Mushroom tincture-based neuroactive drug delivery systems

Abstract

Disclosed is a process for the mushroom tincture based psychedelic drug (tincture-based delivery system) delivery system by a process that comprises: combining (a) a mushroom-based extract obtained by contacting a biocompatible solvent with a mushroom material to obtain an extract composition that contains fats, oils, carbohydrates, proteins, peptides, and any other compounds or bioactive compounds from the mushroom material, with (b) a bioeffective amount of one or psychedelic agents in a bioeffective amount that is in an amount or character different than that obtained directly from said mushroom material. This tincture composition may then be dried to produce a powder that then may be incorporated into tablets, powders, or capsules.

Description

Mushroom Tincture-Based Neuroactive Drug Delivery Systems 407-P022PCTREFERENCE TO RELATED APPLICATIONS

[0001] This application is related to U.S. Provisional patent application Ser. No.63 / 760,865 that was filed on February 20, 2025, and whose disclosure is incorporated herein by reference.FIELD OF THE INVENTION

[0002] The invention relates to formulations of psychedelic compounds and their prodrug compounds, including tryptamine-scaffold and / or phenethylamine-scaffold psychedelic agents that are useful for therapy and / or nutrition and methods for their manufacture.BACKGROUND OF THE INVENTION

[0003] Many people worldwide are afflicted with psychological or mood disorders, such as depression, anxiety, and post-traumatic stress disorders. Many of these conditions are believed to involve a person's serotonin system, including interactions between (A) the neurotransmitter serotonin (often abbreviated 5-HT) and (B) several different subtypes of serotonin neurotransmitter receptors found in the human body.

[0004] A variety of compositions are known to modulate activity at the serotonin receptors. A number of pharmaceuticals (antidepressants, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, etc.) have become available.Almost all these pharmaceuticals target neurotransmitter receptors, e.g., serotonergic receptors, adrenergic receptors, dopaminergic receptors, etc., and in different ways. All ten of the leading pharmaceutical products for treating mood disorders (such as depression, obsessive compulsive disorder, and / or anxiety disorders) target serotonergic, dopaminergic, or adrenergic pathways.

[0005] Although Phan et al. describes many species with potential neurogenerative properties, the psilocybin or psilocybin species (i.e. , "psilocybin-containing") are not mentioned, either alone or in combinations with the edible and medicinal mushroom species (Phan, David et al. 2017). A good summary of the role of psilocybin in humans can be found in Passie (Passie, Seifert et al. 2002). That psilocybin has neurogenerative properties was elucidated by Catlow (Catlow, Songet al. 2013) and further reviewed by Adeyinka (Adeyinka, Forsyth et al. 2025). The disclosures of these publications are hereby incorporated by reference.

[0006] Both the medical establishment and conventional wisdom define psychedelic substances, (including those in the tryptamine and phenethylamine family, and including substances classified as 5-HT2A agonists and antagonists), by their ability to determine certain alterations in consciousness, emotion, and cognition, including positive and negative psychotomimetic symptoms (e.g., psychedelic effects, psychedelic experience, psychotomimetic effects). These effects are known to laymen and doctors for their potential recreational misuse and to researchers in the psychiatric field for their potential bioeffective uses in psychiatry and research applications for the study of brain function.

[0007] Psychedelic substances are presently under investigation for the treatment of several psychiatric and neurological diseases, disorders and symptoms, including but not limited to depression, PTSD, OCD, addiction, and end-stage-cancer-associated anxiety. The psychedelic experience, which includes positive and negative psychotomimetic effects induced by a psychedelic GPCR agonist or antagonist, is an integral part of the intended treatment. For bioeffective purposes, GPCR agonist or antagonistic psychedelic drugs are administered in a particular "setting" and preceded and followed by counseling and or psychotherapy and the whole session is supervised and closely monitored. The administration of the GPCR agonist or antagonist is administered at a dose that produces psychedelic and or psychotomimetic symptoms should be paired with ancillary therapies, which include a particular physical setting, in addition to pre, during, and post drug administration counseling and / or psychotherapy (talk therapy) to achieve bioeffective efficacy for certain psychiatric disorders. The psychedelic experience (which can include alterations in consciousness, emotion, and cognition, and positive and negative psychotomimetic symptoms) is thus viewed by researchers and scientists as integral part of the potential bioeffective efficacy of psychedelic drugs. See US Publication No. 2022 / 0143051 (Manfredi, Inturrisi et al. 2020) which is hereby incorporated by reference.

[0008] Controlled, reliable administration of psychedelic agents within botanical or fungal material is challenging without isolation of the active pharmaceutical ingredients (APIs). Even when "magic mushrooms", for example, are properly identified, those mushrooms vary greatly in terms of the concentration of psilocybin,psilocin, and other (often overlooked) active ingredients. Accordingly, administering a specific composition or a particular dose using mushrooms is not reliable because of the variability in the chemical composition of mushrooms even in the same species or even in the different parts of mushrooms’ anatomy. This is consistent with many botanical and fungal species possessing relevant APIs.

[0009] Psychedelic active pharmaceutical ingredients (APIs), such as psilocybin, mescaline, psilocin, ibogaine, LSD, and bufotenin, are currently under study for their use in the treatment of major depressive disorder (MDD), substance use disorder (SUD), and neurodegenerative disorders, neurological disorders, and inflammatory disorders. Formulation and delivery challenges associated with even the serumsoluble psychedelic APIs and their prodrugs-such as stress-induced degradation, limited bioavailability, and significant first-pass metabolism-have combined to make it difficult to identify functional formulations.

[0010] 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is a naturally occurring tryptamine derivative and analogue of psilocin found in a range of fungal, plant, and animal species such as seeds of the Anadenanthera genus, mushrooms of the Amanita genus, and in the venom and eggs of toads in the Incilius and Alvarius genus. They have been used for millennia for their hallucinogenic effects.

[0011] Seeds of Anadenanthera colubrina and Anadenanthera peregrina were smoked by indigenous peoples of the northern regions of Argentina up to 4000 years ago. These seeds (containing up to 0.04 wt% of 5-MeO-DMT) were dried, roasted and ground to produce a powdered preparation known as a snuff ("hataj", "cohoba", "yopo") for insufflation and smoking in pipes. Modern literature tells us that intranasal, intravenous, and smoking (inhalation) are the common forms of administration due to rapid metabolization of 5-MeO-DMT during oral administration. Inhalation of 5-MeO-DMT (1-5 mg) produces effects within 4-5 mins that last for up to one hour. 5-MeO-DMT is not under international control and has experienced a recent resurgence in interest, along with other psychedelic APIs, for the bioeffective treatment of MDD, SUD, and various neurodegenerative disorders.

