Plant protein-green tea polyphenol conjugates as emulsifiers

Abstract

Disclosed is a process for the assembly of protein-polyphenol conjugate stabilized nanoemulsions (PPCSNEs) by a process that comprises: (a) combining (i) a first surfactant comprised of a pre-synthesized composite species made up of a biocompatible protein and polyphenolic species, (ii) a therapeutic amount of one or more psychedelic APIs, (iii) a triglyceride oil, and optionally (iv) a co- surfactant in a container, (b) high-shear mixing said ingredients in a container to form a coarse-emulsion product, and (c) subjecting the coarse-emulsion through a microfluidic device to produce a protein-polyphenol conjugate nanoemulsion containing a psychedelic agent.

Description

PLANT PROTEIN-GREEN TEA POLYPHENOLCONJUGATES AS EMULSIFIERSThis application is related to U.S. Provisional patent application Ser. No. 63 / 550,914 that was filed on 7 Feb. 2024 and whose disclosure is incorporated herein by reference.Field of the Invention

[0001] The invention relates to formulations of psychedelic compounds including tryptamine-scaffold and phenethylamine-scaffold psychedelic agents that are useful for therapy and / or nutrition and methods for their manufacture.Background of the Invention

[0002] Many people worldwide are afflicted with psychological or mood disorders, such as depression, anxiety, compulsion, 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.

[0003] 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 neurotransmitters, 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 serotonin pathways.

[0004] A composition including psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) or psilocin (4-hydroxy-N,N-dimethyltryptamine) in pure form or extracts from Psilocybe and psilocybin containing mushrooms combined with erinacines or hericenones, or extracts from Hericium mushroom species, and niacin (nicotinic acid or 3-pyridinecarboxylic acid, also known as vitamin B3), uniquely aids in repairing and improving neurologic functioning and signaling, Schartner et al. (2017) reported substantial increased global neural signal diversity in a psilocybin-human clinical study (Nature Scientific Reports, 7:46421). Additionally, niacin is known to be a neural anti-inflammatory, and, in itself, has been implicated in improving neural functioning. As niacin activates nerve endings, the inventor suggests that the addition of niacin contributes an added benefit by enhancing the neurogenic effects ofpsilocybin, psilocin, erinacines and hericenones by helping these nootropics cross the blood brain barrier, and migrate throughout the nervous systems, and to its end points. Moreover, niacin is a vasodilator that improves blood flow in the brain by relaxing constricted blood vessels. This unique combination not only rebuilds myelin upon the axons, it also activates new astrocyte / astroglial cells and neuronal nodes of crossings such as the synaptic regi ons, particularly in the hippocampus. Other medicinal mushroom species also can be added, particularly species oiAntrodia, Beauvena, Copelandia, Cordyceps, Ganoderma, Grifola, Inonotus, Isaria, Panaeohis, Phellinus, and other medicinal mushrooms and their mycelia who’s unique neurogenerative properties may add benefits to this basic formulation. An excellent summary of the prior art related to the use of mushrooms as "brain foods" can be found in Phan et al. (2017), "Edible and Medicinal Mushrooms: Emerging Brain Food for the Mitigation of Neurodegenerative Diseases," Journal of Medicinal Foods 20(1): 1-10. Lion’s Mane (Hericium erinaceus), Bear's Head (H. coralloides), or CombTooth (H. ramosum) mushrooms and mycelium have also been well studied and reported to regenerate myelin on the axons of nerves. Two particular families of compositions are most noteworthy: erinacines and hericenones. Erinacines, including known erinacines A-K, P and Q, are cyanthane terpenes isolated from the mycelia of Hericium erinaceus that promote NGF (nerve growth factor) synthesis. Hericenones, including known hericenones C-H, are cyanthane terpenes located in both the mycelia and fruiting body of Hericium erinaceus that promote NGF synthesis. Friedman et al. (2015) summarizes these activities in "Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion's Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive Compositions, " Journal of Agricultural and Food Chemistry 63: 7108-7123.

[0005] Although Phan et al. describes many species with potential neurogenerative properties, the psilocybin or psilocybian species (i.e., "psilocybin-conlaining") are not mentioned, either alone or in combinations with the edible and medicinal mushroom species described by Phan. A good summary of the role of psilocybin in humans can be found in Passie et al. (2002), "The Pharmacology of Psilocybin," Addiction Biology T. 357-364. That psilocybin has neurogenerative properties was elucidated by Catlow et al. (2013), "Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning," Experimental Brain Research 228: 481-491. See also US Publication Number 2022 / 0313367. The disclosures of these publications are hereby incorporated by reference.

[0006] Both the medical establishment and conventional wisdom define compounds having a psychedelic effect when consumed by a human (including those in the tryptamine and phenethylamine family, and including substances classified as 5-HT2Aagonists) 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 therapeutic uses in psychiatry and research applications for the study of brain function. In the case of most known psychedelic substances (e.g. tryptamine-scaffold- or phenethylamine- scaffold-based drugs), these psychedelic / psychotomimetic effects are thought to be primarily induced by agonist actions at the 5-HT2A receptor in the 5-HT receptor family.

[0007] Psychedelic substances are presently under investigation for the treatment of several psychiatric diseases and symptoms, including depression, PTSD, OCD, addiction, end-stage-cancer-associated anxiety. The psychedelic experience, which includes positive and negative psychotomimetic effects induced by a serotonin agonist, is an integral part of the intended treatment. For therapeutic purposes, serotonin agonist 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 serotonin agonist 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 therapeutic 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 therapeutic efficacy of psychedelic drugs. See US Publication No. 2022 / 0143051 'which is hereby incorporated by reference.

[0008] The development of tryptamine-scaffold psychedelic agent pharmaceuticals and nutraceuticals face challenges because vital active product ingredients (APIs) that are typically derived from such mushrooms are difficult to administer reliably by direct ingestion. Even when "magic mushrooms" 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 doseusing mushrooms is not reliable because of the variability in the chemical composition of mushrooms even in the same species.

[0009] Some of the major challenges to be overcome to create stable, robust, reproducible, and biologically active products include:

[0010] a. Lipophilicity and low water solubility of API,

[0011] b. Limited bioaccessibility of API,

[0012] c. Extensive degradation of API during formulation, storage, or in vivo owing to metabolic pathways, and

[0013] d. Inability of the API to cross the blood-brain barrier if psychoactivity is to be demonstrated.

[0014] It would be desirable to have a composition and method for administering drugs such as psilocin and / or psylocibin that would provide a consistent, therapeutically useful dose.

