Psychedelic lipid nanoparticles for intranasal administration

Abstract

Disclosed is a composition, method of manufacture, and method of therapeutic treatment that delivers a therapeutic amount of an active ingredient that induces a psychedelic effect in a human or mammal patient in a lipid nanoparticle emulsion. Preferably, this emulsion is delivered in controlled doses with a nasal spray matrix as a carrier.

Description

Psychedelic Lipid Nanoparticles for Intranasal Administration407-P017PCTREFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional patent application Ser. No. 63 / 760,828 that was filed on February 20, 2025, and whose disclosure is incorporated herein by referenceFIELD OF THE INVENTION

[0002] The invention relates to compositions containing active ingredient compounds that exhibit a psychedelic effect in a mammal, such as a human patient in need of treatment with such compounds. The present disclosure also relates to methods for the manufacture of such compositions.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 (also known as 5-hydroxytryptamine, often abbreviated 5HT) and (B) several different subtypes of serotonin neurotransmitter receptors (5HTRs) 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] In a review of many mushroom 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 mushroomspecies (Phan, David et al. 2017); however, this is likely an oversight deliberate or otherwise as these molecules specifically act as neurogeneratives. 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, Song et 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-HT2AR 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 therapeutic 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 G-protein coupled receptor (GPCR) agonist or antagonist, is an integral part of the intended treatment. For therapeutic 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 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 byresearchers and scientists as integral part of the potential therapeutic 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 part of a mushroom’s anatomy. This is consistent with many botanical and fungal species possessing relevant APIs

[0009] Some of the major challenges to be overcome to create stable, robust, reproducible, and biologically active products include but are not limited to:

[0010] a. Lipophilicity or hydrophilicity of the API,

[0011] b. Limited bioaccessibility and / or bioavailability of the API,

[0012] c. Extensive degradation of the 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 psychedelics that would provide a consistent, therapeutically useful dose.

[0015] Psychedelic active pharmaceutical ingredients (APIs), such as psilocybin, mescaline, psilocin, ibogaine, LSD, 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 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.

[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 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 most effective common forms of administration because of 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 therapeutic treatment of MDD, SUD, and various neurodegenerative disorders.

[0018] 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 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 psychedelics. Such encapsulating delivery systems can carry the API payload to intracellular or extracellular destinations that are otherwise inaccessible to the unformulated APIs.

[0020] There are very few examples of formulations of psychedelics in the literature (Shen, Lv et al. 2022, Witowski, Hess et al. 2024, Fandiho, Hutton et al. 2025). However, these formulations could readily be consumed in a clinical setting oras a prescription medication without the need for special storage or in situ formulation by a chemist or pharmacist.

[0021] It would be desirable to have an effective formulation for the delivery of psychedelics (such as but not limited to psilocybin, psilocin, ibogaine, LSD, mescaline, 5-MeO-DMT and bufotenin) that would be bioavailable and bioeffective in therapeutically effective doses.

[0022] Recent clinical trials using forms of psychedelics have been on-going. A vaporizable form of 5-MeO-DMT (GH Research PLC, Dublin, Ireland) 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 (Reckweg, van Leeuwen et al. 2023). 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. Furthermore, 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 (thus bypassing the blood-brain-barrier), and instead both seek a simple introduction of the unmodified polar API into the bloodstream.

[0023] Most formulation approaches to improve bioavailability of water insoluble, highly lipophilic drugs are 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 limitations. See U.S. Pat. No. 11 ,617,758 (Dhingra and Bernstein. 2020).

[0024] It would be desirable to have an effective process to make a stable, effective, LNP-based nasal spray (LNP-NS) compositions that could be used with psychedelics.

[0025] It would also be desirable to have a process in creating LNP-NSs 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

[0026] 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 useful dose of an active ingredient inducing a psychedelic effect.

[0027] It is also an objective of the invention to provide a composition and method of administration that would deliver a therapeutically effective amount of psychedelics to a patient in need that would provide a bioavailable, bio-effective dose in therapeutically effective dosages.

[0028] It is further an objective of the invention to provide an effective process to make a stable, effective, LNP-NS delivery composition that could be used with psychedelics.

[0029] Additionally, it is an object of the invention to provide a process for producing LNP-NSs 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.

