, a monoamine oxidase inhibitor (also known as an MAO inhibitor or MAOI), such formulations and compositions being prepared for transdermal administration.

[0075] Certain embodiments of the present specification include pharmaceutical active ingredients that are either (a) indoles of structure (1), structure (2), or structure (3), or (b) psilocybin analogs and combinations thereof, and, optionally, monoamine oxidase inhibitors (also known as MAO inhibitors or MAOIs), and such pharmaceutical formulations and compositions are prepared for oral administration. In certain embodiments, 5-HT antagonists can be used as allosteric regulators or to improve the therapeutic benefits of psilocybin analogs. Certain 5-HT antagonists are known to be able to reduce the psychoactivity induced by psilocybin analogs, which can be beneficial for treatment or for reducing side effects. Certain 5-HT antagonists include, but are not limited to, ketanserin, clozapine, olanzapine, quetiapine, risperidone, asenapine, cyproheptadine, trazodone, mirtazapine, nefazodone, niaprazine, pizotifen, methysergide, or 2-bromo-LSD (BOL-148).

[0076] In certain embodiments, pharmaceutical formulations and compositions containing pharmaceutical active ingredients that are either (a) indoles of structure (1), structure (2), or structure (3), or (b) psilocybin analogs, and combinations thereof are used to treat neurological, mood, and substance use disorders. These formulations and compositions can be prepared for transdermal administration.

[0077] In certain embodiments, pharmaceutical formulations and compositions containing pharmaceutical active ingredients that are either (a) indoles of compounds belonging to the structures of structure (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof are used to treat neurological, mood, and substance use disorders. These formulations and compositions can be prepared for nasal administration.

[0078] In certain embodiments, pharmaceutical formulations and compositions comprising a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof are used to treat neurological, mood and substance use disorders. These formulations and compositions can be prepared for oral administration. Certain embodiments relate to the use of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing pharmaceutical formulations and compositions for treating the specific medical indications provided herein. The pharmaceutical formulations and compositions are intended for transdermal delivery of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, in a subject in need thereof. Transdermal formulations can be manufactured in the form of sprayable liquids, gels, creams, lotions, ointments, and transdermal patches and are applied topically to the desired area.

[0079] Certain embodiments relate to the use of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing pharmaceutical formulations and compositions for treating the specific medical indications provided herein. The pharmaceutical formulations and compositions are intended for oral delivery of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, in a subject in need thereof. Oral formulations can be manufactured in the form of tablets, capsules, softgels, strips, oral patches and are intended for oral delivery to a patient in need of treatment.

[0080] In certain embodiments, the pharmaceutical formulation can be formulated for immediate release of the API. In certain embodiments, the immediate release formulation is a transdermal composition or a nasal composition.

[0081] In certain embodiments, the pharmaceutical formulation can be formulated for immediate release of the API. In certain embodiments, the immediate release formulation is an oral composition.

[0082] In certain embodiments, the pharmaceutical formulation can be formulated for modified release of the API. In certain embodiments, the immediate release formulation is a transdermal composition.

[0083] In certain embodiments, the pharmaceutical formulation can be formulated for modified release of the API. In certain embodiments, the immediate release formulation is an oral composition.

[0084] In certain embodiments, the transdermal composition includes a transdermal patch or a nasal formulation that delivers the pharmaceutically active ingredient into the bloodstream across the skin or mucosa. In certain embodiments, the embodiments herein include the use of a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing a pharmaceutical composition for treating neurological, mood, and substance use disorders, and the composition is prepared for transdermal or nasal administration.

[0085] In certain embodiments, formulations of the pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, result in immediate release of the pharmaceutically active ingredient into the plasma upon transdermal, nasal, or oral administration. In certain embodiments, formulations comprising a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient and, optionally, one or more excipients.

[0086] In certain embodiments of the transdermal, nasal, or oral formulations of the present invention, psilocybin and psilocybin analogs and combinations thereof that can be obtained synthetically or by bioengineering; or that can be extracted from naturally occurring mushrooms, which are well described in the art, are used.

[0087] In certain embodiments of the transdermal, nasal, or oral formulations of the present invention, psilocybin and psilocybin analogs and combinations thereof that can be obtained synthetically or by bioengineering; or that can be extracted from naturally occurring mushrooms, are used by using the novel chemical synthesis techniques or extraction techniques described herein.

[0088] In certain embodiments, the transdermal pharmaceutical administration composition is in the form of a sprayable liquid, gel, cream, lotion, ointment, and transdermal patch, and the pharmaceutically active ingredient is infused together with inactive ingredients that enhance the delivery characteristics of the composition and stabilize the pharmaceutically active ingredient. In one embodiment, the penetration enhancer can be an inactive ingredient. Examples of penetration enhancers can include, but are not limited to, castor oil, coconut oil, medium-chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, shea butter, or other esters, triglycerides, or fatty acids and oils that are functional derivatives thereof.

[0089] In certain embodiments, surfactants may be used in the transdermal delivery system as emulsifiers and stabilizers, and drugs can be encapsulated for good stability and permeability. Examples of surfactants include, but are not limited to, polysorbate (e.g., Tween®, polysorbate 20), sorbitan (Span®), phospholipids (lecithin), lauryl sulfate, betaine, propionate, fatty alcohols and alkanolamides, fatty acid esters, amine oxides, myristate, and azone.

[0090] In certain embodiments, the co-solvent can be used in a transdermal formulation to improve drug solubility and permeability while acting as a wetting agent for a better skin feel. Common co-solvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, Cremophor, siloxane, polyethylene, and water.

[0091] In certain embodiments, a thickening agent can be used in a transdermal formulation to reduce separation and provide a matrix suitable for modified delivery. Common thickening agents include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, gums, resins, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosin, resins, paraffin, and petrolatum.

[0092] In certain embodiments, a tackifier can be used in a transdermal formulation to enhance adhesion for long-term wearability. Common tackifiers include, but are not limited to, gums, resins (natural or modified), carbomers, or other natural or synthetic polymers.

[0093] In certain embodiments, a preservative can be used in a transdermal formulation to improve formulation stability and delay microbial growth. Common preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenol, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols. Finally, the formulation is typically emulsified with a hydrophilic component such as water or Aloe barbadensis juice.