[0015] Psychedelic active pharmaceutical ingredients (APIs), such as psilocybin, mescaline, psilocin, ibogaine and bufotenin, are being studied 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 serum-soluble tryptamine scaffold 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.

[0016] 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.

[0017] Seeds of the Anadenanthera colitbrina 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 within4-5 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 therapeutic treatment of MDD, SUD, and various neurodegenerative disorders.

[0018] Currently, it is statistically significant that people who are prescribed anti- depressants are subjected to difficult and sometimes debilitating side effects that affect their daily lives. Depression is one of tire largest epidemics in the world, which suggests that other classes of therapeutics must be investigated to provide effective therapies for its treatment. This has led to renewed interest in cannabis and entheogen research.

[0019] The fundamental idea behind the current work is a "Trojan Horse" delivery system that uses some type of encapsulating technology to overcome the variable solubility profiles, bio-accessibility, and susceptibility" to enzymatic and oxidative degradation of psilocin APIs. Such encapsulating delivery systems carry' the API payload to intracellular destinations that are otherwise inaccessible to the unformulated APIs.

[0020] There are very few examples of formulations of psychedelics APIs in the literature. However, these formulations could readily be consumed in a clinical setting or as a prescription medication without the need for special storage or in situ formulation by a chemist.

[0021] It would be desirable to have an effective formulation for the delivery psychedelics (such as psilocybin, psilocin, ibogaine, mescaline and bufotenine) that would be bioavailable and bioeffective in therapeutically effective doses.

[0022] Most formulation approaches to improve bioavailability of water insoluble, highly lipophilic drugs ar e based on either particle size reduction technologies (e.g. micronization or nano-particle generation) to increase drug dissolution rate and / or achieve transient solubilization, or technologies to achieve a sustained solubilization of the drug, such as complexation, or use of lipid-based delivery systems. The particle size reduction technologies often fail to overcome bioavailability l-mitations. See U.S. Pat. No. 11,617,758.

[0023] A widely utilized approach to achieve sustained solubilization and overcome poor fasted state bioavailability of lipophilic drugs is to utilize solutions in lipid vehicles containing surfactants that constitute.

[0024] Recent clinical trials using forms of 5-MeO-DMT have been on-going. A vaporizable form of 5-MeO-DMT (GH Research PLC. Dublin, Ireland) “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, 20, 14,1133414.; 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) “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-niethoxy-N,N- dimethyltiyptamine benzoate) in healthy participants” J Psychopharmacol 2024, 38 (8):712- 723; 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 due to 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.

[0025] Protein-polyphenol conjugate stabilized nanoemulsions (PPCSNEs) produce opaque, brown emulsions with lipid droplet sizes of ≤200 nm.

[0026] These emulsions are isotropic mixtures of (a) at least one drug, (b) an organic vehicle, (c) pre-synthesized composite species made up of a biocompatible protein and polyphenolic species, and optionally (d) a co-surfactant. These formulations rapidly form relatively stable oil-in-water (o / w) emulsions after being subjected to microfluidic processing where the drug is contained in nanometer-size droplets.

[0027] Microfluidic process typically fonns a nanoemulsion using a continuous turbulent flow at high pressure. A uniform nanoemulsion can be generated from a premix using a single pass exposure (i.e., for example, within a thirty (30) second lime frame) or in multiple passes. A uniform nanoemulsion can be generated using a pressure of at least 25,000 PSI. See US Patent No. 10,016,364 the disclosure of which is hereby incorporated by reference.

[0028] PPCSNEs show high drug solubilizing capacity and enhancement in both rate and extent of absorption by the lymphatic uptake. Moreover, it is possible to form blends that are composed of several excipients, such as pure triglycerides or mixtures of mono-, di- and triglycerides.

[0029] Protein-polyphenol conjugates possess dual functionality comprising (a) surface activity to form O / W NEs and, (b) antioxidant activity preventing in situ and in vivo oxidative degradation psychedelic APIs contained within nano-meter sized droplets.

[0030] Orally administrated PPCSNEs widen the accessibility of lipidic excipients with to offer flexibility of function with respec t to improving bioavailability of drugs by manipulatin g their release profiles and protecting them from enzymatic and / or chemical degradation while facilitating their passage in the gastrointestinal tract until their intestinal absorption. PPCSNEs may also demonstrate cell-penetrating properties. PPCSNEs can be manufactured using high- energy micro fluidics.

[0031] It would be desirable to have an effective process to make a stable, effective, protein-polyphenol conjugate stabilized nano-emulsion compositions that could be used with psychedelics.

[0032] It would be further desirable to have a PPCSNEs process to make a composition comprising psychedelics in therapeutically effective concentrations to produce a therapeutically effective composition for the treatment of a human or mammal patient.Summary of the Invention

[0033] It is an object of the invention to provide a composition and method for its administration to a patient having a therapeutic need that would provide a consistent, therapeutically usefid dose of a psychedelic.

[0034] It is also an objective of the invention to provide a composition and method of administration that would deliver a therapeutically effective amount of a psychedelic to patient in need that would provide a bioavailable, bio-effective dose in therapeutically effective dosages.

[0035] It is further an objective of the invention to provide an effective process to make a stable, effective, protein-polyphenol conjugate delivery composition that could be used with psychedelics.

[0036] Additionally, it is an obj ect of the invention to provide a PPCSNEs process to make a composition comprising psychedelics in therapeutically effective concentrations to produce a therapeutically effective composition for the treatment of a human or mammal patient.

[0037] 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 formof an oil-in-water nano-emulsion (“NE”) that comprises: (a) a therapeutic amount of one or more psychedelics (such as the tryptamine-scaffold and / or phenethylamine-scaffold psychedelics), (b) a triglyceride oil, (c) a protein-polyphenol conjugate, (d) an optional co- surfactant.

[0038] The invention also contemplates a process for the manufacture of the PPCSNEs of the present invention by a process that comprises: (a) combining (i) a first surfactant comprised of a pre-synthesized composite species made up of a biocompatible protein and polyphenolic species (ii) a therapeutic amount of one or more psychedelics (iii) a triglyceride oil (iv) an optional co-surfactant in a container, (b) high-shear mixing said ingredients in a container to form a coarse-emulsion product followed by (c) subjecting the coarse-emulsion through a microfluidic device outputting a protein-polyphenol conjugate NE containing a psychedelic API.