[0030] In accordance with these and other objects of the invention that will become apparent from the description herein, the invention provide a composition comprising lipid-based nanoparticles (LNPs) that carry a therapeutically effective concentration of an active ingredient that induces a psychedelic effect for the convenient treatment of a human or mammal patient. The invention further comprises a composition that contains these psychedelic LNPs in a nasal spray matrix that maintains comfort of the nasal cavity during treatment while allowing effective uptake of the nanoparticles into the brain.

[0031] The LNP form of the present invention provides a stable formulation that is well-suited for delivery of therapeutic amount(s) of one or more psychedelics via intranasal administration, thereby providing a familiar and comfortable form of dosingto a patient. The small average particle size of the LNPs and ability of the active ingredient to cross or bypass 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

[0032] Disclosed herein is a stable, LNP nasal spray drug delivery system exhibiting nanometer-sized, LNPs that each contain (a) a therapeutic amount of one or more active ingredients exhibiting a psychedelic effect in mammals. Each of these is a hydrophilic or lipophilic drug that is variably soluble in serum and well suited for delivery by nasal spray.

[0033] The composition of the present invention achieves sustained solubilization and overcomes poor bioavailability of lipophilic drugs with solutions in lipid vehicles and surfactants incorporated into matrices designed for intranasal administration. These compositions are presented in the form of lipid-based nanoparticles (LNPs) of opaque or translucent formulations having particle sizes of <500 nm that are well suited for intranasal delivery.

[0034] Lipid-based nanoparticles are isotropic mixtures that contain: (a) at least one drug, (b) optionally, a lipid organic vehicle, (c) a primary surfactant and, optionally, (d) one (or more) co-surfactant(s). These formulations rapidly form relatively stable nanoparticles in water. Particles of this nature can also be produced by high energy processing of combined, pre-formed aqueous and oil phases.

[0035] LNPs show high drug solubilizing capacity and enhancement in both rate and extent of absorption by intranasal 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.

[0036] LNPs can be readily incorporated into a matrix that can increase its biological uptake when administered to the intranasal cavity.

[0037] Intranasally administrated LNPs widen the accessibility of lipidic excipients to offer flexibility of function with respect to improving bioavailability of drugs by manipulating their release profiles and protecting them from enzymatic and / orchemical degradation while facilitating their passage along the olfactory and trigeminal nerves, and ultimately passage into the central nervous system along these nerves. LNPs may also demonstrate cell-penetrating properties.Definitions

[0038] 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, neuropathic pain, 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 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.

[0039] 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.

[0040] The term "inflammatory disorders" 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, neuro-inflammation, metabolic syndrome, impaired glucose tolerance, non-alcoholic fatty liver disease(NAFLD), NAFLD and their complications, non-alcoholic steatohepatitis (NASH) and conjunctivitis.

[0041] The general method of treatment comprises administering to a human or mammal subject in need thereof a therapeutically effective amount of an acceptable psychedelic or psychedelic analogue in one or more pharmaceutically acceptable carriers or excipients.

[0042] 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.

[0043] 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 psilocybin. 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).

[0044] 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, 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, neurocog nitive disorders, personality disorders, paraphilic disorders and for the reduction of suicidal ideation in a patient suffering from a life-threatening disease.

[0045] The term "pharmaceutical composition" means a composition comprising a composition of the invention in combination with at least one additional pharmaceutically acceptable carrier.

[0046] 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.

[0047] As used herein, "intranasal" administration includes inhalation into the nasal cavity. The compositions of this invention can be administered for any of the uses or methods described herein by any suitable means, for example, intranasally, such as powders, granules, elixirs, suspensions (including nano suspensions, micro suspensions, spray-dried dispersions), syrups, and LNPs.

[0048] 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 Depression Rating Scale (GRIDHAMD). A therapeutically effective amount may be less than that required for a psychedelic state.

[0049] 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 clinicalcontext, 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.Nasal Spray Composition

[0050] Preferred therapeutic species of one or more active ingredients inducing a psychedelic effect include psilocybin, 5-MeO-DMT, N,N-DMT, psilocin, mescaline, ibogaine, bufotenin, and / or octanoyl bufotenin in an amount within the range of 1 -80 wt%, preferably 15-30 wt% based on total weight of the LNP-NS. When used in a liquid form, a suitable therapeutic amount of the psychedelic(s) 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.

[0051] The LNPs combined within the nasal spray matrix is generally used in an amount within the range from about 1 - 100 wt%, preferably an amount within the range of 10 - 80 wt%, and even more preferably an amount within the range of 20 - 90 wt%, and most optimally within the range of 30 - 70 wt% based on total LNP-NS’ weight.