[0012] Currently, it is statistically significant that people who are prescribed antidepressants are subjected to difficult and sometimes debilitating side effects that affect their daily lives. Depression is one of the largest epidemics in the world, which suggests that other classes of bioeffective agents must be investigated to provideeffective therapies for its treatment. This has led to renewed interest in cannabis and entheogen research.

[0013] Recent clinical trials using forms of psychedelics have been on-going. A vaporizable form of 5-MeO-DMT (GH Research PLC, Dublin, Ireland) (Reckweg, van Leeuwen et al. 2023); was published that detailed the efficacy of 5-MeO-DMT for treatment-resistant depression and required three daily doses of in situ produced 5-MeO-DMT aerosols for successful biological uptake. Several adverse drug reactions were reported in the study which are more associated with the dosing form rather than the drug itself. Another 5-MeO-DMT intranasal spray has entered phase Ila clinical trials (Beckley Psytech Ltd., Oxford, UK) (Rucker, Roberts et al. 2024); this involves a single inhalable dose of 5-MeO-DMT, is well-tolerated, and produces a sustained antidepressant outcome for 3 months. While no serious adverse events were observed, mild nasal discomforts were reported, possibly linked to the use of NaOH in the nasal composition. Nevertheless, we note that the stated composition may also lead to API degradation in situ because of the alkalinity. In any case, neither composition encapsulated the API to facilitate transmucosal uptake in the nose (bypassing the blood-brain-barrier), and instead both seek a simple introduction of the unmodified polar API into the bloodstream. The disclosure of these publications is hereby incorporated by reference

[0014] A mushroom tincture is a liquid extract prepared by soaking mushroom material in a solvent, typically water and alcohol, to extract bioactive compounds. These tinctures contain bioactives from the mushroom such as polysaccharides, terpenoids, proteins, and peptides (Ali, Alsharbaty et al. 2024). makes mention of their neuroprotective, immunomodulatory, and anti-inflammatory properties, among others biological effects, the disclosure of which is hereby incorporated by reference.

[0015] It would be desirable to have an effective process to make stable, effective, mushroom tincture compositions that could be used with psychedelics.

[0016] It would be further desirable to have process in creating mushroom tinctures to make a composition comprising psychedelics in bioeffective effective concentrations to produce a bioeffective effective composition for the treatment of a human or mammal patient.SUMMARY OF THE INVENTION

[0017] It is an object of the invention to provide a composition and method for its administration to a patient having a bioeffective need that would provide a consistent, bioeffective dose of a psychedelic.

[0018] It is also an objective of the invention to provide a composition and method of administration that would deliver a bioeffective amount of a psychedelic to a patient in need that would provide a bioavailable, bioeffective dose.

[0019] It is further an objective of the invention to provide an effective process to make a stable, effective, mushroom tincture delivery composition that could be used with psychedelics.

[0020] Additionally, it is an object of the invention to provide a process for producing tincture-based delivery systems to provide a composition comprising at least one psychedelic agent in a bioeffective concentration suitable for the treatment of a human or mammal patient.

[0021] In accordance with these and other objects of the invention that will become apparent from the description herein, compositions according to the invention are in the form of mushroom-derived tincture that include a mushroom-derived tincture composition that comprises: (a) an extraction product obtained by extracting a psychedelic or non-psychedelic mushroom material with ethanol, (b) a biocompatible solvent with said extraction product, (c) at least one psychedelic drug. Preferably, at least one psychedelic drug is adjusted to a bioeffective amount that is in an amount or character that is different than what is obtained directly from the extraction of said mushroom material. The tincture composition can also include one or more pharmaceutically acceptable additives that enhance the shelf-life of the composition, the bioavailability of the psychedelic drug, the taste of the tincture composition, and / or inhibit enzymatic degradation of the dissolved psychedelic drug.

[0022] Optionally, the composition is dried to produce a powder that then may be incorporated into tablets, powders, or capsules.

[0023] The tincture-based formulation form of the present invention provides a stable formulation that is well-suited for delivery of one or more psychedelics via ingestion, thereby providing a familiar and comfortable form of dosing to a patient.DETAILED DESCRIPTION OF THE INVENTION

[0024] Disclosed herein is a design of a stable, tincture-based delivery system containing a bioeffective amount of one or more psychedelic agents that may, or may not, be related to any psychedelically active ingredient found in the mushroom material that was extracted to provide the tincture delivery component of the present invention. Preferably, the psychedelic active ingredient component is not only any psychedelic agent obtained from the source mushroom material but is enhanced in its psychedelic profile to provide greater bioefficacy.

[0025] Each of the psychedelic agents useful in the present invention is a hydrophilic or lipophilic drug that is variably soluble in serum and amenable for delivery by the present tincture-based delivery system. Preferred psychedelic agents comprise psilocybin, 5-MeO-DMT, N,N-DMT, psilocin, mescaline, ibogaine, and / or bufotenin in an amount within the range of 1 - 80 wt%, preferably 15-30 wt% based on total weight of the composition. When used in a liquid form, a suitable amount of psychedelic agents combined is an amount within the range from about 0.1 - 1000 mg / mL, preferably an amount within the range of 0.5 - 500 mg / mL, and more preferably an amount within the range of 1 - 100 mg / mL.

[0026] Sustained solubilization and stability of a psychedelically active agent can be attained by incorporating the agent or its prodrug form it into a mushroom-based tincture. The high drug-solubilizing capacity of mushroom-based tinctures provide properties to the composition that provide sustained solubilization and formulation stability upon storage.

[0027] Mushroom tinctures typically produce opaque or colored formulations that contain an overall concentration of >1 mg / mL of bioactives. These formulations are typically composed of (a) at least one psychedelic drug(s), (b) a biocompatible solvent, and (c) fats, oils, carbohydrates, proteins, peptides, and any other compounds or bioactive compounds that are extracted from the mushroom material that comprises the original tincture solution before the addition of the drug, and (d) further additives to enhance shelf-life, bioavailability, taste, color, or inhibit enzymatic degradation of the dissolved psychedelic drug.

[0028] Mushroom tinctures can be produced by mixing the ground-up mushroom material in a volume of solvent and filtering the material. This process can be repeated until the mushroom material is depleted of bioactive compounds.

[0029] Psychedelic tinctures can also be produced by using mushroom material that contains inherent psychedelic drugs or pro-drugs, possibly bypassing the need for further addition of a drug. The present composition provides a delivery system that is effective with psychedelic agents that are enhanced in amount or which are chemically different from any psychedelic agent that is naturally extracted from the mushroom source material.

[0030] Orally administered mushroom tinctures containing a psychedelic offers a familiar form of administration for consumers.

[0031] The composition of the present invention includes a biocompatible organic vehicle, and one or more mushroom species that is pre-extracted with a solvent, which may be the organic vehicle.