[0039] The nano-emulsion form of the present invention provides a stable formulation that is well-suited for delivery of the one or more psychedelics via ingestion thereby providing a familiar and comfortable form of dosing to a patient. The small average droplet size of the nano-emulsion and ability of the active ingredient to cross the blood-brain barrier present unique opportunities for compositions that can deliver therapeutic benefits without the limitations encountered by prior efforts.Detailed Description of the Invention

[0040] Disclosed herein is a design of a stable, protein-polyphenol conjugate nanoemulsion, drug delivery system exhibiting nano-meter sized droplets containing (a) one or more psychedelic agents in the emulsified droplets. Each of these is a hydrophilic or lipophilic drag that is variably soluble in serum and well suited for PPCSNEs delivery. Preferred tryptamine and / or phenethylamine-scaffold psychedelic agents comprise psilocybin, 5-MeO- DMT, DMT, psilocin, mescaline, ibogaine, and / or bufotenine in an amount within the range of 1-80 wt%, preferably 15-30 wt% based on total weight of the PPC SNEs. When used in a liquid form, a suitable amount of the psychedelic agents 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.

[0041] The composition of the present invention also includes (b) an organic vehicle, (c) pre-synthesized composite species made up of a biocompatible protein and polyphenolic species, and optionally (d) a co-surfactant.

[0042] Suitable organic vehicles include medium-chain and long-chain triglyceride oils. The triglyceride oil is generally used in an amount within the range from about 1 -50 wt%, preferably an amount within the range of 10-40 wt%, and even more preferably an amount within the range of 20-35 wt% based on total PPCSNEs weight.

[0043] Suitable pre-synthesized composite species made up of a biocompatible protein and / or polyphenol species derived from biological systems. Exemplary materials include dietary polyphenols, a group of secondary metabolites which widely occur in fruits, vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. They are often derivatives and / or isomers of flavones, isoflavones, flavonols, catechins and phenolic acids, and possess diverse biological properties such as antioxidant, antiapoptosis, anti-aging, anticarcinogen, anti-inflammation, anti-atherosclerosis, cardiovascular protection, improvement of the endothelial function, as well as inhibition of angiogenesis and cell proliferation activity.

[0044] Dietary polyphenols are the most abundant antioxidants in human diets. With over 8,000 structur al variants, they are secondary metabolites of plants and denote many substances with aromatic ring(s) bearing one or more hydroxyl moieties. They are subdivided into groups by the number of phenolic rings and of the structural elements that link these rings, e.g.r (1) phenolic acids with the subclasses derived from hydroxybenzoic acids such as gallic acid and from hydroxycinnamic acid, containing caffeic, ferulic, and coumaric acid; (2) large flavonoids which include the flavonols, flavones, isoflavones, flavanones, anthocyanidins, and flavanols; (3) stilbenes; and (4) lignans and the polymeric lignins. The two main classes of polyphenol are flavonoids (isoflavones, quercetins, cyanidins, and catechins) and phenolic acids (caffeic and ferulic acids).

[0045] The most abundant flavonoids in the typical diet are flavanols (catechins plus proanthocyanidins), anthocyanins and their oxidation products. The main polyphenol dietary sources are fruit and beverages (fruit juice, wine, tea, coffee, chocolate and beer) and, to a lesser extent, vegetables, dry legumes and cereals.

[0046] Suitable co-surfactant is generally a hydrophilic surfactant that is selected from p- isononylphenoxypoly glycidol, PEG laurate, one or more of the polyoxyethylene sorbitan monooleates (e.g., Tween 20, Tween 40, Tween 60, Tween 80), PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl- 10 laurate, plyglyceryl- 10 oleate, polyglyceryl- 10 myristate, poly glyceryl- 10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl — Dglucopyranoside, n-decyl— D-maltopyranoside, n-dodecyl—D-glucopyranoside, n-dodecyl- —D-maltoside, heptanoylN- methylglucamide, n-heptyl — D-glucopyranoside, n-heptyl — -D- thioglucoside, n-hexyl — D-glucopyranoside, nonanoyl-N-methylglucamide, n-noyl — D- glucopyranoside, octanoy 1-N-methy Iglucamide, n-octy 1 - D-glucopyranoside, octyl — D- thioglucopyranoside; cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoic anhydride, ascorbic acid, 2-pyrrolidone-5- carboxylic acid, sodium pyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cycoihiairime, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B 12, vitamin KS. vitamin K6, vitamin K6, and vitamin U; albumin, immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins, a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, benzalkonium chloride, benzethonium chloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium: chloride, and dialkylesters of sodium sulfonsuccinic acid, L- ascorbic acid and its salt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4- hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol, xylitol, cyclodextrin, (2- hydroxypropylj-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, salts ofany organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra( ethylene glycol), penta(ethylene glycol), poly(ethylene glycol) oligomers, difpropylene glycol), tri(propylene glycol), tetra(propylene glycol, and penta(propylene glycol), polypropylene glycol) oligomers, a block copolymer of polyethylene glycol and polypropylene glycol, and derivatives and combinations thereof. An especially preferred lipophilic surfactant is polyoxyethylene (80) sorbitan monooleate.

[0047] A preferred pre-synthesized composite species made up of a biocompatible protein and polyphenolic species surfactant comprises commercially available hemp protein covalently or non-covalently linked to green tea polyphenols. The linkage to green tea polyphenols protects compounds and biological membranes from oxidation. This is due to reactions with lipid radicals produced in the lipid peroxidation chain reaction or through a fat when its lipid content undergoes oxidation by reacting with more-reactive lipid radicals to form more stable products. Hemp protein can be purchased from Manitoba Harvest Hemp Foods (Tilray, New York, NY, USA) and green tea polyphenols can be purchased from Creative Enzymes (Upton, NY, USA).

[0048] The total amounts of pre-synthesized composite species made up of a biocompatible protein and polyphenolic species surfactant and optional co-surfactant, combined, are generally within a range from about 1-50preferably an amount within the range of 10-40 wt%, and more preferably an amount within the range from about 15-35 wt% of the total PPCSNEs weight,

[0049] Tire general method of treatment comprises administering to a human or mammal subject in need thereof a therapeutically-effective amount of an acceptable psychedelic in one or more pharmaceutically acceptable carriers or excipients.

[0050] The administered composition is formulated for oral, sublingual, intranasal, pulmonary administration, buccal, sublingual, rectal, transdermal, transmucosal, epidural, intrathecal, intraocular topical, creams, lotions, gels and eye drops 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 liquid PPCSNEs into a patient’s mouth.

[0051] In another aspect, the invention comprises a method of treating a mental disorder, comprising 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 bipolardepressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0052] The invention provides for the treatment and / or prevention of psychiatric disorders, and / or neurological disorders, and / or degenerative disorders, and / or 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.

[0053] 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. Tn 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 with the 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 NMD AR 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 spectrumdisorders, 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, insomnia, disturbed sleep patern; 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.

[0054] The term "degenerative disorders" refers to one or more disorders selected from the following degenerative disorders, neurodegenerative diseases of the 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.