[0052] The nasal spray matrices of the invention include some or all of the following ingredients, such as (a) tonicity adjusters, (b) preservatives, (c), chelating agents, (d) suspending agents, (e) humectants, (f) penetration enhancers, (g) surfactants, (h) co-solvents, (i) buffer / pH control components, (j) mucoadhesives, (k) ciliostatic or cilio-inhibiting agents, (I) aggregation inhibitory agents, and (m) enzyme inhibitory agents. In some embodiments, one ingredient may be able to perform one or more of these functions.

[0053] Suitable tonicity adjusters are generally selected from, but not limited to, biosafe alkali metal salts derived from calcium, sodium, magnesium, and potassium, or other species such as dextrose, glycerin, mannitol, and the like. An especially preferred tonicity adjuster is sodium chloride.

[0054] The total amounts of tonicity adjusters, combined, are generally within a range from about 0.1 - 30 wt%, and preferably an amount within the range of 0.5 -15 wt%, and optimally an amount within 0.7 - 3 wt%, of the total LNP-NS’ weight.

[0055] Suitable preservatives are generally selected from, but not limited to, benzalkonium chloride, ethanol, propylene glycol, benzyl alcohol, chlorobutanol, methyl paraben, methyl 4-hydroxy benzoate, propyl paraben, propyl 4-hydroxybenzoate, benzoic acid, sodium benzoate, 2-phenylethanol, potassium sorbate, thimerosal, benzyl benzoate, boric acid, phenol, sorbic acid, and the like. An especially preferred preservative is 2-phenylethanol.

[0056] The total amounts of preservatives, combined, are generally within a range from about 1 - 10 wt%, and preferably an amount within the range of0.1 - 1 wt %, and optimally an amount within the range of 0.1 - 0.5 wt%, of the total LNP-NS’ weight.

[0057] Suitable chelating agents are generally selected from, but not limited to, sodium phytate, citrate, ethylenediaminetetraacetic acid, pentetic acid, nitrilotriacetic acid, sodium pyrophosphate, pentasodium diethylenetriamine pentaacetate, sodium gluconate, sodium chloride, disodium orthophosphate, cyclodextrins, ethylene glycol tetraacetic acid, and their derivatives. An especially preferred cation chelating agent is ethylenediaminetetraacetic acid.

[0058] The total amounts of chelating agents, combined, are generally within a range from about 1 - 10 wt%, and preferably an amount within the range of0.1 - 1 wt%, and optimally an amount within the range of 0.1 - 0.5 wt%, of the total LNP-NS’ weight.

[0059] Suitable suspending agents are generally selected from, but not limited to, microcrystalline cellulose, carboxymethylcellulose, polyacrylic acid, xanthan gum, hydroxypropylmethylcellulose, and the like. An especially preferred suspending agent is carboxymethylcellulose.

[0060] The total amounts of suspending agents, combined, are generally within a range from about 1 - 10 wt%, and preferably an amount within the range of1 - 5 wt%, and optimally an amount within the range of 0.1 - 2 wt%, of the total LNP-NS’ weight.

[0061] Suitable humectants are generally selected from, but not limited to, glycerin, sorbital, and mannitol, and the like. An especially preferred humectant is glycerin.

[0062] The total amounts of humectants, combined, are generally within a range from about 1 - 10 wt%, and preferably an amount within the range of 0.1 - 1 wt%, and optimally an amount within the range of 0.1 - 0.5 wt%, of the total LNP-NS’ weight.

[0063] Intranasal penetration ability is a parameter that can be adjusted by the other components of the matrix, including the base LNP itself. Therefore, suitable penetration enhancers are selected from, but not limited to, the species listed following suitable tonicity adjusters, preservatives, chelating agents, suspending agents, humectants, penetration enhancers such as borneol, menthol, and muscone, surfactants, co-solvents, buffer / pH control components, mucoadhesives, ciliostatic or cilio-inhibiting agents, and aggregation inhibitory agents. An especially suitable penetration enhancer is oleic acid.