[0032] A suitable organic vehicle is ethanol. Ethanol is generally used in an amount within the range from about 1 - 99 wt%, preferably an amount within the range of 10 - 50 wt %, and even more preferably an amount within the range of 20 -35 wt %, and most optimally within the range of 1 - 10 wt% based on total tincturebased delivery system’ weight.

[0033] Suitable mushroom fungal species are generally selected from edible macro fungi that may, or may not contain a psychedelic active agent, such as but not limited to Ganoderma lucidum, Ganoderma tsugae, Ganoderma brownii, Hericium erinaceus, Psilocybe cubensis, Amanita muscaria, Hericium abietis, Cordyceps sinensis, Cordyceps militaris, Fomitopsis pinicola, Trametes versicolor, Inonutus obliquus, Grifola frondosa. An especially preferred edible macro fungal species is Hericium erinaceus.

[0034] The total amounts of extracted material from (a) mushroom species, combined, are generally within a range from about 1 - 50 wt%, preferably an amount within the range of 10 - 40 wt%, and more preferably an amount within the range from about 15-35 wt%, and optimally within the range of 1 - 10 wt% of the total tincture-based delivery systems weight.

[0035] The general method of treatment comprises administering to a human or mammal subject a bioeffective amount of an acceptable psychedelic or psychedelic analogue in one or more pharmaceutically acceptable carriers or excipients.

[0036] The administered composition is formulated for oral, sublingual, or buccal delivery using one or more excipients that are traditionally used in such formulations.A preferred form of delivery is by way of a measured aliquot of a volume of a tincture-based delivery system into a consumer's mouth.

[0037] In another aspect, the invention comprises a method of treating a mental disorder, (such as a mood disorder, psychiatric disorder, and / or neurological disorder) by a process that comprises the step of administering an effective amount of a ligand described herein. In some embodiments, the mental disorder is a depressive condition, including unipolar and bipolar depressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0038] The invention provides for the treatment and / or prevention of psychiatric disorders, neurological disorders, degenerative disorders, inflammatory disorders. In another aspect, the invention relates to the use of a composition described herein to treat a mental disorder, or in the manufacture of a medicament for treating a mental disorder, such as depression. All such treatments include a step that comprises administering to an afflicted patient a bioeffective amount of a composition according to the invention.Definitions

[0039] As used herein, the term "neurological disorders" refers to any structural, biochemical and / or electrical abnormalities in the brain, spinal cord or other nerves and includes neurodevelopment and neurodegenerative diseases that may benefit from neural plasticity modulation. In a preferred embodiment, the term "neurological disorder" refers to one or more disorders selected from the following acquired brain injury, ataxia brain tumor, dementia, dystonia epilepsy, temporal lobe epilepsy, pain associated with neurological disorders, headache disorders, functional and dissociative neurological symptoms, neuroinfections, meningitis, disorders associated with malnutrition, motor neuron disease, multi-system atrophy, multiple sclerosis, amyotrophic lateral sclerosis, mesial temporal lobe hippocampal sclerosis, muscular dystrophy, myalgic encephalomyelitis, Parkinson's disease, progressive supranuclear palsy, cerebral palsy, Huntington's disease, Alzheimer's disease, frontal lobe dementia, vascular dementia, dementia with Lewy bodies, mild cognitive impairment (MCI) associated with aging and chronic disease and its treatment, including chemotherapy, immunotherapy and radiotherapy, mild corticobasal degeneration, disorders associated with accumulation of beta amyloid, and / or withthe accumulation or disruption of tau protein and its metabolites, Lyme encephalopathy, toxic encephalopathy, cognitive decline associated with aging, spina bifida, hydrocephalus, spinal injury, stroke, Tourette syndrome, and transverse myelitis, corticobasal degeneration, supranuclear palsy, epilepsy; nervous system trauma, nervous system infections, nervous system inflammation, including inflammation from autoimmune disorders, including NMDAR encephalitis, and cytopathology from toxins (including microbial toxins, heavy metals, and pesticides etc.), stroke, multiple sclerosis, Huntington's disease, mitochondrial disorders, Fragile X syndrome, Angelman syndrome, hereditary ataxias, neuro-otological and eye movement disorders, amyotrophic lateral sclerosis, tardive dyskinesias (TD), hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorders; restless leg syndrome, autism spectrum disorders, tuberous sclerosis, Rett syndrome, cerebral palsy, disorders of the reward system including eating disorders [including anorexia nervosa (AN) and bulimia nervosa (BN), and binge eating disorder (BED), trichotillomania, dermotillomania, nail biting, migraine, fibromyalgia, and peripheral neuropathy of any etiology. Symptoms or manifestations of nervous system disorders that may be treated or prevented by neuroplastogen substances and drugs include a decline, impairment, or abnormality in cognitive abilities including executive function, attention, cognitive speed, memory, language functions (speech, comprehension, reading and writing) orientation in space and time, praxis, ability to perform actions, ability to recognize faces or objects, concentration, and alertness; abnormal movements including akathisia, bradykinesia, tics, myoclonus, dyskinesias, including dyskinesias relate to Huntington's disease, levodopa induced dyskinesias and neuroleptic induced dyskinesias, dystonias, tremors, including essential tremor, and restless leg syndrome; parasonmias, insonmia, disturbed sleep pattern; psychosis; delirium; agitation; headache; motor weakness, spasticity, impaired physical endurance; sensory impairment, including impairment of vision and visual field defects, smell, taste, hearing and balance, and dysesthesias; dysautonomia; and ataxia, impairment of balance or coordination, tinnitus, neuro-otological and eye movement impairments, neurological symptoms of alcohol withdrawal, including delirium, headache, tremors, hallucinations, hypertension.

[0040] The broad term "degenerative disorders" refers to one or more disorders selected from the following degenerative disorders, neurodegenerative diseases ofthe retina like glaucoma, diabetic retinopathy and age-related macular degeneration, retinitis pigmentosa, Usher disease and Bardet-Biedl syndrome, motor neuron disease, prion disease, spinocerebelluar ataxia and apathy syndrome.

[0041] The term "inflammatory disorders" generally refers to one or more disorders selected from the following inflammatory disorders, of atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn's disease, septicemia, depression, schizophrenia, multiple sclerosis, conjunctivitis, Alzheimer's disease, chronic obstructive pulmonary disease, neuroinflammation, metabolic syndrome, impaired glucose tolerance, non-alcoholic fatty liver disease (NAFLD), complications of NAFLD, non-alcoholic steatohepatitis (NASH) and conjunctivitis.

[0042] The general method of treatment comprises administering to a human or mammal subject in need thereof a bioeffective amount of an acceptable psychedelic or psychedelic analogue composition according to the invention in one or more pharmaceutically acceptable carriers or excipients.