[0055] The term "inflammatory disorders" refers to one or more disorders selected from lire 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, neuro-inflammation, metabolic syndrome, impaired glucose tolerance, non-alcoholic fatly liver disease (NAFLD), (NAFL) and their complications, non-alcoholic steatohepatitis (NASH) and conjunctivitis.

[0056] The general method of treatment comprises administering to a human or mammal subject in need thereof a therapeutically effective amount of an acceptable psychedelic analogue in one or more pharmaceutically acceptable carriers or excipients.

[0057] 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.

[0058] 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), LSD, mescaline or psilocybin. Other known psychedelic drags include but are not limited to, 4-hydroxy analogs of .N-methyl-N-isopropyltryptamine (MiPT) and WA’-diisopropyhryptamine (DiPT).

[0059] The term "psychiatric disorders" refers to one or more disorders selected from the following psychiatric disease as defined as defined by DMS5 and ICD11 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, compulsive sexual behavior disorder, impulse-control, and conduct disorders, substance related and addictive disorders, panic disorder, 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, neurocognitive disorders, personality disorders, paraphilic disorders and for the reduction of suicidal ideation in a patient suffering from a life-threatening disease.Formulations and Compositions

[0060] The invention also provides pharmaceutically acceptable compositions which comprise a therapeutically effective 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 therapeutic 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.

[0061] The term "pharmaceutical composition" means a composition comprising a composition of the invention in combination with at least one additional pharmaceutically acceptable carrier.

[0062] 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, i.e., adjuvant, excipient or vehicle, 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.

[0063] 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.

[0064] The dosage regimen for the compositions described herein will, of course, vary depending upon known factors, such as the pharmacokinetic and pharmacodynamic chara cteri stics 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 ofexcretion 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.

[0065] 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.

[0066] 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 anti-depressant effect that may extend for 1, 2, 3 or 6 months, or more.

[0067] 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.

[0068] 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, microcrystaliine 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.

[0069] 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 (monohydrale, spray dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0070] 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.

[0071] 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.

[0072] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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 nano-emulsion is substantially consistent from dose to dose.

[0078] 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.

[0079] Drug cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion 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 / 11 172, WO 94 / 02518 and WO 98 / 55148, the disclosures of which are incorporated herein by reference in their entireties.

[0080] 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 those of 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 therapeutic response for a particular patient, composition, and mode of administration.

[0081] 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 therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0082] 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 therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0083] As used herein, a "therapeutically effective 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 therapeutically effective 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 DepressionRating Scale (GRIDHAMD). A therapeutically effective amount may be less than that required for a psychedelic state.

[0084] 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 therapeutic 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.Therapeutic Methods and Uses

[0085] Treatment with the drug / prodrug 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 of depression. 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 .). Without restriction to a theory, it is believed that the psychedelic state is associated with the beneficial effects, ho wever, some compositions which are 5HT2AR agonists may provide the desired therapeutic effect without the psychedelic state. One aspect of the invention comprises prodrugs of those 5HT2AR agonists which do provide a beneficial therapeutic state

[0086] 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 5HT2AR agonist, or the use of a composition of the present invention herein to manufacture a medication to trea t any disease or disorder which may be alleviated by a 5HT2AR agonist, or a method of treating any disease or disorder which may be alleviated by a 5HT2AR agonist. The present invention is also suitable treating diseases or disorders that are related to 5HT2AR agonists.

[0087] In some embodiments, the invention may comprise the use of the compos itions 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: 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 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.

[0088] In some embodiments, the invention may comprise a method of treating mental disorders comprising administering to a subject in need thereof a therapeutically effective 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 need thereof therapeutically effective amount of a composition of the present invention. The depression effects may be drug-resistant depression or major depressive disorder.

[0089] 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. Wlien 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.

[0090] To further alleviate any anxiety that may occur relative to therapy, the physician may prefer to divide the therapeutic dose and thereby reduce the initial onset of psychoactivity before applying the full complement of the dosage to achieve the full effect.

[0091] 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. Psychotherapy may continue asneeded 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

[0092] Our testing was done with 5-methoxy-dimethyltryptamine (5-MeO-DMT). an analogue of psilocin that is not regulated as a controlled substance, but which behaves in formulation in ways that are similar to controlled tryptamine-scaffold psychedelic drugs.

[0093] Described herein are studies that were performed to develop an encapsulating nano-emulsion composition and its method of manufacture psychedelic agents. The experimental design provided multiple compositions of different ratios of oil, protein- polyphenol conjugate, and cosurfactant, of which two compositions were identified that exhibited unusually good performance metrics. These compositions were initially prepared by synthesizing the hemp protein - polyphenol conjugate through covalent (HP-GTPcov), and non- covalent ( HP-GTPnoncov) linkage. The thus created nanoemulsions are prepared by high-shear mixing HP-GTPcovor HP-GTPnoncovpre-dissolved in waler with a co-surfactant and adding to the container hemp oil that possesses 5-MeO-DMT pre-dissolved to create a coarse emulsion. The nano-emulsions are then created by high-pressure homogenization of the coarse emulsion post high-shear mixing. The two created emulsions are known as covalent conjugate emulsion (CCE) and non-covalent conjugate emulsion (NCCE) possess augmented properties with respect to each other. The CCE and NCCE showed enhanced colloidal stability under physical and chemical stressors, as well as upon storage. Formulated 5-MeO-DMT showed higher chemical stability when compared to a solution of pure 5-MeO-DMT dissolved in ethanol in the presence of stressors. The believed process for covalent or non-covalent linkage of the protein polyphenol is shown below:

[0094] Accelerated oxidation stress tests were performed to confirm the augmented stability of the nano-formulated 5-MeO-DMT within the nano-emulsions (NEs). Flow cytometry, fluorescence imaging, and high-performance liquid chromatography established decidedly that cellular uptake of formulated 5-MeO-DMT is order of magnitude higher than that of 5-MeO-DMT dissolved in biological buffers.

[0095] The emulsions produced in our examples show enhanced stability under physical and chemical duress, as well as upon storage (0 % API loss upon 4 weeks storage at 4 ° C in formulation.; 12 % API loss upon 7 days ambient storage in direct sunlight for neat material.;2.5 % API loss upon 7 days ambient storage in direct sunlight for 5-MeO-DMT dissolved in 2- propanol).

[0096] The preferred formulations offer enhanced protection to the API under conditions of simulated pro-oxidative stress (0 % 5-MeO-DMT loss; heat at 37° C for 48 h in the presence of 0.05 M Cu(NO3)2) in comparison with unformulated 5-MeO-DMT dissolved in ethanol (37 % loss).