[0064] The total amounts of penetration enhancers, combined, are generally within a range from about 1 - 100 wt%, and preferably an amount within the range of 10 -50 wt%, and optimally an amount within the range of 1 - 10 wt%, and most optimally within the range of 0.1 - 1 wt% of the total LNP-NS’ weight

[0065] Suitable surfactant(s) is generally selected from but not limited to apricot kernel oil PEG-6 esters, PEG-6 esters, arachidyl glucoside, beheneth-5, beheneth-10, beheneth-20, beheneth-25, beheneth-30, butylene glycol, C9-11 pareth-3, C14-22 alcohol, C12-20 alkyl glucoside, bile salts, calcium stearoyl lactylate, caprylyl / capryl glucoside, caprylyl / decyl glucoside, ceteareth-6, stearyl alcohol, ceteareth-10, ceteareth-12, ceteareth-15, ceteareth-20, ceteareth-23, ceteareth-25, ceteareth-30, ceteareth-33, ceteareth-80, ceteareth-100, ceteareth-20, cetearyl alcohol, ceteareth-30, PEG-40 castor oil, sodium cetearyl sulfate, cetearyl alcohol, polysorbate 60, cetearyl alcohol, cetearyl alcohol, sodium cetearyl sulfate, sodium lauryl sulfate cetearyl glucoside, cetearyl olivate, sorbitan olivate, cetearyl wheat straw glycosides, ceteth-2, ceteth-5, ceteareth-7, ceteth-10, ceteth-20, sphingomyelin, phosphatidylcholine, cholesterol, cetrimonium chloride, cetyl palmitate, cetyl PEG / PPG-10 / 1 dimethicone, oleic acid, cocamide DEA, cocamide MEA, coco glucoside, corn oil PEG-6 esters, d-a-tocopheryl polyethylene glycol 1000 succinate, decaglyceryl tetraoleate, deceth-3, decyl glucoside, diacetyl tartaric acid esters of mono- and diglycerides (DATEM), diethylene glycol monoethyl ether,diethylene glycol monooleate, diglyceryl dioleate, diglyceryl monooleate, diisostearoyl polyglyceryl-3 dimer dilinoleate, dimethyl isosorbide, distearyldimonium chloride, erythorbyl laurate, ethoxylated monodiglycerides, ethoxylated monodiglycerides, ethylene glycol, ethylhexyl stearate, glycerol mono and distearate, polyoxyethylene stearate, glyceryl behenate, glyceryl caprylate, glyceryl caprylate / caprate, glyceryl laurate, glyceryl monooleate, Kolliphor HS15, glyceryl myristate, glyceryl oleate, glyceryl oleate citrate, glyceryl stearate, PEG-100 stearate, glyceryl stearate citrate, glyceryl stearate SE, glyceryl stearate SE, sucrose stearate, glycol distearate, glycol stearate, hexaglyceryl monolaurate, laureth-3, laureth-4, laureth-5, laureth-7, laureth-9, laureth-10, laureth-23, lauroyl polyoxyl-32 glycerides, lauryl glucoside, lecithin, linoleamide DEA, linoleoyl polyoxyl glycerides, lysolecithin, macrogol 6 glycerol caprylocaprate, methyl glucose sesquistearate, methyl laurate, propylene glycol, isostearate, methylpropanediol, monolaurin, myristyl glucoside, nonylphenol ethoxylate, nonylphenol ethoxylate, nonylphenol polyoxyethylene ether, octoxynol-40, octyldodeceth-20, octyldodecyl xyloside, octylphenol polyoxyethylene ether, oleth-2, oleth-3, oleth-5, oleth-10, oleth-20, oleth-30, olive oil PEG-7 esters, palmitamidopropyltrimonium chloride, PEG-4 dilaurate, PEG-4 rapeseedamide, PEG-5 glyceryl stearate, PEG-7 glyceryl cocoate, PEG-7 olivate, PEG-8 beeswax, PEG-8 C12-C20 alkyl ester, PEG-8 caprylic / capric glycerides, PEG-8 dioleate, PEG-8 laurate, PEG-8 oleate, PEG-12 dimethicone, PEG-12 laurate, PEG-20 almond glycerides, PEG-20 glyceryl stearate, PEG-20 methyl glucose sesquistearate, PEG-25 hydrogenated castor oil, PEG-30 dipolyhydroxystearate, PEG-30 glyceryl cocoate, PEG-30 glyceryl stearate, PEG-32 hydrogenated palm glycerides, PEG-40 hydrogenated castor oil, PEG-40 sorbitan peroleate, PEG-60 almond glycerides, PEG-60 glyceryl isostearate, PEG-75 lanolin, PEG-75 shea butter glycerides, PEG-80 sorbitan laurate, PEG-100 stearate, pentylene glycol, polyethylene glycol octyl ether, polyglyceryl oleate, polyglyceryl-2 dipolyhydroxystearate, polyglyceryl-2 oleate, polyglyceryl-2 sesquioleate, polyglyceryl-2 stearate, polyglyceryl-3 beeswax, polyglyceryl-3 caprate, polyglyceryl-3 caprylate, polyglyceryl-3 dicitrate / stearate, polyglyceryl-3 distearate, glyceryl stearate citrate, polyglyceryl-3 methylglucose distearate, polyglyceryl-3 oleate, polyglyceryl-3 polyricinoleate, polyglyceryl -6 polyhydroxystearate, polyglyceryl-6 polyricinoleate, polyglyceryl-6 behenate, polyglyceryl-6 stearate,polyglyceryl-6 behenate, C18-22 hydroxyalkyl hydroxypropyl guar, polyglyceryl-10 caprylate, polyglyceryl-10 caprylate / caprate, polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10 oleate, polyglyceryl-10 pentahydroxystearate, polyglyceryl-10 tristearate, polyoxyl 20 cetostearyl ether, polyoxyl castor oil, polysorbate 20, polysorbate 22, polysorbate 23, polysorbate 24, polysorbate 60, polysorbate 65, polysorbate 80 , polysorbate 85, sorbitan oleate, polyglyceryl-3 polyricinoleate, sorbitan olivate, sorbitan palmitate, sorbitan sesquioleate, sorbitan stearate, sorbitan stearate (and) sucrose cocoate, sorbitan trioleate, sorbitan tristearate, stearamide MEA, steareth-2, steareth-20, steareth-21, steareth-100, sucrose cocoate, sucrose distearate, sucrose esters, sucrose laurate, sucrose monolaurate, sucrose palmitate, sucrose stearate, tetraglyceryl monooleate, tetraglyceryl monostearate, trideceth-3, trideceth-5, trideceth-6, trideceth-7, trideceth-8, trideceth-9, trideceth-9, PEG-40 hydrogenated castor oil, trideceth-10, trideceth-12, trideceth-12, tridecyl stearate, triglyceryl monooleate, trilaureth-4 phosphate, p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween 60, polysorbate 80 (polyoxyethylene (80) sorbitan monooleate), 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, polyglyceryl- 10 palmitate PEG sorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, cholic acid, PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, propylene glycol isostearate, oleth-10, polysorbate 60 NF, isosteareth-20, isoceteth-20, PEG-100 stearate, decanoyl-N-methylglucamide, n-decyl-Dglucopyranoside, n-decyl-D-maltopyranoside, n-dodecyl-D-glucopyranoside, n-dodecyl-D-maltoside, heptanoyl-N- methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-D-thioglucoside, n-hexyl-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-D-glucopyranoside, octanoyl-1-N-methylglucamide, n-octyl 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, maleicanhydride, succinic anhydride, diglycolic anhydride, glutaric anhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine; cycothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite, menadoxime, vitamin B12, vitamin K, vitamin B6, 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 docecyl sulfates, 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-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acids, acetic acid, salts of any organic acid and organic amine, polyglycidol, glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), polyethylene glycol) oligomers, di(propylene 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, and the like. An especially preferred hydrophilic surfactant is polysorbate 80.