[0043] The term "treating", "treat" or "treatment" as used herein embraces both preventative, i.e. , prophylactic, and palliative treatment, i.e. , relieve, alleviate, or slow the progression of the patient's disease, disorder, or condition.

[0044] As used herein, "psychedelic state" is an altered state of consciousness experienced by a person, which may include intensified sensory perception, perceptual distortion or hallucinations, and / or feelings of euphoria or despair.Psychedelic states have been described as resulting from psychedelic drugs such as DMT (dimethyltryptamine), 5-MeO-DMT, LSD, mescaline or psilocin. Other known psychedelic drugs include the but are not limited to, 4-hydroxy analogs of N-Methyl-N-isopropyltryptamine (MiPT) and N,N-diisopropyltryptamine (DiPT).

[0045] The term "psychiatric disorders" refers to one or more disorders selected from the following psychiatric disease as defined as defined by DSM-5 and ICD-11 that may benefit from modulation of neural plasticity, including Schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders, COVID depressive disorder, generalized anxiety disorders, obsessive-compulsive and related disorders, trauma- and stressor-related disorders, dissociative disorders, somatic symptom and related disorders, feeding and eating disorders, elimination disorders, sleep-wake disorders, sexual disruptive, impulsecontrol, and conduct disorders, substance related and addictive disorders, panicdisorder, agoraphobia, social anxiety disorder, phobias, posttraumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, anorexia nervosa, binge eating disorder, bulimia nervosa, psychosis, schizophrenia, substance addiction, personality disorders, neurocog nitive disorders, personality disorders, paraphilic disorders and for the reduction of suicidal ideation in a patient suffering from a life-threatening disease.

[0046] The term "pharmaceutical composition" means a composition according to the invention combined with at least one additional pharmaceutically acceptable carrier.

[0047] A "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including but not limited to adjuvants, excipients or vehicles, such as diluents, osmotic complement, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, polymers, solubilizing agents, stabilizers, antioxidants and dispensing agents, depending on the nature of the mode of administration and dosage forms. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0048] As used herein, "oral" administration includes swallowing for ingestion in the stomach or gut, and further includes lingual, sublingual, buccal and oropharyngeal administration. The compositions of this invention can be administered for any of the uses or methods described herein by any suitable means, for example, orally, such as tablets, capsules (each of which may include sustained release or timed release formulations), pills, powders, granules, elixirs, suspensions (including nano suspensions, micro suspensions, spray-dried dispersions), syrups, and emulsions; sublingually (e.g. as thin films, effervescent tablets or tablets that dissolve spontaneously under the tongue); parenterally, such as by subcutaneous, intravenous, intramuscular injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; or rectally such as in the form of suppositories.Formulations and Compositions

[0049] The invention provides bioeffective compositions which comprise a bioeffective amount of one or more of the compositions described herein, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally, one or more additional bioeffective agents. While it is possible for a composition described herein to be administered alone, it is preferable to administer the composition as a pharmaceutical composition.

[0050] The dosage regimen for the compositions described herein will, of course, vary depending upon factors known and readily determinable by those with no more than an ordinary level of skill in this art, such as the pharmacokinetic and pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient; and, the effect desired. The selected dosage level may also depend on the additional factors including the activity of the particular compositions and pharmaceutical compositions described herein, whether an ester, salt or amide substituent is of the composition is used, the time of administration, the rate of excretion or metabolism of the particular composition being employed, the rate and extent of absorption, the duration of the treatment, other drugs that may be administered to the patient, compositions and / or materials used in combination with the particular composition employed and like factors well known in the medical arts.

[0051] Generally, the dosage of the drug or prodrug for a therapy session, when used for the indicated effects, will range between about 0.001 to about 500 mg per dose, preferably between about 0.01 to about 200 mg per dose, and most preferably between about 0.1 to about 50 mg per dose, such as 10, 20, 30, 40, 50, 100 or 200 mg. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during a constant rate infusion.

[0052] Compositions of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in multiple divided doses, such as two, three, or four times daily. Alternatively, the doses may be provided on a weekly, biweekly, or monthly basis. In a preferred embodiment, only one or two doses are required for an antidepressant effect that may extend for 1 , 2, 3 or 6 months, or more.

[0053] For tablet dosage forms, depending on dose, the composition of the present invention may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.

[0054] In addition to the present composition, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

[0055] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0056] Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

[0057] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

[0058] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

[0059] Exemplary tablets contain up to about 80 wt% of the present composition, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

[0060] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet, dry, or melt granulated,melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

[0061] A typical capsule for oral administration contains at least one of the formulations of the present invention (e.g. 25 mg), lactose (e.g. 75 mg), and magnesium stearate (e.g. 15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0062] Liquid formulations include suspensions, solutions, syrups, and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[0063] Liquid formulations may also be administered in the form of a nasal spray that provides direct contact with mucosal membranes in relatively close proximity to the blood-brain barrier. A preferred mechanism for delivery is a nasal spray that delivers a metered amount with each pump, so the volume of sprayed formulation is substantially consistent from dose to dose.

[0064] Compositions of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol containing polymers, in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0065] Drug cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and noninclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. The materials most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148, the disclosures of which are incorporated herein by reference in their entireties.

[0066] Regardless of the route of administration selected, the compositions of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to thoseof skill in the art. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired bioeffective response for a particular patient, composition, and mode of administration.

[0067] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compositions of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired bioeffective effect and gradually increase the dosage until the desired effect is achieved.

[0068] In general, a suitable daily dose of a composition of the invention will be an amount of the composition which is the lowest dose effective to produce a bioeffective effect. Such an effective dose will generally depend upon the factors described above.

[0069] As used herein, a "bioeffective amount" refers to that amount of a composition being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of depression, a bioeffective amount refers to that amount which has the effect of reducing the severity of depression. Depression severity may be assessed using well-known structured assessment tools such as Structured Clinical Interview for DSM-5 (SCID-5) and the GRID-Hamilton Depression Rating Scale (GRIDHAMD). A bioeffective amount may be less than that required for a psychedelic state.

[0070] An effective dosage can be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, composition, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or bioeffective treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, composition or pharmaceutical composition may or may not be achieved in conjunction with another therapy, drug, composition, or pharmaceutical composition.Bioeffective Methods and Uses

[0071] Treatment with the novel compositions of the present invention may substantially alleviate clinical or subclinical depression and may avoid relapse, particularly if used in combination with psychotherapy for the treatment ofdepression. It is known that administration of an effective dose of psilocybin produced rapid and large reductions in depressive symptoms, and many subjects achieve remission through a four-week follow up Davis et al. (2021), “Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial,” JAMA Psychiatry 78(5): 481-489. Without restriction to a theory, it is believed that the psychedelic state is associated with the beneficial effects, however, some compositions which are 5HT2AR agonists or antagonists may provide the desired bioeffective effect without the psychedelic state. One aspect of the invention comprises prodrugs of those 5HT2AR agonists which do provide a beneficial bioeffective state.