[0094] In certain embodiments, formulations comprising a pharmaceutical active ingredient of (a) an indole of structure (1) or (b) a psilocybin analog and combinations thereof provide controlled release of the pharmaceutical active ingredient upon administration. In certain embodiments, a formulation comprising a pharmaceutical active ingredient comprises a therapeutically or prophylactically effective amount of the pharmaceutical active ingredient(s) and a drug release control component capable of controlled sustained release of the pharmaceutical active ingredient directly into the bloodstream.

[0095] In certain embodiments, the transdermal dosage form is a transdermal delivery device. Any device conventional in the art for transdermally delivering a therapeutic agent to a patient can be used for transdermal delivery of the compositions of the present invention and as a transdermal delivery device. For example, the transdermal delivery device can be a reservoir-type transdermal delivery device, a polymeric matrix-type transdermal delivery device, or a drug-in-adhesive type transdermal delivery device or a multilaminate type transdermal delivery device. The transdermal delivery device is designed such that when in contact with the skin of the patient, the pharmaceutical active ingredient of the present invention is delivered in a therapeutically effective amount.

[0096] In certain embodiments, the transdermal delivery device is a drug-containing adhesive device that includes a pharmaceutically active ingredient directly dispersed in a pressure-sensitive adhesive matrix. The adhesive matrix is preferably supported on the top surface by an impermeable backing film and on the side facing the skin by an impermeable release liner. To administer the pharmaceutically active ingredient, the release liner is removed to expose the adhesive matrix, and the device is brought into contact with the skin. The adhesive matrix adheres the device to the skin and typically functions to control the delivery rate of the pharmaceutically active ingredient. Similar to the polymer matrix design, the drug-containing adhesive design allows the pharmaceutically active ingredient to diffuse from the adhesive matrix, contact the patient's skin, and permeate through the skin. The delivery rate of the pharmaceutically active ingredient is usually determined by the diffusion rate of the pharmaceutically active ingredient(s) from the adhesive matrix. For longer extended delivery, multiple drug-containing adhesive layers can be laminated together between rate-controlling membranes. The delivery rate is such that an effective amount of the pharmaceutically active ingredient is delivered to a patient in need of the pharmaceutically active ingredient.

[0097] In certain embodiments, the reservoir-type transdermal delivery device preferably includes a reservoir (usually liquid or semi-solid) located between an impermeable backing film and a rate-controlling membrane covered with a pressure-sensitive adhesive skin contact layer. The reservoir may be a solution or dispersion and contains the composition of the present invention. The transdermal delivery device is preferably supported by an impermeable backing film, and the adhesive surface is protected by a release liner. To administer the pharmaceutically active ingredient of the present invention, the release liner is peeled off to expose the pressure-sensitive adhesive, and the pressure-sensitive adhesive is brought into contact with the skin. The pharmaceutically active ingredient of the present invention can penetrate through the rate-controlling membrane, permeate through the rate-controlling membrane and the adhesive, contact the skin, and penetrate through the skin. The delivery rate of the active pharmaceutical invention is usually determined by the rate at which the pharmaceutically active ingredient penetrates through the rate-controlling membrane.

[0098] In certain embodiments, the transdermal delivery device is a polymer matrix design. In the polymer matrix design, the silibinin analogs and combinations thereof are dispersed in a polymer matrix that controls the delivery rate of the pharmaceutical active ingredient. Preferably, the reservoir of the polymer matrix is supported on an impermeable backing layer. An adhesive layer is attached to the surface of the polymer matrix. To administer the pharmaceutical active ingredient, the release liner is removed to expose the polymer matrix and the ring of pressure-sensitive adhesive, and the device is brought into contact with the skin. The adhesive holds the device against the skin so that the polymer matrix is in direct contact with the skin. When the polymer matrix contacts the skin, the pharmaceutical active ingredient(s) diffuse from the polymer matrix, contact the patient's skin, and permeate the skin. The delivery rate of the pharmaceutical active ingredient is typically determined by the diffusion rate of the pharmaceutical active ingredient from the polymer matrix.

[0099] The adhesive contains crosslinking monomer units or sites and can be incorporated into an adhesive polymer. For example, crosslinking monomers can be incorporated into a polyacrylate polymer. The crosslinking monomer can provide sites, for example, for crosslinking the polymer matrix after dispersing the silibinin analogs and combinations thereof in the polymer. Known adhesives contain crosslinking monomers for polyacrylate polymers and include, for example, polymethacrylic acid esters of polyols such as butylene diacrylate, butylene dimethacrylate, and trimethylolpropane trimethacrylate, polyisobutylene-type adhesives, and silicones. Other monomers that provide crosslinking sites include allyl acrylate, allyl methacrylate, diallyl maleate, silyl ether, and silane. The monomers are then polymerized using methods known to those skilled in the art to include a crosslinking agent, functional groups, or an adhesive matrix of polyacrylate (acrylic), polysiloxane (silicone), or polyisobutylene (or other rubber) containing vinyl acetate to suspend, stabilize, and release the pharmaceutical active ingredient.

[0100] In one embodiment of the present invention, the transdermal delivery device may optionally include one or more penetration enhancers that increase the rate at which the pharmaceutically active ingredient permeates through the patient's skin. Preferably, the penetration enhancer permeates through the rate-controlling membrane or diffuses from the polymeric matrix or the adhesive matrix to contact the patient's skin and improve the permeation of the pharmaceutically active ingredient as defined herein through the patient's skin. Suitable penetration enhancers for use in the transdermal delivery devices and compositions of the present invention include, for example, C 2-4Alcohols, such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, polysorbate, sorbitan, fatty acids, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoesters content of at least 51% (the monoesters having from 10 to 20 carbon atoms), and mixtures of mono-, di- and tri-glycerides of fatty acids are included. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid. Examples of monoglyceride penetration enhancers include glycerol monooleate, glycerol monolaurate and glycerol monolinoleate. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane and increase API permeability. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene and humulene. In certain embodiments, the transdermal patches described herein are used in co-administration with a permeation enhancer. In certain embodiments, permeation enhancers can include, but are not limited to, castor oil, coconut oil, medium chain triglycerides (MCT), jojoba oil, sunflower oil, argan oil, almond oil, olive oil, mineral oil, petrolatum, cocoa butter, and shea butter. Other permeation enhancers for use in transdermal patches include, for example, C 2-4Alcohols, such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, polysorbate (Tween®), sorbitan (Span®), fatty acids, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoesters content of at least 51% (the monoesters having from 10 to 20 carbon atoms), and mixtures of mono-, di- and tri-glycerides of fatty acids are included. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid. Examples of monoglyceride penetration enhancers include glycerol monooleate, glycerol monolaurate and glycerol monolinoleate. Terpenes and terpenoids are derived from natural isoprene biosynthesis and can also be utilized to disrupt the skin membrane and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene and humulene.