[0066] The total amounts of primary surfactant and co-surfactant(s), combined, are generally within a range from about 0.1 - 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 LNP-NS’ weight.

[0067] Suitable co-solvents are generally selected from species that maintain solubility of the active ingredient in the form of a freebase, a salt, or a solvate. These can be in the form of delivery vehicle carriers which can form complexes or associates with the active ingredient. These can also be in the form of volatiles that are non-toxic, and / or non-toxic at trace amounts. These can also be in the form of species that encapsulate the active ingredient and provide enhanced bioavailability, as in the form of the present invention which encapsulates the active ingredient within an LNP. An especially preferred co-solvent is pre-encapsulating the active ingredient into a nanoemulsion.

[0068] The total amounts of co-solvents, combined, are generally within a range from about 1 - 100 wt%, and preferably an amount within the range of 10 - 50 wt%, and more preferably an amount within the range of 1 - 50 wt%, and especially preferred in an amount within the range of 0.1 - 10 wt% of the total LNP-NS’ weight

[0069] Suitable buffer / pH control components are generally selected from species that maintain the pH of the formulation ranging from about 3 to 5. In some embodiments, the pH of the formulation ranges from about 4 to 7.5. In some embodiments the pH control is a base, acid, buffer, or a combination thereof selected from, but not limited to, citric acid, phosphate buffer, calcium carbonate, sodium bicarbonate, sodium lactate. An especially preferred buffer / pH control component citric acid / citrate buffer.