[0097] Cell uptake studies including flow cytometry and fluorescence microscopy of glioma (brain) cells exposed to the formulation containing 5-MeO-DMT confirm about 100% uptake of formulated 5-MeO-DMT by the cells.

[0098] Cytotoxicity assays on four ceil lines reveal negligible toxicity of formulated 5- MeO-DMT at therapeutic concentrations.

[0099] As can be expected, selection of excipients and titration of their respective ratios are important to the final composition. For our tested systems, we used hemp oil as the lipid and tween 80 as the hydrophilic co-surfactant.

[0100] For our primary emulsifier, however, the following properties were desired: (i) low histamine release to prevent allergic reactions; (ii) thermal stability, suitable for sterilization and other heating events during creation of the formulation; (iii) lower hemolytic activity; and (iv) inherent biocompatibility. Solubilizers currently used for parenteral administration such as Cremophor EL and polysorbate 80 have been implicated in clinically important adverse effects such as hypersensitivity reactions and a highly increased systemic drug exposure along with a reduced cellular uptake. To overcome these problems, we used protein-polyphenol conjugates as bi-fimctional emulsifiers possessing both surface activity and antioxidant capacity, as well as high physical and chemical stability owing to the chemical linkage of the two species.

[0101] Antioxidant capacity of the thus created protein-polyphenol conjugates HP-GTPcovand HP-GTPnoncov, was confirmed by DPPH assay as well as pro-oxidative experiments as mentioned above.

[0102] Tire results of our studies led us to two representative formulations, formulation A (hemp protein - green tea polyphenol covalently linked (HP-GTPcov)) and formulation B (hemp protein - green tea polyphenol non-covalently linked ( HP-GTPnoncov)). The resulting nanoemulsions were then characterized by dynamic light scattering to determine the average diameter of micellar droplets as well as to measure changes in poly dispersity index and surface charge (ζ-potential). Emulsion droplets were imaged using a scanning electron microscope after appropriate sample preparation.

[0103] The nano-emulsions were stress tested under different chemical and physical environments mimicking commercial production and storage conditions to evaluate its longterm stability. The average droplet sizes, polydispersity index, and zeta potentials for onr nanoemulsions were promising under this stress testing.

[0104] Biological assays were used to evaluate the effect of our nano-emulsions on cells. Cytotoxicity was evaluated using normal and cancer cells for both formulations A and B. Cellular uptake studies confirmed that formulations A and B both exhibited greater uptake of 5-MeO-DMT by human cells without attendant toxicity.

[0105] Literature-recommended qualitative (fluorescence microscopy) and quantitative (flow cytometry) analyses show augmented cellular' uptake in comparison with the unformulated 5-MeO-DMT solution.

[0106] The PPCSNEs oil-in-water (O / W) NEs of 5-MeO-DMT stabilized by the HP - GTP conjugates were prepared by a method previously described by Banerjee et al., “Synthesis, characterization and stress-testing of a robust quillaja saponin stabilized oil-in-water phytocannabinoid nanoemulsion” Journal of Cannabis Research 2021, 3, 43, with some modifications, the disclosure of which is hereby incorporated by reference. A round-bottom flask equipped with a stir bar was charged with 5-MeO-DMT and a requisite amount of hemp oil under an N2atmosphere. The solution was heated in a water bath at 65 °C to ensure the complete dissolution of 5-MeO-DMT in the hemp oil. The aqueous phase was prepared by- adding the requisite amount of HP - GTPnoncov / covsurfactant, along with any optional co- surfactant (e.g. Tween 80), to HPLC grade water. This aqueous phase was then centrifuged at 2500 rpm for 5 minutes (VWR® Centrifuge with 15 mL rotor, 76019-132) and the supernatant was retained; this removed any insoluble protein aggregates. The two phases were then combined and mixed using a rotor-stator mixer (IKA T18 digital) at 10,000 rpm for 3 cycles of 60 sec on, and 60 sec off to avoid excessive internal heating. The resulting coarse emulsion was then placed in the high-pressure homogenizer (Nano DeBee, BEE International, USA) and homogenized at a pressure of 20,000 - 25,000 psi in five sequential cycles using the Z8 nozzle with an aperture size of 0.20 mm. The resulting brown solutions of the NEs were then kept in sealed transparent vials at ~4 °C for long-term storage. The 5-MeO-DMT NE formed from HP - GTPnoncovis referred to as the non-covalent conjugate emulsion (NCCE), while that formed from HP - GTPcovis referred to as the covalent conjugate emulsion (CCE). For the preparation of Nile Red doped NEs, 1 mgg1of Nile Red, with respect to the final concoction, was added into the oil phase at the same time as the 5-MeO-DMT. The rest of the process was conducted as described above.

[0107] In the first test, we looked at a variety of other commercial proteins to conjugate to the green tea polyphenol species. The quality of the thus created emulsifiers was tested bydetermining the emulsion activity and stability indices. The results of this study determined hemp proteins as the most surface active and stable species.

[0108] In the second test, we investigated how much lipid can be loaded into the delivery composition of formula A at a constant conjugate emulsifier and tween-80 amounts of 2.0 and 0.4 wt %, respectively without colloidal instability (measured by dzexceeding 300 nm). In the lipid phase, API.Hemp oil ratio (wt) was kept constant at 5: 1. We found that a 2 wt % lipid payload (5: 1 APIrHemp oil) appeared optimal and was used as the loading level of choice for the next round of tests. Loading of 5-MeO-DMT can be increased as required. Weight percents are based on the total mass of the formulation.

[0109] In order to determine lipid particle size distributions in the nano-emulsions, dynamic light scattering (DLS), also known as photon correlation spectroscopy, was applied. This technique generated Z-average diameters of the dispersed lipid phase droplets (dz), as well as the polydispersity index (PDI). Diluted samples (50- to 100-fold dilutions) were used to avoid multiple scattering. The measurements were conducted with the Zetasizer (Nano Z S, Malvern Instruments Ltd., UK). The Z-average diameters of the dispersed phase droplets was calculated from the autocorrelation function of the intensity of light scattered from the particles. Phase-separated nano-emulsions were re-mixed by shaking prior to dilution for DLS measurements.Effect of inherent antioxidant capacity

[0110] Given the instability of 5-MeO-DMT as an API, we used a pre-synthesized bi- functional protein - polyphenol conjugate as an emulsifier and antioxidant. These species are linked covalently and non-covalently to produce formulation A and formulation B, respectively. We found that the inherent antioxidant capacity appeared to improve the encapsulated API’s chemical stability of the resulting nano-emulsion after exposure to a variety of chemical stressors. With both formulations possessing similar native colloidal characteristics with formulation A possessing a dzof 203.6 nm and formulation B possessing a dzof 200.2. The result of testing the formulations’ ability to respond to a variety of chemical and physical stress tests shows complementary stability between the two formulations.