[0101] In certain embodiments, the delivery rate of the pharmaceutically active ingredient can be delivered with once-daily transdermal patch application. In certain embodiments, the delivery rate of the API can be delivered over a period of 6 to 12 hours. In certain embodiments, the delivery rate of the API can be delivered over a period of 12 to 24 hours. In certain embodiments, the delivery rate of the API can be delivered over a period of 24 to 48 hours. In other embodiments, the transdermal patch can be applied once every 2 days; once every 3 days; once every 4 days; once every 5 days; once every 5 days; or once every 7 days. The delivery rate options for the transdermal patch promote patient compliance while delivering a steady-state systemic safe and effective drug concentration.

[0102] As described herein, certain embodiments provide methods regarding different dosages and / or administration periods; provide alternative pharmacokinetic profiles, pharmacodynamic profiles, and / or safety profiles; enable long-term maintenance therapy; provide tests for new indications for psilocybin analogs; and provide transdermal formulations of the pharmaceutical active ingredients described herein that are useful in other potential advantageous benefits. In certain embodiments, the formulations provided herein (e.g., sprayable liquids, gels, creams, lotions, ointments, or transdermal patches for dermal delivery of a pharmaceutical active ingredient) contain the pharmaceutical active ingredient ((a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) alone or in combination of Table (2)) in a specific pharmaceutically active amount. In certain embodiments, the specific amount of the pharmaceutical active ingredient disclosed herein in the formulation is, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, at least about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or at least 100 mg.In certain embodiments, a specific amount of the silibinin analog in the formulation is, for example, at least about 1 mg, at least about 2 mg, at least about 3 mg, at least about 4 mg, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 26 mg, at least about 27 mg, at least about 28 mg, at least about 29 mg, at least about 30 mg, at least about 31 mg, at least about 32 mg, at least about 33 mg, at least about 34 mg, at least about 35 mg, at least about 36 mg, at least about 37 mg, at least about 38 mg, at least about 39 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg or at least 100 mg.

[0103] In more specific embodiments, a specific amount of the pharmaceutically active ingredient disclosed herein in the formulation is, for example, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg or at least 100 mg.

[0104] In more specific embodiments, the specific amount of the pharmaceutically active ingredient in the formulation is, for example, at least about 5 mg, at least about 6 mg, at least about 7 mg, at least about 8 mg, at least about 9 mg, at least about 10 mg, at least about 11 mg, at least about 12 mg, at least about 13 mg, at least about 14 mg, at least about 15 mg, at least about 16 mg, at least about 17 mg, at least about 18 mg, at least about 19 mg, at least about 20 mg, at least about 21 mg, at least about 22 mg, at least about 23 mg, at least about 24 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg or at least 100 mg.

[0105] In certain embodiments, the pharmaceutically active ingredient in the pharmaceutical formulation is, for example, about 5 mg to 100 mg, or about 5 mg to 25 mg, or about 25 mg to 50 mg, or about 50 mg to 75 mg, or about 75 mg to 100 mg.

[0106] As described herein, certain embodiments provide a transdermal formulation of the pharmaceutically active ingredient described herein with respect to the skin application size for a transdermal delivery device. The application area is an important metric for determining drug flux, varying the dosage, and providing a sufficient area for efficient transdermal delivery. In certain embodiments, the API ((a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) syrosingopine analogs, or (d) compounds of Table (2) (alone or in combination) are included within a drug delivery device (e.g., a sprayable liquid, gel, cream, lotion, ointment, or transdermal patch) and are 1 cm or less, or at least 2 cm 2 , at least 3 cm 2 , at least 4 cm 2 , at least 5 cm 2 , at least 6 cm 2, at least 7 cm 2 , at least 8 cm 2 , at least 9 cm 2 , at least 10 cm 2 , at least 15 cm 2 , at least 20 cm 2 , at least 25 cm 2 , at least 30 cm 2 , at least 35 cm 2 , at least 40 cm 2 , at least 45 cm 2 , at least 50 cm 2 , at least 60 cm 2 , at least 70 cm 2 , at least 80 cm 2 , at least 90 cm 2 , or at least 100 cm 2 , at least 150 cm 2 , at least 200 cm 2 , at least 250 cm 2 , at least 300 cm 2 , at least 350 cm 2 , at least 400 cm 2 , at least 450 cm 2 , at least 500 cm 2 , at least 600 cm 2 , at least 700 cm 2 , at least 800 cm 2 , at least 900 cm 2 , or at least 1000 cm 2 is applied to the skin of a human or mammal in an area of...

[0107] In certain embodiments, the API is included, alone or in combination, within a drug delivery device (e.g., a sprayable liquid, gel, cream, lotion, ointment, or transdermal patch), and is 1 cm or less, or at least 2 cm 2 , at least 3 cm 2 , at least 4 cm 2 , at least 5 cm 2 , at least 6 cm 2 , at least 7 cm 2, at least 8 cm 2 , at least 9 cm 2 , at least 10 cm 2 , at least 15 cm 2 , at least 20 cm 2 , at least 25 cm 2 , at least 30 cm 2 , at least 35 cm 2 , at least 40 cm 2 , at least 45 cm 2 , at least 50 cm 2 , at least 60 cm 2 , at least 70 cm 2 , at least 80 cm 2 , at least 90 cm 2 , or at least 100 cm 2 and is applied to the skin of a human or mammal in an area of

[0108] In one embodiment, the API is, alone or in combination, about 1 cm 2 to 10 cm 2 , about 10 cm 2 to 40 cm 2 , about 40 cm 2 to 100 cm 2 , or more preferably 5 cm 2 to 40 cm 2 and is applied to the skin of a human or mammal in an area of

[0109] In certain embodiments, the pharmaceutically active ingredient is delivered in an oral pharmaceutical formulation composition comprising a capsule or tablet that delivers the API into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0110] In certain embodiments, the oral composition is swallowed and the pharmaceutically active ingredient is further delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0111] In certain embodiments, the oral composition comprises tablets, cachets, or strips that deliver the pharmaceutically active ingredient into the bloodstream through the sublingual, buccal, or other oral mucosa.