[0070] The total amounts of buffer / pH control components, combined, are generally within a range from about 1 - 100 wt%, and preferably an amount within the range of 10 - 50 wt%, and more preferably an amount within the range of 1 - 50 wt%, and especially preferred in an amount within the range of 0.1 - 10 wt% of the total LNP-NS’ weight

[0071] Suitable mucoadhesive agents are generally selected from species that increase the adherence of the spray formulation to the nasal lining, increasing formulation residence time in the nasal mucosa, hereby increasing the absorption of the formulation and subsequently increasing bioavailability. This parameter can be adjusted by the other components of the matrix, including the base LNP itself.Therefore, mucoadhesives are selected from, but not limited to, the species listed following suitable suspending agents, humectants, penetration enhancers,surfactants, co-solvents, mucoadhesives, ciliostatic or cilio-inhibiting agents, and aggregation inhibitory agents. An especially preferred mucoadhesive component is carboxymethylcellulose.

[0072] The total amounts of mucoadhesives, combined, are generally within a range from about 1 - 100 wt%, and preferably an amount within the range of 10 -50 wt%, and more preferably an amount within the range of 1 - 50 wt%, and especially preferred in an amount within the range of 0.1 - 10 wt% of the total LNP-NS’ weight

[0073] Suitable ciliostatic or cilio-inhibiting agents are species that immobilize or inhibit the beats of cilia and reduce the occurrence of mucociliary clearance by preventing irritation of the nasal cavity, hereby increasing bioavailability by disallowing the disruption of drug absorption. In the present embodiment, ciliostatic or cilio-inhibiting agents are species that do not irritate the nasal cavity and are typically but not limited to mucoadhesive agents. An especially preferred ciliostatic or cilio-inhibiting agent is carboxymethylcellulose.

[0074] The total amounts of ciliostatic or cilio-inhibiting agents, combined, are generally within a range from about 1 - 100 wt%, and preferably an amount within the range of 10 - 50 wt %, and more preferably an amount within the range of 1 - 50 wt%, and especially preferred in an amount within the range of 0.1 - 10 wt%, of the total LNP-NS’ weight.

[0075] Suitable aggregation inhibitory agents are species that inhibit the aggregation of the LNPs contained within the nasal spray matrix. These are typically pre-incorporated within the LNP but can also be incorporated within the nasal spray matrix. A suitable aggregation inhibitory agent is polysorbate 80.

[0076] The total amounts of aggregation inhibitory agents, combined, are generally within a range from about 1 - 100 wt%, and preferrably an amount within the range of 10 - 50 wt%, and more preferably an amount within the range of 1 - 50 wt%, and especially preferred in an amount within the range of 0.1 - 10 wt%, of the total LNP-NS’ weight

[0077] Suitable enzyme inhibitory agents are species that inhibit the function of a biological enzyme.

[0078] The total amounts of enzyme inhibitory agents, combined, are generally within a range from about 1 - 10 wt%, and preferrably an amount within the range of 1 - 5 wt %, and optimally an amount within the range of 0.1 - 1 wt%, of the total LNP-NS’ weight.

[0079] A preferred nasal spray matrix composition according to the invention includes a citrate buffer for pH control, sodium chloride, polyethylene glycol, disodium EDTA, carboxymethylcellulose, and glycerin.

[0080] The inclusion of a LNP-containing a psychedelic into the nasal spray matrix will be more effective over simply administering the LNP to the nasal cavity by other methods. Without the matrix, there might still be uptake, but there will be much more variability and potential discomfort due the lack of a buffering component and osmolality. Sodium chloride in the preferred composition makes the formulation isotonic to the cells. The presence of the carboxymethylcellulose helps suspend the nanoparticles in solution, the glycerin prevents drying of the nasal cavity, and the EDTA prevents the growth of bacteria during storage.

[0081] The nasal spray matrix in the composition of the present invention can be produced by high shear mixing and microfluidic processing of the nasal spray matrix components. The nasal spray matrix may also be produced by simple dissolution of the ingredients into the aqueous buffer using conventional heating, stirring, or mixing.Treatment

[0082] The general method of treatment comprises administering to a human or mammal subject a therapeutically-effective amount of an acceptable psychedelic or psychedelic analogue in one or more pharmaceutically acceptable carriers or excipients.