[0072] In general, the present invention includes the use of a composition of the present invention herein, to treat any disease or disorder which may be alleviated by a psychedelic and / or a 5HT2AR agonist, or the use of a composition of the present invention herein to manufacture a medication to treat any disease or disorder which may be alleviated by a psychedelic and / or 5HT2AR agonist, or a method of treating any disease or disorder which may be alleviated by a psychedelic and / or 5HT2AR agonist. The present invention is also suitable for treating diseases or disorders that are related to 5HT2AR agonists.

[0073] In some embodiments, the invention may comprise the use of the compositions of the present invention to treat mental disorders. In some embodiments, the invention may comprise the use of the compositions of the present invention to treat depression, and particularly drug resistant depression. Other conditions that may be treated include but are not limited to: anxiety disorders, including anxiety in advanced stage illness e.g. cancer as well as generalized anxiety disorder, depression including major depressive disorder, postpartum depression, cluster headaches, obsessive compulsive disorder, personality disorders including conduct disorder, drug and substance use disorders including: alcohol dependence, nicotine dependence, opioid dependence, cocaine dependence and other addictions including gambling disorder, eating disorder and body dysmorphic disorder, chronic pain, or chronic fatigue.

[0074] In some embodiments, the invention may comprise a method of treating mental disorders comprising administering to a subject in need thereof a bioeffective amount of a composition of the present invention. In one embodiment, there is provided a method of treating depression by administering to a subject in needthereof a bioeffective amount of a composition of the present invention. The depression effects may be drug-resistant depression or major depressive disorder.

[0075] For example, a patient diagnosed with depression may be screened prior to treatment, and then prepared for a dosing session by a trained psychotherapist. Within a dosing session, a composition of the present invention may be administered by injection of a sterile solution at a rate of 0.01 - 0.3 mg / kg to the patient or any of the other methods for delivery described herein. The patient is preferably seated for the duration of the session while being blindfolded. For safety, a trained health care professional may monitor the patient throughout the dosing session, which may last up to 12 hours. In some cases, music may be played for the patient. When the health care professional can determine that the drug substance has cleared, the psychotherapist may assist the patient with any questions relating to the psychedelic experience, and then the patient may be discharged.

[0076] To further alleviate any anxiety that may occur relative to therapy, the physician may prefer to divide the bioeffective dose and thereby reduce the initial onset of psychoactivity before applying the full complement of the dosage to achieve the full effect.

[0077] In some embodiments, treatment with a composition of the present invention may be combined with concomitant treatment with another anti-depressant drugs, either concurrently or consecutively. In preferred embodiments, treatment with a composition of the present invention is combined with psychotherapy, which may be applied prior to or after treatment. If prior to, the session may focus the patient on the intent of treatment. If after, psychotherapy is preferably performed within 48 hours of the dosing session to help the patient integrate any feelings, emotions, visions or thoughts that may have occurred during the session, as well as to allow the psychotherapist to offer advice on how best to change thinking or behavior patterns so as to improve anti-depression outcomes, as appropriate. Psychotherapy may continue as needed after the dosing session, for example, up to an additional 3 months, to help the patient integrate any experiences or learnings that occurred to the patient during the dosing session.EXAMPLES

[0078] Our testing was done with Lion’s Mane mushroom extract incorporating bufotenin, O-octanoyl bufotenin (OBf), a novel lipidic prodrug of bufotenin, and 5-MeO-DMT that is not regulated as a controlled substance, but which behaves in formulation in ways that are similar to controlled psychedelics.

[0079] Described herein are studies that were performed to develop a mushroom tincture composition and its method of manufacture for psychedelics. The experimental design provided multiple compositions of different ratios of psychedelics API and different mushroom species. These compositions were initially prepared by grounding up the mushroom material into a powder and mixing the powder with solvent. The mixture is heated and filtered to extract as many bioactives from the fungal material as possible. The filtered solution is then centrifuged and (a) psychedelic(s) is added to the supernatant tincture. The psychedelics incorporated into the mushroom tincture do not experience any significant degradation in the mushroom tincture, except OBf which is susceptible to ester cleavage.

[0080] The tincture-based delivery system produced in our examples show drug stability under physical and temporal duress, where no API degradation was detected over 12 weeks storage at 4 °C in formulation.

[0081] Cytotoxicity assays on human hepatocellular carcinoma cell lines (HepG2) revealed negligible toxicity bioeffective concentrations and much of the cellular toxicity can be derived from the ethanolic organic vehicle rather than the psychedelics.

[0082] For our chosen mushroom species, the following properties were desired: (i) low histamine release to prevent allergic reactions; (ii) thermally stable bioactives, suitable for sterilization and other heating events during creation of the formulation; (iii) lower hemolytic activity; and (iv) inherent biocompatibility.

[0083] The resulting tincture-based delivery system was characterized by high performance liquid chromatography to determine drug stability over time as well as Bradford assay to determine protein content and p-glucan content, a bioactive contained within some mushrooms that possesses a wide range of bioeffective effects. A publication exhibiting the benefits of p-glucans is disclosed within (Bashir and Choi. 2017).The stability of the drug incorporated into the tincture-based delivery system was analyzed temporally, and under different physical environments mimicking commercial production and storage conditions to evaluate its long-term stability. Biological assays were used to evaluate the effect of our tincture-based delivery system on cells. Cytotoxicity was evaluated using normal and cancer cells.

[0084] The TBDDPS of the present invention were prepared by first extraction of the macrofungal material into a tincture-based formulation and incorporating (a) psychedelic(s) within the tincture. The extraction into a mushroom tincture began with an initial solid material mass to the extraction solvent volume ratio of 1 :5. The extraction protocol starts grinding up the mushrooms into a powder and mixing the powder with five times its mass in the solvent volume in a 50 mL amber centrifuge tube. This mixture was then heated in a water bath (Labnique model) set to 35 °C for 1 hour and filtered through four layers of Olicity cheesecloth (Grade 90), then the extracted liquid was centrifuged at 300 rpm for 3 minutes then the supernatant was stored at 4 °C. For sonicated-assisted extraction, the same procedure was adapted using a 2.0 L ultrasonic cleaner (Labnique model), operating at a frequency of 40 kHz, with adjustable heating settings. A measured amount of psychedelic(s) was then added to the supernatant which is the mushroom tincture. This then forms the tincture-based delivery system.