[0112] In certain embodiments, the oral composition comprises an oral patch or an oral film that delivers the pharmaceutically active ingredient into the bloodstream sublingually, buccally, or through other oral mucosa.

[0113] In certain embodiments, the oral composition is swallowed and the pharmaceutically active ingredient is further delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0114] In certain embodiments, the oral composition comprises a powder, a solution, or a suspension that delivers the pharmaceutically active ingredient into the bloodstream sublingually, buccally, or through other oral mucosa.

[0115] In certain embodiments, the oral composition is swallowed and the pharmaceutically active ingredient is further delivered into the bloodstream through the membranes of the esophagus, stomach, and / or intestine.

[0116] In certain embodiments, formulations of pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, result in immediate release of the pharmaceutically active ingredient into the plasma upon oral administration. In certain embodiments, formulations comprising pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient and, optionally, one or more excipients.

[0117] In certain embodiments, formulations of pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, result in modified release of the pharmaceutically active ingredient into the plasma upon oral administration. In certain embodiments, formulations comprising pharmaceutically active ingredients of (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, comprise a therapeutically or prophylactically effective amount of the pharmaceutically active ingredient and, optionally, one or more excipients.

[0118] In certain embodiments, the embodiments herein include the use of a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing a pharmaceutical composition for treating neurological, mood and substance use disorders, and the composition is prepared for oral administration.

[0119] In certain embodiments, the embodiments herein include the use of a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof, for preparing a pharmaceutical composition for treating neurological, mood and substance use disorders, and the composition is prepared for oral administration.

[0120] In certain embodiments, the oral composition contains inactive ingredients that enhance drug delivery properties and stabilize the active ingredient.

[0121] In one embodiment, a filler may be included as an inactive ingredient. The filler can act as a matrix that affects the dissolution time or as a binder to improve tablet stability. Fillers can include, but are not limited to, starch, citric acid, tartaric acid, bicarbonate, phosphate, polyvinylpyrrolidone, cellulose (natural and modified), croscarmellose, glycolate, acrylate, acetate, gelatin, gum, alginate, pectin, chitosan, chitin, salts, polysaccharides, mucilage, sugars, sucrose, lactose and dextrose.

[0122] In another embodiment, a lubricant may be included as an inactive ingredient. The lubricant acts to improve powder flowability or reduce friction of manufacturing parts. These can include, but are not limited to, magnesium stearate, talc, stearic acid, and silicon dioxide.

[0123] In yet another embodiment, a flavoring agent may be included as an inactive ingredient. The flavoring agent can mask the taste of the bitter agent or improve the taste of the oral composition. These include, but are not limited to, sugar, dextrose, sucrose, sucralose, stevia, essential oils, citric acid, and natural or artificial flavoring agents. Optionally, a colorant can be included in the powder to improve visual properties or to differentiate the product offering. These colorants can be natural or artificial dyes, pigments, chelates or metals.

[0124] In certain embodiments, the oral composition contains a surfactant which is an emulsifier and stabilizer capable of encapsulating the drug for better stability, taste, permeability and drug release characteristics. Surfactants include, but are not limited to, vegetable oils, triglycerides, esters, polysorbates (Tween®), sorbitans (Span®), phospholipids (e.g., lecithin), lauryl sulfate, betaines, propionates, fatty acids, fatty alcohols, saponins and alkanolamides, amine oxides, cyclodextrins, myristates and azones.

[0125] In certain embodiments, the oral composition contains a co-solvent for improving drug solubility, dissolution and permeability. Co-solvents include, but are not limited to, alcohols such as ethanol, isopropanol, glycerin, propylene glycol, dipropylene glycol, polyethylene glycol, diethylene monoethyl ether, cremophor, siloxane, polyethylene, and water.

[0126] In certain embodiments, the oral composition contains a thickening agent to reduce dissolution and provide a matrix suitable for delivery. Examples of thickening agents include, but are not limited to, acrylates, carbomers, cellulose matrices, silicones, carrageenan, polysaccharides, and high melting point waxes and oils such as beeswax, coconut oil, palm oil, soybean oil, stearic acid, rapeseed, cocoa butter, shea butter, gums, rosins, resins, paraffin, and petrolatum.

[0127] In certain embodiments, the oral composition contains a preservative to improve formulation stability and delay microbial growth. Examples of preservatives include, but are not limited to, parabens, sorbates, benzoates, silica, chlorides, phenol, chlorhexidine, citric acid, triclosan, vitamin E (or tocopherol), chelating agents, metals, salts, and alcohols.

[0128] In certain embodiments, the oral composition contains an enteric coating to modify and extend release within the gastrointestinal tract. Examples of enteric coatings include high melting point waxes, fatty acids, sugars, fibers, and polymers.

[0129] In another embodiment, the oral composition contains excipients that change the physical properties of the drug delivery system such as pH, solubility, dissolution, hydrophobicity, and stability. Many such compounds are known to those skilled in the art.

[0130] In certain embodiments, the oral composition contains a membrane permeation enhancer to increase systemic delivery. Suitable permeation enhancers for use in oral compositions include, for example, C 2-4Alcohols, such as ethanol and isopropanol, polyethylene glycol monolaurate, polyethylene glycol-3-lauramide, dimethyl lauramide, sorbitan (Span®), polysorbate (e.g., Tween®, polysorbate 20), fatty acids, esters of fatty acids having from about 10 to about 20 carbon atoms, monoglycerides, or mixtures of monoglycerides of fatty acids having a total monoester content of at least 51% (the monoesters having from 10 to 20 carbon atoms), and mixtures of mono-, di- and tri-glycerides of fatty acids are included. Suitable fatty acids include, for example, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid and palmitic acid. Examples of monoglyceride penetration enhancers include glycerol monooleate, glycerol monolaurate and glycerol monolinoleate. Terpenes and terpenoids, which are derived from natural isoprene biosynthesis, can also be utilized to disrupt the skin membrane and increase API permeability. Terpenes and terpenoids, which are derived from natural isoprene biosynthesis, can also be utilized to disrupt the skin membrane and increase API permeability. Examples of terpenes include, but are not limited to, menthol, menthone, camphor, nerolidol, limonene, myrcene, anethole, eugenol, 1,8-cineole, terpinolene, pinene and humulene.