[0083] The administered composition is formulated for oral, sublingual, intranasal, pulmonary administration, buccal, 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 metered dose spray into a patient’s or animal’s intranasal cavity.

[0084] 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 bipolar depressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0085] 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.Dosage

[0086] The dosage regimen for the compositions described herein will, of course, vary depending upon known factors, 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.

[0087] 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.

[0088] 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.

[0089] Other conventional ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical compositionrequired. 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.

[0094] 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.Therapeutic Treatment

[0095] 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 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, Barrett et al. 2021). 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 therapeutic effect without the psychedelic state. One aspect of the invention comprises prodrugs of those 5HT2AR agonists which do provide a beneficial therapeutic state.

[0096] 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 5HT2AR agonist, or a method of treating any disease or disorder which may be alleviated by a psychedelic and / or a 5HT2AR agonist (Jain, Gumpper et al. 2025). The present invention is also suitable for treating diseases or disorders that are related to 5HT2AR agonists.

[0097] 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 presentinvention 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 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.

[0098] In some embodiments, the invention may comprise a method of treating mental disorders comprising administering to a subject 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 a therapeutically effective amount of a composition of the present invention. The depression effects may be drug-resistant depression or major depressive disorder.

[0099] 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.

[0100] 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.

[0101] In some embodiments, treatment with a composition of the present invention may be combined with concomitant treatment with another anti-depressantdrugs, 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

[0102] Our testing was done with 5-MeO-DMT, which is not regulated as a controlled substance in Canada, but which behaves in formulation in ways that are similar to controlled psychedelics.

[0103] Described herein are studies that were performed to develop an encapsulating lipid nanoparticle composition and its incorporation into nasal spray format and its method of manufacture for psychedelics. The experimental design provided multiple compositions of different ratios of oil, primary, and co-surfactant(s). These compositions were initially prepared by creating an ethanolic solution of oil, surfactants, and the psychedelic agent. The ethanol in the solution is removed under vacuum and water is added to form the LNP. The nasal spray matrix containing tonicity adjusters, preservatives, chelating agents, suspending agents, humectants, penetration enhancers, surfactants, co-solvents, buffer / pH control components, mucoadhesives, ciliostatic or cilio-inhibiting agents, aggregation inhibitory agents, and enzyme inhibitory agents is subjected to high pressure homogenization and the LNP is incorporated into the nasal spray matrix. The resulting LNP-NS possessed a uniform monomodal distribution of nanometer sized droplets.

[0104] Cytotoxicity assays on three cell lines reveal negligible toxicity of formulated 5-MeO-DMT at therapeutic concentrations.

[0105] 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 medium chain triglycerides (MCT) oil as the lipid, Kolliphor HS15 as the primary surfactant, and polysorbate 80 as the co-surfactant.

[0106] 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.

[0107] The resulting LNP-NS was characterized by dynamic light scattering to determine the average diameter of micellar droplets as well as to measure changes in polydispersity index and zeta potential (^-potential).

[0108] Biological assays were used to evaluate the effect of our LNP-NS on cells. Cytotoxicity was evaluated using normal and cancer cells.

[0109] The preparation of the LNP-NS is as follows. Initially, the LNPs were prepared using an ethanol-assisted emulsification approach by Banerjee (Banerjee, Hosie et al, 2024), with slight modifications. All the excipients, Kolliphor HS15 (4 wt%), polysorbate 80 (1 wt%), a-tocopherol (1 wt%), MCT oil (2 wt%), and psychedelic (2 wt%) were added to a round bottom flask and dissolved in ethanol by sonication for 15 min followed by magnetic stirring at 1000 rpm for another 15 min. The ethanol was then removed through rotary evaporation (P = 50 mbar; 40 min), producing a viscous, syrupy system that solidifies in the refrigerator. Finally, HPLC-grade water was added to the flask at 37 °C and magnetic stirring at 1000 rpm for 30 min to hydrate the LNP concentrate and make an emulsion with the desired 5-MeO-DMT concentration. The nasal spray matrix was prepared in a separate vessel containing citrate buffer (84.99 wt%), NaCI (1.9 wt%), 2-phenylethanol (0.25 wt%), polyethylene glycol (10 wt%), disodium ethylenediaminetetraacetic acid (0.5 wt%), carboxymethylcellulose (2 wt%), glycerin (0.23 wt%), and oleic acid (0.13 wt%). The nasal spray matrix was stirred at 1500 rpm for 30 minutes and subsequently high shear mixed at 12,000 rpm for 3 cycles of 60 seconds on followed by 60 seconds off. The coarse nasal spray matrix is then subjected to high-pressure homogenization for 4 cycles using the Z8 nozzle (0.2 mm aperture size) at a pressure of 15,000 -20,000 psi. The LNP is then incorporated into the stable nasal spray matrix in a ratioof 1 :1 v / v%. The LNP-NS is then vortexed to completely solubilize the LNP within the matrix and stored in transparent glass vials at 4 °C.