[0085] As Table 1 shows, the incorporated drug(s) remains stable over 12 weeks in a refrigerator stored in translucent vials, except prodrug OBf, which is susceptible to ester cleavage and degrades into bufotenin. Any increase in concentration can be derived from evaporation of ethanol.TABLE 1 - Lion’s Mane tincture-based delivery system drug stabilityExperimental Details - Materials

[0086] All materials were purchased from Sigma Aldrich (St. Louis, MO, USA) unless otherwise stated and used as received. Anhydrous EtOH was used for all experiments. Lion’s Mane, Reishi, and Cordyceps mushroom powder was obtained from Sich Bio-tech Co. LTD (Henan, China). HPLC-grade water (EMD Millipore, Burlington MA, USA) was used in all experiments. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) was purchased from Aaron Chemicals (San Diego, CA, USA). Bufotenin, O-octanoyl bufotenin (OBf), and 5-MeO-DMT was synthesized in the Trant synthetic lab and was used as received. Measurements of pH were conducted using a freshly calibrated, according to the manufacturer’s instructions, pH meter (Milwaukee MW102 PRO+).

[0087] HepG2: liver cancer cells (ATCC) was used for the cytotoxic evaluation of the tested formulation.Preparation of the tincture-based delivery system

[0088] The tincture-based delivery system of the present invention were prepared by first extraction of the macrofungal material into a tincture-based formulation and incorporating (a) psychedelic(s) within the tincture. The extraction into a mushroom tincture began with an initial solid material mass to the extraction solvent volume ratio of 1 :5. The extraction protocol starts grinding up the mushrooms into a powder and mixing the powder with five times its mass in the solvent volume in a 50 mL amber centrifuge tube. This mixture was then heated in a water bath (Labnique model) set to 35 °C for 1 hour and filtered through four layers of Olicity cheesecloth (Grade 90), then the extracted liquid was centrifuged at 300 rpm for 3 minutes then the supernatant was stored at 4 °C. For sonicated-assisted extraction, the same procedure was adapted using a 2.0 L ultrasonic cleaner (Labnique model), operating at a frequency of 40 kHz, with adjustable heating settings. A measured amount of psychedelic(s) was then added to the supernatant which is the mushroom tincture. This then forms the tincture-based delivery system.

[0089] Long-term storage: To examine the effect of long-term storage on the chemical stability of the incorporated psychedelic within the tincture-based delivery system we stored them in tightly translucent vials in a refrigerator at 4 °C. An aliquot is handed off as-is to the Trant analytical lab. Measurements were performed immediately after preparation of the tincture-based delivery system, and after that, once every seven days for up to six weeks.

[0090] Megazyme Assay p-glucan Analysis: The p-d-glucan assay was conducted according to the method outlined by Neogen Corporation and Megazyme (2023), ensuring precise measurement of p-d-glucan content in yeast and mushroom samples. Measurement of Total glucan: Commenced with the treatment of 90 mg of mushroom extract with 2 mL of cold 12 M sulphuric acid, followed by incubation in anice bath for two hours, with vigorous stirring every 20 minutes. Subsequently, the mixture was diluted with 10 mL of distilled water and subjected to a two-hour boiling water bath. The resultant solution was transferred to a 100 mL volumetric flask, neutralized with 6 mL of 8 M NaOH, and brought to volume with 200 mM sodium acetate buffer (pH 4.5). This process was uniformly applied across all samples and controls. A sample aliquot was then transferred to a microcentrifuge tube and was centrifuged at 13,000 rpm for 5 minutes. 100 pL aliquots of the supernatant from centrifuged extract were transferred to a test tube, mixed with 100 pL of enzyme solution from bottle 1 which is a mixture of exo-1 ,3-p-glucanase plus p- glucosidase, to hydrolyze residual glucan fragments into glucose, followed by a 60 minute incubation at 40 °C. During this period, reagent blanks were prepared using 200 pL of 200 mM NaOAc buffer (pH 4.5), and standards were prepared with 100 pL of the same buffer plus 100 pL of D-glucose standard solution. After incubation, 3 mL of GOPOD reagent was added to each tube, including standards, blanks, and samples, and further incubated for 20 minutes at 40 °C before measuring absorbance at 510 nm against the reagent blank. Measurement of a-glucan: 100 mg of the sample were dissolved in 2 mL of 1.7 M NaOH and placed in an ice water bath for 20 minutes to dissolve phytoglycogen / starch, with subsequent stirring. This was followed by the addition of 8 mL of 1.2 M NaOAc buffer (pH 3.8) to each tube, and immediately thereafter, 0.2 mL of p-Glucan Kit Bottle 2: enzyme: Amyloglucoside plus invertase from Megazyme Kit was introduced. After a 30 minute incubation at 40 °C, the mixture was transferred to a 100 mL volumetric flask and volume adjusted with distilled water. Post centrifugation at 13,000 rpm for 10 minutes, 100 pL of the supernatant was combined with 100 pL of 200 mM NaOAc buffer (pH 4.5) in test tubes, followed by the addition of 3 mL of GOPOD reagent. The mixture was then incubated at 40 °C for 20 minutes, with absorbance readings taken at 510 nm.Standards and reagent blanks previously prepared for total glucan analysis were also employed for a-glucan analysis.

[0091] Bradford Assay (Protein Analysis): The Bradford assay, using the BioRad Quick Start Bradford assay kit, was conducted to determine protein concentrations. Blank Preparation: A critical step for accurate measurements involves adding 10 pL of ethanol or water (matching the sample’s solvent) into a cuvette, followed by 990 pL of Bradford Reagent x1. The blank was used to calibrate the spectrophotometer to zero absorbance. Standard Curve Generation: BovineSerum Albumin (BSA) was used to create a standard curve, with concentrations ranging from 0.078125 to 5 mg / mL. Each standard involved mixing 10 pL of BSA with 990 pL of Bradford Reagent in a 3 mL cuvette. Absorbance was measured at 595 nm. Sample Analysis: Protein concentration in mushroom extracts was analyzed by preparing a mixture of 10 pL extract and 990 pL Bradford Reagent x1. This was placed in a 3 mL cuvette, and absorbance read at 595 nm. Protein concentration was determined by interpolating the absorbance value against the standard curve.

[0092] Bufotenin extraction procedure: 50 - 100 mg of samples were weighed individually into 15 mL falcon tubes and 5 mL methanol (HPLC grade) were added to the samples. Samples were vortexed for 10 seconds and placed in an ultrasonic bath for 15 min at room temperature. After the sonication, sample was spun at 400x g for 5 min in a centrifuge (Avantor). Aliquots of resultant clear supernatant were used for HPLC analysis.