[0131] In certain embodiments, the pharmaceutically active ingredient of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least one matrix of the oral composition. In another embodiment, the pharmaceutically active ingredient of ((a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least two matrices of the oral composition. In another embodiment, the pharmaceutically active ingredient of (a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (1), and combinations thereof, is included in at least three matrices of the oral composition. In another embodiment, the pharmaceutically active ingredient of ((a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least four matrices of the oral composition. In yet another embodiment, the pharmaceutically active ingredient of ((a) indoles of compounds belonging to the structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2), and combinations thereof, is included in at least five matrices of the oral composition.

[0132] In certain embodiments, the pharmaceutical active ingredient is a single active ingredient. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in capsule form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table 1, (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in tablet form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in cachet form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in strip form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered via a transdermal patch. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in powder form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in suspension form. In preferred embodiments, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) a compound of Table (2) is orally administered in solution form.

[0133] In another embodiment, the mixture of psilocybin analogs is delivered in the same oral composition as described herein. In a preferred embodiment, (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is administered orally in the oral composition described herein, alone or in combination with other (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2).

[0134] In certain embodiments, the oral composition comprises a pharmaceutically effective amount of at least 1 mg, at least 2 mg, at least 3 mg, at least 4 mg, at least 5 mg, at least 6 mg, at least 7 mg, at least 8 mg, at least 9 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 120 mg, at least 140 mg, at least 160 mg, at least 180 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, and / or at least 500 mg of (a) an indole of a compound belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) Table (2), and combinations thereof.

[0135] In certain embodiments, the systemic drug release of an oral composition containing a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) Table (2), and combinations thereof occurs with a therapeutically active onset of 1 minute or less, 3 minutes or less, 5 minutes or less, 7 minutes or less, 9 minutes or less, 11 minutes or less, 13 minutes or less, 15 minutes or less, 17 minutes or less, 19 minutes or less, 21 minutes or less, 23 minutes or less, 25 minutes or less, 27 minutes or less, 30 minutes or less, 45 minutes or less, 60 minutes or less, 90 minutes or less, 120 minutes or less, 150 minutes or less, and 180 minutes or less.

[0136] In certain embodiments, the duration of the therapeutic or prophylactic effect of an oral composition containing a pharmaceutically active ingredient of (a) an indole of a compound belonging to the structures (1), (2), (3), (b) Table (1), (c) a sirolimus analog, or (d) Table (2), and combinations thereof lasts for at least 5 minutes, at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 120 minutes, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 18 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, and at least 1 week.

[0137] As described herein, certain embodiments provide methods regarding different dosages and / or administration periods; provide alternative pharmacokinetic profiles, pharmacodynamic profiles, and / or safety profiles; enable long-term maintenance therapy; provide testing for new indications for sirolimus analogs; and provide oral compositions of the pharmaceutically active ingredients described herein that are useful in other potential advantageous benefits.

[0138] Methods for preventing, managing, and treating post-treatment Lyme syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression, anxiety, addiction, including neurological, mood, or addiction disorders, substance abuse including but not limited to opioid intoxication, alcohol intoxication, nicotine intoxication, cannabinoid intoxication, headache, central nervous system inflammation, dementia, cognition, and memory by administering psilocybin analogs transdermally, nasally, or orally are provided herein.

[0139] In certain embodiments, the pharmaceutically active ingredient is a single pharmaceutically active ingredient. In preferred embodiments, (a) an indole of a compound belonging to the structures of formulas (1), (2), (3), (b) Table (1), (c) a psilocybin analog, or (d) a compound of Table (2) is delivered by a transdermal patch delivery system. In preferred embodiments, the pharmaceutically active ingredient is transdermally delivered by a transdermal patch delivery system.

[0140] In another embodiment, a mixture of psilocybin analogs is delivered by the same transdermal delivery system. In preferred embodiments, the psilocybin analogs are transdermally delivered alone or in combination with other psilocybin analogs in a transdermal patch delivery system.

[0141] In another embodiment, the pharmaceutically active ingredient is co-administered with one or more therapeutic agents. The co-administered agent can be an MAOI. In another embodiment, a compound from another class of neurologically active agents is co-administered to provide a synergistic therapeutic effect. Other neurologically active agents include compounds classified into the following classes of compounds: antipsychotics, antidepressants, anxiolytics, stimulants, reuptake inhibitors (SSRI or SSNRI), monoamine oxidase inhibitors (MAOI), cognitive enhancers, tricyclic antidepressants, mood stabilizers, NMDA antagonists, and 5-HT antagonists.

[0142] In yet another embodiment, (a) indoles of compounds belonging to the structures of structures (1), (2), (3), (b) Table (1), (c) psilocybin analogs, or (d) Table (2) are co-administered, either alone or as a mixture, with one or more therapeutic agents to reduce substance abuse. For the treatment of opioid addiction, other co-administered compounds can include methadone, buprenorphine, naloxone, naltrexone, and the like. For the treatment of alcohol dependence, other co-administered compounds can include ethyl alcohol, disulfiram, naltrexone, acamprosate, benzodiazepine, and the like. For the treatment of nicotine addiction, other co-administered compounds can include low-dose nicotine, bupropion, varenicline, and the like.

[0143] Methods for preventing, managing, and treating post-treatment Lyme disease syndrome, dementia, Alzheimer's disease, post-traumatic stress disorder, anorexia nervosa, depression, anxiety, neurological, mood or addiction disorders including addictions, opioid addiction, alcohol addiction, nicotine addiction, cannabinoid addiction, headache, central nervous system inflammation, dementia, cognition and memory by transdermally administering a psilocybin analog are provided herein.

Example

[0144] Example 1: Purified N,N-dimethyltryptamine (DMT 1.8% w / w, wet) was dissolved in a combination of ethyl acetate (7.2% w / w, wet) and ethanol (7.2% w / w, wet), incorporated into Duro-Tak 4098 acrylate adhesive (83.8% w / w, wet), and mixed well. The mixture was formulated to a thickness of 150 μm on the silicon-treated surface of a Scotchpak 9709 release liner. The formulation was dried at 75°C and laminated onto a backing of occlusive Scotchpak 9733 polyester, after which the transdermal patch was cut to a size of 10 cm 2 and stored in a heat-sealed aluminum pouch to reduce oxidation.

[0145] Linear drug release (n = 3 transdermal patches) was observed over 72 hours, and more than 80% of DMT was released within 72 hours (Figure 1). The average DMT flux was quantified over 72 hours at 37 ug / cm 2* hr.