[0111] As Table 1 shows, both formulations A and B form emulsions with average droplet sizes of about 200 nm, a narrow range of nanoparticle sizes, and good loading levels that can be further increased. We expect that this basic formulation will produce nano-emulsions having an average droplet size within the range from about 10 nm to less than 300 nm, preferablywithin the range of about 20-250 nm, and even more preferably within the range of about 30- 200 mn.TABLE 1Stress Tests

[0112] The nano-emulsions of the present invention that were produced upon high-energy processing of the two pre-constituted phases (aqueous phase containing HP-GTPcov or HP- GTPnoncovand tween 80, and oil phase containing hemp oil and 5-MeO-DMT) were stress- tested to examine the effect of storage times, heat, freeze / thaw cycles, and chemical additives on emulsion stability and 5-MeO-DMT potency. The results show that the present nano- emulsion composition offered enhanced protection to 5-MeO-DMT under conditions of simulated oxidative stress in comparison with unformulated 5-MeO-DMT dissolved in ethanol. None of the stressors examined could induce phase separation in the thus created PPCSNEs.

[0113] Cellular uptake studies showed quantitative penetration of glioma cells by the formulation. Cytotoxicity studies for these systems showed dilution dependent cytotoxicity to different cell lines, tapering to negligible toxicity values at therapeutic API doses.

[0114] We also confirmed that 5-MeO-DMT in an ethanolic solution is unstable under a variety of conditions that mimic commercial production conditions. This dictates that 5-MeO- DMT must be specially formulated to protect the API from exposure and environmental stress. Testing of the nano-emulsion formulations A and B containing 5-MeO-DMT proved that the emulsions are extremely stable even in the presence of stressors. Formulation B shows greater colloidal stability to highly alkaline or acidic environments, and no colloidal destabilization phenomena is observed visually. See Tables 2 and 3 below:

[0115] Pro-oxidation stress tests: 5-MeO-DMT dissolved in ethanol (approx. 10-12 mg / g) showed between 20 and 40 % API loss when exposed to various oxidation-promoting stressors. Upon exposing Formulas A and B to the same conditions, it was observed that the formulations offered strong protection against 5-MeO-DMT degradation in all of the three pro-oxidation environments studied. Heating at 37° C for 48 hours led to negligible API loss in Formula A and in Formula B, but the unformulated 5-MeO-DMT showed about 22 % API degradation after 48 h. Similarly, when exposed to the oxidation catalyst Cu(NO3) 0.05 M) at 37° C for 48 h, Formula A suffered no API loss while Formula B suffered 32 % API loss, but the unformulated 5-MeO-DMT degraded by 37 % after 48 h. As well, in the presence of peroxides, both formulations provide strong antioxidant capabilities, the unformulated API experienced 23 % API degradation after 48 h.

[0116] Biological studies on 5-MeO-DMT: Untreated cells were run first to set the negative control as indicated by the absence of fluorescence. The cells treated with both of Formulas A and B showed about 95.9 and 100 % cellular uptake, respectively. The fluorescentpeak completely shifted to the zone of positive fluorescence, with no part of the curve even laying close to the negative / absent fluorescence region. Formulations A andB were both taken up by cells. These results further demonstrate that the nanoemulsions of the present invention can increase the permeability and liquidity of the membrane, promote the transmembrane transfer of the API, and increase the amount of cel l intake of the API.£00117] Cytotoxicity evaluation: our tests show a dilution dependent cytotoxicity of Formulas A and B. The unformulated 5-MeO-DMT shows increased toxicity over the formulations at 275 μg / g owing to the highly biocompatible nature of the excipients.Experimental Details - Materials

[0118] All materials were purchased from Sigma Aldrich unless otherwise stated and used as received. The hemp protein used was purchased from Manitoba Harvest Hemp Foods (Tilray, New York, NY, US A). The hemp oil was purchased from Nature’s Oil (Aurora, OH, USA). Green tea polyphenols (green tea extract, 98 % tea polyphenols) were purchased from Creative Enzymes (Upton, NY, USA). All the above agents are food-grade. Corn oil and Tween 80 were purchased from Charles Tennent and Company Ltd. (North York, ON, Canada). HPLC -grade water (EMD Millipore, Burlington MA, USA) was used in all experiments. CaCT and sucrose were purchased from Sigma Aldrich (St. Louis, MO, USA). 4',6-diamidino-2- phenylindole (DAPI) was purchased from Aaron Chemicals (San Diego, CA, USA). 5-MeO- DMT was synthesized in-house by the Trant organic synthesis lab and used as received.

[0119] Five different cell lines were used for the evaluation of the tested formulations and unfonnulated 5-MeO-DMT.

[0120] L2: The rat lung cell line https: / / www.atcc.org / products / ccl-149

[0121] GBM 251: The glioblastoma cancer cells https: / / www.cytion.com / U-251-MG- Cells / 300385

[0122] GBM U87 : The glioblastoma cancer cells https: / / wvw.atcc.org / products / htb-l 4

[0123] MDA-MB-231 : The human breast cancer cells https : / / www.atcc . org / products / crm-htb-26Preparation of the 5-MeO-DMT Nano-Emulsions

[0124] The nano-emulsions of Formulas A and B were prepared by a method previously described by Banerjee et al., “Synthesis, characterization and stress-testing of a robust quillaja saponin stabilized oil-in-water phytocannabinoid nanoemulsion” Journal of CannabisResearch 2021, 3, 43, with some modifications, the disclosure of which is hereby incorporated by reference. A round-bottom flask equipped with a stir bar was charged with 5-MeO-DMT and a requisite amount of hemp under an Ni atmosphere. The solution was heated in a water bath at 65 °C to ensure the complete dissolution of 5-MeO-DMT in the hemp oil. The aqueous phase was prepared by adding the requisite amount of HP - GTPnoncov / covsurfactant along -with any secondary surfactant (e.g. Tween 80) to HPLC grade water. This aqueous phase was then centrifuged at 2500 rpm for 5 minutes (VWR® Centrifuge with 15 mL rotor, 76019-132) and the supernatant was retained; this removed any insoluble protein aggregates. The two phases were then combined and mixed using a rotor-stator mixer (IKA T 18 digital) at 10,000 rpm for 3 cycles of 60 sec on, and 60 sec off to avoid excessive internal heating. The resulting coarse emulsion was then placed in the high-pressure homogenizer (Nano DeBee, BEE International, USA) and homogenized at a pressure of 20,000 - 25,000 psi in five sequential cycles using the Z8 nozzle with an aperture size of 0.20 mm. The resulting brown solutions of the NEs were then kept in sealed transparent vials at ~4 °C for long-term storage. The 5-MeO-DMT NE formed from HP-GTPnoncovis referred to as the non-covalent conjugate emulsion (NCCE), while that formed from HP - GTPcovis referred to as the covalent conjugate emulsion (CCE). For the preparation of Nile Red doped NEs, 1 mg g-1of Nile Red, with respect to the final concoction, was added into the oil phase at the same time as the 5-MeO-DMT. The rest of the process was conducted as described above.