[0093] Bufotenin sample acquisition and data analysis: Chromatographic analysis of supernatants from sample extraction was performed using an Agilent 1260 Liquid Chromatography system fitted with a photodiode array detector and using an Agilent Zorbax SB-C18 column (4.6 x 150 mm, 5 pm). For data acquisition, the following gradient run was applied using a mobile phase combination of methanol / 0.01% phosphoric acid and water: 50% CH3CN for 0 - 4 mins, 90% CH3CN for 5 - 12 mins, and 50 % CH3CN for 13 - 16 mins. The flow rate of mobile phase was set at 0.5 mL-min-1, with an injection volume of 5 pL for the sample. OBf was detected at a wavelength of 282 nm, with column compartment set to 45 °C. Mobile phase solvents were of HPLC grade and filtered with 0.20 pm filters before analysis. Standard dilutions of OBf range from 1.0165 mL-min-1to 0.01065 mL-min-1were run alongside sample extracts and standard peak areas with their corresponding concentration used to plot a calibration curve for calculating the concentration of OBf in the samples.

[0094] OBf extraction procedure: 50 - 100 mg of samples were weighed individually into 15 mL falcon tubes and 5 mL methanol (HPLC grade) were added to the samples. Samples were vortexed for 10 seconds and placed in an ultrasonic bath for 15 min at room temperature. After the sonication, sample was spun at 400x g for 5 min in a centrifuge (Avantor). Aliquots of resultant clear supernatant were used for HPLC analysis.

[0095] OBf sample acquisition and data analysis: Chromatographic analysis of supernatants from sample extraction was performed using an Agilent 1260 Liquid Chromatography system fitted with a photodiode array detector and using an Agilent Zorbax SB-C18 column (4.6 x 150 mm, 5 pm). For data acquisition, the following gradient run was applied using a mobile phase combination of methanol / 0.01% phosphoric acid and water: 50% CHaCN for 0 - 4 mins, 90% CHaCN for 5 - 12 mins, and 50 % CHaCN for 13 - 16 mins. The flow rate of mobile phase was set at 0.5 mL-min-1, with an injection volume of 5 pL for the sample. OBf was detected at a wavelength of 282 nm, with column compartment set to 45 °C. Mobile phase solvents were of HPLC grade and filtered with 0.20 pm filters before analysis.Standard dilutions of OBf range from 1.0165 mL-min-1to 0.01065 mL-min-1were run alongside sample extracts and standard peak areas with their corresponding concentration used to plot a calibration curve for calculating the concentration of OBf in the samples.

[0096] 5-MeO-DMT extraction procedure: 50 - 100 mg of samples were weighed individually into 15 mL falcon tubes and 5 mL methanol (HPLC grade) were added to the samples. Samples were vortexed for 10 seconds and placed in an ultrasonic bath for 15 min at room temperature. After the sonication, sample was spun at 400x g for 5 min in a centrifuge (Avantor). Aliquots of resultant clear supernatant were used for HPLC analysis.

[0097] 5-MeO-DMT sample acquisition and data analysis: Chromatographic analysis of supernatants from sample extraction was performed using an Agilent 1260 Liquid Chromatography system fitted with a photodiode array detector and using an Agilent Zorbax SB-C18 column (4.6 x 150 mm, 5 pm). For data acquisition, the following gradient run was applied using a mobile phase combination of methanol / 0.01% phosphoric acid and water: 50% CHaCN for 0 - 4 mins, 90% CHaCN for 5 - 12 mins, and 50 % CHaCN for 13 - 16 mins. The flow rate of mobile phase was set at 0.5 mL-min-1, with an injection volume of 5 pL for the sample. OBf was detected at a wavelength of 282 nm, with column compartment set to 45 °C. Mobile phase solvents were of HPLC grade and filtered with 0.20 pm filters before analysis. Standard dilutions of OBf range from 1.0165 mL-min-1to 0.01065 mL-min-1were run alongside sample extracts and standard peak areas with their corresponding concentration used to plot a calibration curve for calculating the concentration of OBf in the samples.

[0098] Cell culture: The human hepatocellular cell line HepG2 was cultured in Dulbecco's Modified Eagle's Medium (DMEM, Sigma-Aldrich) supplemented with 10% FBS (Gibco) and 1% penicillin / streptomycin (Sigma-Aldrich) at 37 °C in an incubator humidified with 5% CO2 atmosphere. HepG2 cells lines are adherent and were subcultured twice per week at 70-80% confluency using standard concentrations of trypsin-EDTA (ethylenediaminetetraacetic acid).

[0099] Cell viability was assessed using the MTT, a widely used colorimetric method for evaluating cytotoxicity. MTT is a water-soluble tetrazolium salt that is reduced by mitochondrial dehydrogenase enzymes in metabolically active (viable) cells to form insoluble purple formazan crystals. The amount of formazan produced is directly proportional to the number of living cells. HepG2 cells were seeded into 96-well plates at densities of 6x103cells per well, respectively, and incubated for 24 h at 37 °C allowing them to adhere and proliferate. Negative control and blank wells were included in all experiments. The negative control consisted of untreated cells cultured in complete medium, while blank wells contained culture medium without cells to account for background absorbance. The culture medium was then replaced with 100 pL of fresh medium containing various concentrations of niosome (100, 50, 25, 10, 5, and 1 pM), and the cells were incubated for an additional 24 h. Following treatment, the medium was carefully aspirated and 100 pL of MTT solution (1 mg / mL) was added to each well. The plates were incubated for 4 h at 37 °C in a humidified atmosphere containing 5% CO2. After incubation, the MTT solution was removed, and the resulting formazan crystals were dissolved in 100 pL of dimethyl sulfoxide per well. The absorbance was measured at 570 nm using a microplate reader (SpectraMax M5e, Molecular Devices, USA). Cell viability (%) was calculated relative to untreated control cells using the following formula (OD = optical density):

[0100] Unless otherwise indicated, all experiments were performed in triplicate, data is represented as means ± standard deviation and the data was analyzed using either MS Excel or Origin Pro 8.5 graphing software (MA, USA). For the stress tests, three replicate studies were performed, and either the average of the measured values used, or both values plotted on the relevant graph.Patent Citations

[0101] W02012007868A2, 2012-01-19, Pfizer Ltd Great Britain, Chemical compounds.

[0102] W02023108260A1 , 2023-06-22, Reunion Neuroscience Canada Inc., Tryptamine prodrugs.

[0103] W02020181194A1, 2020-09-10, University of Padova, Compositions and methods of use comprising substances with neural plasticity actions administered at non-psychedelic / psychotomimetic dosages and formulations.