[0146] Example 2: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (8.0% w / w, wet), incorporated into Duro-Tak 4098 adhesive (90.0% w / w, wet), and thoroughly mixed. The mixture was formulated to a thickness of 250 μm on a release liner. After drying the formulation and laminating it onto a occlusive backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (6.4% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 72 hours at 43 μg / cm 2* hr.

[0147] Example 3: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (8.1% w / w, wet), incorporated into silicone adhesives Bio PSA 7-4302 (44.9% w / w, wet) and Bio PSA 7-4202 (44.9% w / w, wet), and thoroughly mixed. The mixture was formulated to a thickness of 150 μm on a release liner. After drying the formulation and laminating it onto a occlusive backing, the transdermal patch was cut into 10 cm 2 sized pieces. The final transdermal patch (3.9% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 48 hours at 31 μg / cm 2* hr.

[0148] Example 4: Purified DMT (2.0% w / w, wet) was dissolved in ethanol (4.0% w / w, wet), incorporated into Duro-Tak 6908 polyisobutylene adhesive (94.0% w / w, wet), and mixed thoroughly. The mixture was formulated to a thickness of 150 μm on a release liner. After drying the formulation and laminating it onto a closed backing, the transdermal patch was cut into a size of 10 cm 2 . The final transdermal patch (5.4% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 30 hours at 7 μg / cm 2* hr.

[0149] Example 5: Purified DMT (3.8% w / w, wet) was dissolved in ethanol (15.9% w / w, wet), incorporated into Duro-Tak 4098 adhesive (80.3% w / w, wet), and mixed thoroughly. The mixture was formulated to a thickness of 200 μm on a release liner. After drying the formulation and laminating it onto a closed backing, the transdermal patch was cut into a size of 10 cm 2 . The final transdermal patch (10.9% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 48 hours at 57 μg / cm 2* hr.

[0150] Example 6 Purified DMT (4.2% w / w, wet) was dissolved in ethanol (11.2% w / w, wet), incorporated into Duro-Tak 4098 acrylate adhesive (77.5% w / w, wet), and after that, isopropyl myristate (7.1% w / w, wet) was added and mixed thoroughly. The mixture was formulated to a thickness of 200 μm on a release liner. After drying the formulation and laminating it onto a closed backing, the transdermal patch was cut into a size of 10 cm 2 . The final transdermal patch (10.3% w / w DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average DMT flux was quantified over 48 hours at 145 μg / cm 2* hr.

[0151] Example 7: The purified 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT, 3.2% w / w, wet) was dissolved in ethanol (12.4% w / w, wet) and incorporated into Duro-Tak 4098 acrylate adhesive (84.4 w / w, wet) and mixed thoroughly. The mixture was formulated to a thickness of 200 μm on the silicone-treated surface of a release liner. The formulation was dried and laminated onto an occlusive polyester backing, and then the transdermal patch was cut into 10 cm 2 sizes. The final transdermal patch (9.0% w / w 4-AcO-DMT) was stored in a heat-sealed aluminum pouch to reduce oxidation. The average 4-AcO-DMT flux was quantified over 48 hours at 98 μg / cm 2* hr.

[0152] Example 8: A second DIA containing the excipients listed above is poured directly onto the backing and laminated onto the rate control membrane. Then, the DIA-coated liner from Example 1 is laminated onto the backing / DIA / membrane material to form a multilayer delivery system. The transdermal patch is then die-cut to the appropriate size.

[0153] The DIA poured onto the liner (and then applied directly onto the skin) does not require as high a drug load as the second DIA. The second DIA acts as a reservoir and diffuses the drug through the rate control membrane after manufacture until equilibrium between the first DIAs is achieved. When applied, the second DIA permeates the drug through the membrane to the skin at a zero-order rate until the drug reservoir is sufficiently depleted.

[0154] Example 9: The N,N-dimethyltryptamine (DMT) free base was dissolved in 25 mg / mL acetone. 7 mg / mL of fumaric acid was added dropwise to precipitate DMT fumarate. The precipitate was washed twice with fresh acetone and dried under nitrogen.

[0155] DMT fumarate (18.0% w / w) was dissolved in deionized water (82.0% w / w) to obtain a therapeutically effective aqueous gel vehicle for nasal absorption at an appropriate pH = 6. The formulation of the DMT fumarate gel can be administered via the nasal cavity in a small volume of 0.04 - 0.50 mL for a therapeutic effect. Potency analysis using tryptamine internal standard quantification revealed a DMT free base concentration of 135.5 mg / mL, and after storage for 106 days under dark conditions at room temperature, there were no other decomposition by-products.

[0156] Example 10: Using a Franz cell apparatus, API release and permeability through a human skin mimic (Strat - M membrane, Millipore) were determined, and the patch effectiveness of Examples 1 - 8 was compared. The receptor well (10% ethanol in water) was maintained at 32°C throughout the experiment, and 10 mL was removed at each sampling point. The drug flux was determined using the gradient of zero - order permeating API over the specified time range. In Examples 1 - 9, tryptamine (50 μg / mL) was added as an internal standard, and LC - MS was used to achieve potency analysis of the API while using UV detection at 280 nm to quantify the API.

[0157] Example 11: Free base 4 - AcO - DMT (8% w / w) was dissolved in ethanol (4% w / w), and further polyvinylpyrrolidone (2% w / w), butylated hydroxytoluene (1% w / w), and FD&C Blue No.1 were added. This solution was added to Ceolus KG 1000 microcrystalline cellulose (16% w / w) and mannitol (47% w / w), mixed simultaneously, and then dried to form a uniformly coated powder. Further, Prosolv HD 90 silicified microcrystalline cellulose (20% w / w), Cabosil silicon dioxide (1% w / w), and magnesium stearate (1% w / w) were added and blended until homogeneous. Using a die set and sufficient force, 250 mg tablets for the ingestion of 4 - AcO - DMT for therapeutic use were formed.