[0125] Long-term storage: To examine the effect of long-term storage on the colloidal and chemical stability of the nano-emulsion and encapsulated API, we stored them in tightly capped amber glass vials in a refrigerator at 4 °C. Two aliquots were periodically removed from the vials, one aliquot is diluted in preparation for DLS, and the other is handed off as-is to the Trant analytical lab. Measurements were performed immediately after high pressure homogenization, and after that, once every seven days for up to four weeks.

[0126] Flash heating: 1 g of the optimized nano-emulsion was placed in a preheated water bath and the internal temperature of the nano-emulsion was maintained at 80 °C for 1 minute. This protocol is a more extreme version of the high-temperature short-time (HTST) pasteurization process (typically, 71.5 °C. for 15 s) that fruit juices and milk beverages are subjected to in the industry. The nano-emulsion was then allowed to cool to room temperature, and a part of it was diluted for DLS study. The rest was retained for HPLC analysis

[0127] Freeze-thaw cycle: 1 g of the optimized nanoemulsion was placed in a freezer at a temperature of -20 °C for 1 hour. The nano-emulsion was then removed from the freezer and allowed to revert to room temperature. A part of the thawed nano-emulsion was diluted for DLS study, and the rest was retained for HPLC analysis.

[0128] Additives: In a representative experiment, varying masses of CaCl 2H2O, sucrose, and potassium sorbate were added individually to 1 g portions of the nano-emulsions at certain pre-determined concentrations. To ensure complete dissolution of the additive, the aliquots were vortexed for 1 min each. After an incubation period of 12-18 h, the aliquots were vortexed again for 1 min prior to dilution with DLS studies. It is to be noted that HPLC analysis studies were not carried out in the context of salt, sugar and preservative addition to the nanoemulsions, given that they are not expected to degrade 5-MeO-DMT in any meaningfill way. Any drop in 5-MeO-DMT for these experiments may be attributed to colloidal events leading to instability rather than to chemical transformations.

[0129] Extraction procedure: Approximately 50 mg of emulsion samples were weighed individually into 15 mL falcon tubes and 5 mL methanol (HPLC grade) was added. Samples were vortexed (Vevor® Vortexer Mixer) for 10 seconds and placed in an ultrasonic bath (Avantor, VWR symphony) for 15 minutes at room temperature. After sonication, each sample was spun at 400 g for 5 mins in a centrifuge (Avantor). Aliquots of resultant clear supernatant were used for HPLC analysis.

[0130] Sample acquisition and data analysis: Chromatographic analysis of supernatants from sample extraction was performed using an Agilent 1 100 Liquid Chromatography system fitted with a photodiode array detector and using an Agilent Zorbax Eclipse Plus -Cl 8 column (4.6 x 150 mm, 3.5 pm). For data acquisition, the method reported by Cao et al,18was modified for proper and faster elution of the analyte. A gradient run using the mobile phase combination of 10 mmol ammonium acetate buffer containing 0.2% acetic acid (A) and 100% acetonitrile (B) for a total of 18 minutes was applied at a flow' rate of 1 mL / min. The gradient run was as follows: 0 - 3.68 (3% B), 3.68 - 6.35 (5% B), 6.35 - 7.68 (15% B), 7.68 - 12.60 (15% B), 13.60 - 15.01 (100% B), 15.01 - 16.50 (3% B) and 16.50 - 18.00 (3% B). Mobile phase solvents were of HPLC grade and fdtered with 0.20 um filters before analysis. Standard dilutions of 5-MeO-DMT from 0.119 mg mL-1to 0.001 mg mL-1were run alongside sample extracts and data generated from standard dilutions acquisition was used to plot a calibration curve for calculating the concentration of 5-MeO-DMT in emulsion samples.

[0131] Cell culture: The rat lung cell line L2 was purchased from American Type Culture Collection (ATCC, Rockville, MD, USA) and was cultured in Dulbecco’s Modified Eagle’s Medium / Nutrient Mixture F-12 Ham (DMEM-F12, Sigma-Aldrich, St. Louis, MO, USA), 10% fetal bovine serum (FBS, Sigma-Aldrich), and 1% penicillin / streptomycin (Sigma- Aldrich) at 37 °C under 5% CO2in a humidified atmosphere. The human breast cancer cell line MDA-MB-231 was obtained from ATTC and were grown in Dulbecco’s modified Eagle's medium (DMEM, Sigma- Aldrich), 10% FBS (Sigma- Aldrich), and 1% penicillin / streptomycin (Sigma-Aldrich) at 37 °C in a 5% CO2atmosphere with 95% humidity. The human glioblastoma cell U87 was purchased from ATTC and cultured in Minimal Essential Medium+ Earl’s Balanced Salts (MEM / EBSS, Hyclone, Logan, UT, USA), 10% FBS (Sigma-Aldrich), and 1% penicillin / streptomycin (Sigma- Aldrich) at 37 °C at 5% CO2 and 95% humidity . All the cell lines were sub-cultured w'hen they got to 70% confluency. The human glioblastoma cell U251 was purchased from Cytion and cultured in DMEM, 10% FBS (Sigma- Aldrich), and 1% penicillin / streptomycin (Sigma-Aldrich) at 37 °C in a 5% CO2 atmosphere with 95% humidity. All cell lines were subcultured upon reaching 70% confluency.