[0104] WO1991011172A1, 1991-08-08, University of Kansas, Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof.Non-Patent Citations

[0105] Adeyinka D, Forsyth D, Currie S, Faraone N. Neurobiology of psilocybin: a comprehensive overview and comparative analysis of experimental models. Front Syst Neurosci. 2025 Aug 5;19:1585367. doi: 10.3389 / fnsys.2025.1585367. PMID: 40894380; PMCID: PMC12392120.

[0106] Ali SS, Alsharbaty MHM, Al-Tohamy R, Naji GA, Elsamahy T, Mahmoud YA, Kornaros M, Sun J. A review of the fungal polysaccharides as natural biopolymers: Current applications and future perspective. Int J Biol Macromol. 2024 Jul;273(Pt 2):132986. doi: 10.1016 / j.ijbiomac.2024.132986. Epub 2024 Jun 10.PMID: 38866286.

[0107] Bashir KMI, Choi JS. Clinical and Physiological Perspectives of p-Glucans: The Past, Present, and Future. Int J Mol Sci. 2017 Sep 5;18(9):1906. doi: 10.3390 / ijms18091906. PMID: 28872611; PMCID: PMC5618555.

[0108] Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-Ramos J. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res. 2013 Aug;228(4):481-91. doi: 10.1007 / s00221 -013-3579-0. Epub 2013 Jun 2. PMID: 23727882.

[0109] Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021 May 1 ;78(5):481-489. doi: 10.1001 / jamapsychiatry.2020.3285. Erratum in: JAMA Psychiatry. 2021 Feb 10;78(5):569. doi: 10.1001 / jamapsychiatry.2020.4714. PMID: 33146667; PMCID: PMC7643046.

[0110] Passie T, Seifert J, Schneider U, Emrich HM. The pharmacology of psilocybin. Addict Biol. 2002 Oct;7(4):357-64. doi: 10.1080 / 1355621021000005937. PMID: 14578010.

[0111] Phan CW, David P, Sabaratnam V. Edible and Medicinal Mushrooms: Emerging Brain Food for the Mitigation of Neurodegenerative Diseases. J Med Food.2017 Jan;20(1):1-10. doi: 10.1089 / jmf.2016.3740. PMID: 28098514.

[0112] Reckweg JT, van Leeuwen CJ, Henquet C, van Amelsvoort T, Theunissen EL, Mason NL, Paci R, Terwey TH, Ramaekers JG. A phase 1 / 2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression. Front Psychiatry. 2023 Jun 20;14:1133414. doi: 10.3389 / fpsyt.2023.1133414. PMID:37409159; PMCID: PMC10319409.

[0113] Rucker JJ, Roberts C, Seynaeve M, Young AH, Suttle B, Yamamoto T, Ermakova AO, Dunbar F, Wiegand F. Phase 1 , placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants. J PsychopharmacoL 2024 Aug;38(8):712-723. doi:10.1177 / 02698811241246857. Epub 2024 Apr 14. PMID: 38616411 ; PMCID:PMC11311898.

[0114] Thomann J, Kolaczynska KE, Stoeckmann OV, Rudin D, Vizeli P, Hoener MC, Pryce CR, Vollenweider FX, Liechti ME, Duthaler U. In vitro and invivo metabolism of psilocybin's active metabolite psilocin. Front Pharmacol. 2024 Apr 29;15:1391689. doi: 10.3389 / fphar.2024.1391689. PMID: 38741590; PMCID:PMC11089204.

[0115] Sun X, Shi Y, Shi D, Tu Y, Liu L. Biological Activities of Secondary Metabolites from the Edible-Medicinal Macrofungi. J Fungi (Basel). 2024 Feb 11 ;10(2) : 144. doi: 10.3390 / jof 10020144. PMID: 38392816; PMCID: PMC10890728.

Claims

CLAIMS1. A mushroom-derived tincture composition that comprises: (a) an extraction product obtained by extracting a psychedelic or non-psychedelic mushroom material with ethanol, (b) a biocompatible solvent with said extraction product, (c) at least one psychedelic drug.

2. A composition as in claim 1 wherein said mushroom material comprises non-psychedelic mushroom species.

3. A composition as in claim 2 wherein said mushroom species comprises Hericium erinaceus.

4. A composition as in claim 1 wherein said biocompatible solvent comprises ethanol.

5. A composition according to claim 1 wherein said psychedelic drug comprise 5-MeO-DMT, 4-MeO-DMT, 4-AcO-DMT (4-acetoxy-dimethyltrypamine, LSD, psilocybin, psilocin, mescaline, ibogaine, octanoyl bufotenin, and / or bufotenin.

6. A composition according to claim 5 wherein said psychedelic drug comprises bufotenin, ibogaine, octanoyl bufotenin, or 5-MeO-DMT.

7. A composition according to claim 6 wherein said psychedelic drug comprises a mixture of bufotenin, octanoyl bufotenin, and 5-MeO-DMT.

8. A composition according to claim 1 in a liquid form and having a concentration of psychedelic drugs in an amount within a range from about 0.1-1000 mg / mL.

9. A composition according to claim 8 comprising a concentration of psychedelic drugs in an amount within the range of 1-100 mg / mL.

10. A mushroom-derived tincture composition that comprises: (a) an extraction product obtained by extracting a mushroom material with ethanol, (b) a biocompatible solvent with said extraction product, (c) at least one psychedelic drug in a bioeffective amount that is in an amount or character that is different than that obtained directly from said mushroom material.

11. A composition according to claim 10 wherein said at least one psychedelic drug is present in said composition in an amount within the range of 1 -80 wt% based on total weight of said composition.

12. A composition according to claim 10 wherein said at least one psychedelic drug is present in said composition in an amount within the range of 15-30 wt% based on total weight of the composition.

13. A composition according to claim 10, wherein when used in a liquid form, said at least one psychedelic drug is present is an amount within a range from 0.1 - 1000 mg / mL.

14. A composition according to claim 10, wherein when used in a liquid form, said at least one psychedelic drug is present is an amount within a range of 0.5 - 500 mg / mL.

15. A composition according to claim 10, wherein when used in a liquid form, said at least one psychedelic drug is present is an amount within a range of 1 -100 mg / mL.

16. A composition according to claim 10 wherein said psychedelic drug comprises bufotenin, ibogaine, octanoyl bufotenin, or 5-MeO-DMT.

17. A composition according to claim 10 wherein said psychedelic drug comprises a mixture of bufotenin, octanoyl bufotenin, and 5-MeO-DMT.

18. A process for the manufacture of the tincture-based delivery systems of the present invention by a process that comprises: (a) combining a mushroom-based extract that was obtained by contacting a source mushroom material with ethanol under extraction conditions, and (b) and adding to said extract a bioeffective amount of one or more psychedelic drugs in a bioeffective amount that is in an amount or character that is different than that obtained directly from said mushroom material.

Images