[0158] Example 12: 2-(2-Chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine A mixture of tryptamine hydrochloride (1 g, 5.1 mmol) and N-chlorosuccinimide (NCS, 0.69 g, 5.2 mmol) in acetic acid (50 mL) and formic acid (15 mL) was stirred for about 20 minutes. The product 2-chloro-tryptamine (confirmed by 2D NMR spectroscopy) was dried, purified, and 211 mg (1.09 mmol) was further reacted with sodium cyanoborohydride (139.26 mg, 2.22 mmol) in methanol (21 mL) and formaldehyde (0.222 mL, 2.75 mmol) at 0 °C under nitrogen and stirred for 2.5 hours. The reaction was quenched with 1.0 M sodium hydroxide (27 mL) and extracted three times with methyl-tert-butyl ether (MTBE). The residue was dried over sodium sulfate and concentrated as a light brown oil / solid. LC-MS, 1 H and 13 C Based on the NMR data, the final product contained mostly 2-chloro-N,N-dimethyltryptamine. The formula of the product C 12 H 15 N2Cl m / z 222.0924, [M+H] + 223.0997 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.13 (s, 6 H) 2.34 - 2.38 (m, 2 H) 2.68 - 2.80 (m, 3 H) 6.91 - 6.99 (m, 1 H) 7.02 (t, J=7.54 Hz, 2 H) 7.20 (d, J=7.99 Hz, 2 H) 7.40 (d, J=7.81 Hz, 1 H) 11.53 (br s, 1 H)

[0159] Example 13: 2-(2-Bromo-1H-indol-3-yl)-N,N-dimethylethane-1-amine Using the previously recorded method, N,N-dimethyltryptamine (2.88 mmol) was synthesized and dissolved in anhydrous acetonitrile (36 mL, 15 mg / mL) under inert conditions. This was combined with copper(II) bromide (1.93 g, 8.65 mmol) and stirred for 2 hours. The reaction was quenched with 40 mL of water, 100 mL of EtOAc was added, and then 40 mL of saturated ammonium carbonate was added. The organic layer was washed, dried over sodium sulfate, filtered, and concentrated to a light brown oil (302.3 mg). The final major product, 2-bromo-N,N-dimethyltryptamine, was confirmed by LC-MS, 1D, and 2D NMR spectroscopy. Formula of the product: C 12 H 15 N2Br m / z 266.0419, [M+H] + 267.0491 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.21 (s, 6 H) 2.38 - 2.47 (m, 2 H) 2.73 - 2.88 (m, 3 H) 6.93 - 7.03 (m, 1 H) 7.03 - 7.11 (m, 1 H) 7.28 (br d, J=7.99 Hz, 1 H) 7.46 - 7.51 (m, 1 H) 11.61 (br s, 1 H)

[0160] Example 14: 2-Bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate Using the previously recorded method, 4-acetoxy-N,N-dimethyltryptamine (14.9 mg, 0.06 mmol) was synthesized and dissolved in anhydrous acetonitrile (1 mL) under inert conditions. Copper(II) bromide (40.5 mg, 0.18 mmol) was added and the reaction was stirred for 2 hours. During the workup, the major product, 2-bromo-4-acetoxy-N,N-dimethyltryptamine, was confirmed by LC-MS and 1D NMR spectroscopy. Formula of the product: C 14 H 17N2O2Br m / z 324.0473, [M+H] + 325.0546 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.21 - 2.25 (m, 13 H) 2.32 - 2.39 (m, 12 H) 2.71 - 2.75 (m, 3 H) 6.74 (d, J=7.63 Hz, 1 H) 7.06 - 7.10 (m, 2 H) 7.18 (d, J=8.17 Hz, 2 H) 11.91 (s, 1 H)

[0161] Example 15: 2-(2-Chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine Using a previously recorded method, 4-methoxy-N,N-dimethyltryptamine (130 mg, 0.6 mmol) was synthesized and dissolved in anhydrous acetonitrile (3.6 mL). Copper(II) chloride (241 mg, 1.8 mmol) was added and stirred overnight under an inert atmosphere. It was quenched with water (14 mL), extracted three times with EtOAc, and washed with saturated ammonium carbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give an orange semi-solid (38.2 mg, 25% yield). This was purified by HPLC to give 2-chloro-4-methoxy-N,N-dimethyltryptamine, which was confirmed by LC-MS, 1D, and 2D NMR spectroscopy.

[0162] Formula of the product: C 13 H 17 N2OCl m / z 252.1029, [M+H] + 253.1102 1 H NMR (600 MHz, DMSO-d6) δ ppm 2.27 - 2.39 (m, 14 H) 2.50 - 2.60 (m, 6 H) 2.89 - 3.05 (m, 5 H) 3.84 - 3.99 (m, 9 H) 6.54 - 6.66 (m, 2 H) 6.92 (d, J=8.17 Hz, 1 H) 7.03 - 7.19 (m, 2 H) 11.71 (s, 1 H)

[0163] Example 16: 1-(-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide The nitro group of N-methyl-3-nitrobenzenesulfonamide is reduced to aniline via palladium carbon (H2 / Pd / C) and aqueous HCl in an ethanol solvent and then to hydrazine using sodium nitrite to obtain a diazonium salt, followed by reduction with SnCl2 (all at 0 °C). The hydrazone is formed upon condensation with 4,4-dimethyoxy-N,N-dimethylbutylamine in aqueous hydrochloric acid. The final product is formed via a Fischer indole reaction in which the hydrazone reacts with polyphosphoric acid in refluxing chloroform to initiate cyclization.

[0164] This compound can be further halogenated at the C-2 position according to the copper(II) halide protocol of the previous example.

[0165] Example 17: Computational Analysis Six different receptor models were tested according to the crystal structures recorded in the RCSB Protein Data Bank (PDB) for various serotonin receptors and sigma-1. These receptor structures include 5-HT 2A , 5-HT 2B , 5-HT 1B , and σ1 (the PDB IDs are also shown in the column headings).

[0166] For each static protein structure, to increase the accuracy as much as possible, the PDB file of the crystal structure containing the binding ligand that is most chemically similar to the scaffold of tryptamine was used (e.g., LSD and ergotamine binding). The overall workflow was executed using various aspects of the Schrödinger software suite. 3D SMILES for each ligand were uploaded according to the protonation and / or charge of tryptophan recommended in the literature, and various conformers were generated and minimized using Schrödinger LigPrep. The final list of compounds was screened using the Glide scores generated by Schrödinger Glide, including the structures listed in Table 3. The validation of this technique was performed by including known agonists of 5-HT and σ1 receptors and comparing with experimental binding assay data. The docking scores of the known agonists and experimental data were equivalent and within the experimental error for activity. For example, the (+)-LSD enantiomer showed greater activity in vitro at the 5-HT 2A receptor than the (-)-LSD enantiomer, and the values rendered in our calculations showed the same trend in activity.