[0132] Cellular uptake studies: Flow cytometry analysis of human glioblastoma U87 cells, used as a model for brain cells in this research, were seeded in 6-well plates at a density' of 1x106cells per / well (1 mL inclusive of media, per well) and incubated for 24 hours at 37 °C with 5% CO2and 95% humidity to allow for cell adherence and growth. The Nile Red-loaded NEs were prepared for flow cytometry by diluting with MEM / EBSS (Hyclone) growth medium to achieve specific concentrations: 1.44 mg mL-1for CCE and 1.14 mg mL-1for NCCE; this ensured a final Nile Red concentration of 40 gg-mL1. The culture media was then replaced with this fresh media containing the respective NEs, and the cells were incubated for an additional 24 hours (37 °C, 5% CO2, 95% humidity). The media was then removed by aspiration, and the cells were gently washed with PBS to remove any remaining NEs. Subsequently, the cells were harvested and washed with phosphate-buffered saline (PBS) containing EDTA. The cells were suspended in PBS containing 2 mM ethylenediaminetetraacetic acid (EDTA). and a 500 μL single-cell suspension was analyzed using the BD LSRFortessa™ X-20 flow cytometer (Becton Dickinson). Fluorescence imaging analysis: Human glioblastoma U87 cells at a density of 1x106cells / per well were seeded onto coverslips within the wells of a 6-well plate containing 2 mL of tire MEM / EBSS (Hyclone). Following this, the plates were incubated at 37 °C with 5% CO2, and 95% humidity, allowingthe cells to adhere and proliferate over a 24-hour period. Nile Red-loaded NEs were diluted with the growth medium to achieve specific concentrations: 1.44 mg mL1for CCE and 1.14 mgmL-1for NCCE ensuring a final Nile Red concentration of 40 μg mL-1. Subsequently, the medium EMEM (MEM / EBSS Eagle’s minimum essential media, Hyclone) was replaced with a fresh medium containing the respective NEs, and the cells were incubated for an additional 24 hours (37 °C, 5% CO2). After incubation, the media was aspirated from each well, and the cells were washed with PBS to remove non-internalized NEs. The cells were then fixed using 4% paraformaldehyde for 15 minutes at room temperature. Following fixation, the cells were rinsed with PBS and stained with DAPI (1 pg / mL) for 20 minutes. Afterward, excess DAPI solution was removed by washing the cells with PBS. Finally, the coverslips containing the stained cells were mounted onto glass slides, imaged, and analyzed using a Leica CRT 6500 fluorescence microscope.£00133] The cytotoxicity of the NEs were measured by the MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide) assay on four different cell lines: L2 rat lung, MDA- MB-231 human breast cancer cells, and human glioblastoma U87 and U251 cells. Briefly, the cells were seeded at 1 x 103cells / well for L2 cell, 2x 103cells / well for MDA-MB-231, and 3x 103cells / well for U87 and U251 cells in a 96-well micro titer plates (100 pL inclusive of media, per well). After 24 h incubation in the wells at 37 °C in 5% CO2with 95% humidity, cells were treated with 50 μL of the analyte at four different dilutions (275, 27.5, 2.75, and 0.275 pg g-1). After incubation for 48 h, the media was discarded and 100 μL of 0.5 mg-mL-1MTT stock solution was added to each well and the plates were incubated for an additional 4 h at 37 °C under 5% CO2and 95% humidity. After discarding the MTT solution from wells, the obtained formazan crystals were solubilized with 100 μL / well of DMSO (dimethyl sulfoxide), and the absorbance ’was measured at 570 nm using a microplate reader (SpectraMax M5e, Molecular Devices, USA). Cell viability (%) was calculated as a ratio of absorbance in treated cells to absorbance in control cells (intact cells without treatment).

[0134] 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.

Claims

IS CLAIMED IS:

1. An oil-in-water nano-emulsion comprising: (a) a therapeutic amount of one or more compounds having a psychedelic effect when consumed by a human, (b) a first surfactant comprised of a pre-synthesized composite species made up of a biocompatible protein and polyphenolic species, (c) a triglyceride oil as an organic vehicle and optionally, (d) a cosurfactant.

2. A nano-emulsion as in claim 1 wherein said protein-polyphenol composite species is comprised of hemp protein chemically linked to a phenolic or polyphenolic species.

3. A nano-emulsion as in claim 2 wherein polyphenols are green tea polyphenols.

4. A nano-emulsion as in claim 3 wherein said hemp proteins and green tea polyphenols are either covalently or non-covalently linked.

5. A nano-emulsion according to claim 1 further comprising an optional co-surfactant.

6. A nano-emulsion according to claim 5 wherein said optional co-surfactant comprises a polyoxyethylene sorbitan monooleate.

7. A nano-emulsion according to claim 1 wherein one or more psychedelic compounds comprises at least one of a tryptamine-scaffold or a phenethylamine-scaffold psychedelic.

8. A nano-emulsion according to claim 7 wherein the one or more psychedelic compounds is 5-acetoxy-N,N-dimethyltryptamine (“5-AcO-DMT”), 4-methoxy-N,N- dimethyltryptamine (“4-MeO-DMT”), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), 4- acetoxy-N,N-dimethyltryptamine (“4-AcO-DMT”), psilocybin, psilocin, mescaline, ibogaine, or bufotenin.

9. A nano-emulsion according to claim 8 wherein one or more psychedelic compounds is a tryptamine-scaffold psychedelic that comprises 5-MeO-DMT, 4-MeO-DMT, or 4-AcO- DMT.

10. A nano-emulsion according to claim 1 having an average droplet size in said emulsion that is within a range from about 10 nm to less than 300 nm.

11. A nano-emulsion according to claim 10 wherein the average droplet size is within a range from about 50-250 nm.

12. A nano-emulsion according to claim 11 wherein the average droplet size is within a range from about 30-200 nm.

13. A nano-emulsion according to claim 1 in liquid form and having a concentration of psychedelic agent an amount within a range from about 0.1-1000 mg / ml.

14. A nano-emulsion according to claim 13 comprising a concentration of psychedelic agent in an amount within the range of 1-100 mg / ml.

15. A process for the manufacture of protein-polyphenol conjugate stabilized nanoemulsions (“PPCSNEs”) by a process that comprises: a. combining (i) a first surfactant comprised of a pre-synthesized composite species made up of a biocompatible protein and polyphenolic species, (ii) a therapeutic amount of one or more psychedelic API, (iii) a triglyceride oil, and (iv) a co-surfactant in a container, b. mixing said ingredients in a container to form a coarse-emulsion product, and c. forming a nanoemulsion from said coarse-emulsion product.

16. A stable O / W nanoemulsion composition comprising: (a) a primary surfactant comprising a protein-polyphenol conjugate species , (b) a triglyceride oil, and optionally (c) a co-surfactant. .

17. A stable O / W nanoemulsion composition according to claim 16 wherein said proteinpolyphenol conjugate species is made of a hemp protein chemically linked to a phenolic or polyphenolic species.

18. A stable 0 / W nanoemulsion composition according to claim 17 wherein the polyphenol species comprises one or more green tea polyphenols.

19. A stable O / W nanoemulsion composition according to claim 18 wherein said hemp protein and a green tea polyphenol are covalently or non-covalently linked.