[0167]

Table 3-1

Table 3-2

Table 3-3

Table 3-4

[0168] This disclosure has been described in connection with specific embodiments and examples. However, unless otherwise indicated, the claimed invention should not be unduly limited to such specific embodiments and examples. In certain embodiments, for example, the following are provided: (Item 1) A compound of the following formula: Structure (2) [Chemical formula] Wherein R1 is selected from the group consisting of H, F, Cl, Br, I or CF3; R2 is H or CH3; R3 and R4 are each independently, optionally, selected from the group consisting of H, CH3, C2H5, (H3C)2CH, or H2C=CH-CH2; R5 is selected from the group consisting of OCH3, OCOCH3, O-phosphate, O-polyethylene glycol (PEG), O-(CH2)2(COOH)2 (succinate), O-(CH2)2(COOH) (hemisuccinate) and CH2SO2NHCH3 (sulfonamide); a compound wherein when R1 is H, R5 is CH2SO2NHCH3, and pharmaceutically acceptable salts or solvates thereof. (Item 2) The compound according to item 1, selected from the group consisting of 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, and 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide. (Item 3) A compound of the following formula: Structure (3) [Chemical formula] In the formula, R1 is selected from the group consisting of F, Cl, Br, I or CF3; R2 is CH3; R3 and R4 are each independently, optionally, selected from the group consisting of H, CH3, C2H5, (H3C)2CH, or H2C=CH-CH2. (Item 4) A compound according to item 3, selected from the group consisting of 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinyl ethenamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine. (Item 5) A pharmaceutical composition comprising a pharmaceutical active ingredient, wherein the pharmaceutical active ingredient is a compound selected from the group consisting of a compound of structure (2), a compound of structure (3), or a psilocybin analog. (Item 6) The composition according to item 5, wherein the psilocybin analog is selected from the group consisting of psilocybin, psilocin, 4-hydroxy-indole-3-acetic acid, 4-hydroxytryptofol, 4-hydroxytryptophan, norsilocin, aeruginascin, baeocystin, norbaeocystin, 4-hydroxy-N-methyl-N-ethyltryptamine (4-OH-MET), 4-hydroxy-N,N-diethyltryptamine (4-OH-DET), 4-hydroxy-N,N-dipropyltryptamine (4-OH-DPT), 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), N,N-dimethyltryptamine (DMT), indole-3-acetic acid, N,N-dimethyltryptamine-N-oxide (DMT-NO), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), bufotenin (5-OH-DMT), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), lysergic acid diethylamide (LSD), 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), ibogaine, and combinations thereof. (Item 7) The composition according to item 5, wherein the compound is selected from the group consisting of 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl acetate, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl hydrogen phosphate, 2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-ol, 2-(2-chloro-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-bromo-4-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 1-(2-chloro-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, 1-(2-bromo-3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide, or 1-(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-N-methylmethanesulfonamide. (Item 8) The composition according to item 5, wherein the compound is selected from the group consisting of 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-dimethylethane-1-amine, (R)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)propan-2-amine, (S)-1-(2-chloro-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, (R)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N,N-dimethylpropan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)propan-2-amine, (S)-1-(2-bromo-1H-indol-3-yl)-N-methylpropan-2-amine, 2-(2-chloro-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, N-(2-(2-chloro-1H-indol-3-yl)ethyl)-N-vinyl ethenamine, 2-(2-bromo-1H-indol-3-yl)-N,N-diethylethane-1-amine, N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine, or N-(2-(2-bromo-1H-indol-3-yl)ethyl)-N-isopropylpropan-2-amine. (Item 9) The pharmaceutical composition according to item 5, wherein the composition is for oral delivery, nasal delivery or transdermal delivery of the pharmaceutically active ingredient. (Item 10) The pharmaceutical composition according to item 5, wherein the transdermal composition is selected from the group consisting of a sprayable liquid, a gel, a cream, a lotion, an ointment, or a transdermal patch. (Item 11) The pharmaceutical composition according to item 5, wherein the oral composition is a tablet, a capsule, a cachet or a strip. (Item 12) The pharmaceutical composition according to item 5, wherein the nasal composition is selected from the group consisting of a gel, a sprayable liquid, an emulsion, or an ointment. (Item 13) A method of treating or preventing a disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of structure (2), structure (3) or a psilocybin analog. (Item 14) The method according to item 16, wherein the disease is a neurological disorder, a mood disorder or a substance use disorder. (Item 15) The method according to item 16, wherein the disease is selected from the group consisting of depression, central nervous system inflammation, addiction, headache or dementia, or a disorder of cognition and memory. (Item 16) The method according to item 7, wherein the disease is selected from the group consisting of epilepsy, headache, dementia, traumatic injury, substance abuse, multiple sclerosis or Parkinson's disease. (Item 17) A method for preparing the compound according to item 2. (Item 18) A method for preparing the compound according to item 4.

Claims

1. A pharmaceutical product for delivery across a mucosa, comprising a therapeutically effective amount of N,N-dimethyltryptamine (DMT) or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier, wherein the DMT or pharma- ceutical acceptable salt thereof is capable of passing through the mucosa.

2. The pharmaceutical product of claim 1, wherein the mucosa is sublingual, buccal, nasal, or oral.

3. The pharmaceutical product of claim 2, wherein the pharmaceutical product is in the form of a solution, gel, suspension, emulsion, liposome, or microparticle.

4. The pharmaceutical product of claim 1, wherein the pharma- ceutically acceptable carrier is an adhesive polymer.

5. The pharmaceutical product of claim 1, wherein the pharma- ceutically acceptable salt of DMT is DMT fumarate.

6. The pharmaceutical product of claim 2, wherein the product is in the form of a spray.

7. The pharmaceutical product of claim 2, wherein the product is in the form of a film.

8. The pharmaceutical product of claim 7, wherein the pharmaceutical product is in the form of a sublingual film.

9. The pharmaceutical product of claim 1, wherein the product is in the form of a nasal spray.

10. The pharmaceutical product of claim 1, further comprising a monoamine oxidase inhibitor (MAOI).

11. The pharmaceutical product of claim 10, wherein the MAOI is selected from the group consisting of harmala alkaloids, harmine, harmane, harmaline, hydrazine, iproniazid, isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, bifemelane, moclobemide, pirlindole, toloxatone, rasagiline, selegiline, and safinamide.

12. The pharmaceutical product of claim 11, wherein the MAOI is harmine.

Images