[0110] In order to determine lipid particle size distributions in the LNP-NS, dynamic light scattering, 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 (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 were calculated from the autocorrelation function of the intensity of light scattered from the particles.

[0111] The LNP-NS’s effect on cell viability was evaluated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The results of the cytotoxicity evaluation revealed negligible toxicity of both the nasal spray matrix itself, and the incorporation of the psychedelic LNP into the nasal spray matrix owing to the biocompatible nature of both the formulation’s excipients and the encapsulated psychedelic.

[0112] The ability for the LNP to encapsulate 5-MeO-DMT was tested by encapsulation efficiency. 5 g of formulation was added to Amicon® Ultra Centrifugal Filter, 3 kDa MWCO. They were centrifuged for 25 minutes at 20 °C at 4500 rpm. The pellet and supernatant were massed and aliquoted for HPLC. The encapsulation efficiency was calculated according to the following formula:

[0113] As Table 1 shows, the LNP-NS forms emulsions with average droplet sizes of ca. 60 nm, a narrow range of nanoparticle sizes, and the incorporated LNP possesses exceptional encapsulation efficiency of ca. 95%. We expect that this basic formulation will produce lipid nanoparticles having an average particle size within the range from about 10 nm to less than 300 nm, preferably within the range of about 20 - 250 nm, and even more preferably within the range of about 30 - 200 nm.TABLE 1 - LNP-NS fingerprintExperimental Details - Materials

[0114] All materials were purchased from Sigma Aldrich (St. Louis, MO, USA) unless otherwise stated and used as received. Medium chain triglycerides (MCT oil) were purchased from Charles Tenant and Company Ltd. (North York, ON, Canada). Polysorbate 80, carboxymethylcellulose, 2-phenylethanol, Kolliphor HS15 was purchased from Aaron Chemicals (San Diego, CA, USA). Citric acid was purchased from Oakwood Chemical (Estill, SC, USA). Glycerin was purchased from ACP Chemicals (Montreal, QC, Canada). 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). 5-Methoxy-N,N-dimethyltryptamine (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+).

[0115] Three different cell lines were used for the evaluation of the tested formulations and unformulated 5-MeO-DMT.

[0116] L2: The rat lung cell line https: / / www.atcc.org / products / ccl-149.

[0117] GBM U251 : The glioblastoma cancer cells https: / / www.cytion.com / U-251-MG-Cells / 300385.

[0118] HepG2: The hepatocellular carcinoma https: / / www.atcc.org / products / hb-8065.Preparation of the 5-MeO-DMT lipid nanoparticle - nasal sprays

[0119] The preparation of the LNP-NS is as follows. Initially, the LNPs were prepared using an ethanol-assisted emulsification approach by Banerjee (Banerjee, Hosie et al, 2024), with slight modifications. All the excipients, (Kolliphor HS15 (4wt%), polysorbate 80 (1 wt%), a-tocopherol (1 wt%), MCT oil (2 wt%), and psychedelic (2 wt%) were added to a round bottom flask and dissolved in ethanol by sonication for 15 min followed by magnetic stirring at 1000 rpm for another 15 min. The ethanol was then removed through rotary evaporation (P = 50 mbar; 40 min), producing a viscous, syrupy system that solidifies in the refrigerator. Finally, HPLC-grade water was added to the flask at 37 °C and magnetic stirring at 1000 rpm for 30 min to hydrate the LNP concentrate and make an emulsion with the desired 5-MeO-DMT concentration. The nasal spray matrix was prepared in a separate vessel containing citrate buffer (84.99 wt%), NaCI (1.9 wt%), 2-phenylethanol (0.25 wt%), polyethylene glycol (10 wt%), disodium ethylenediaminetetraacetic acid (0.5 wt%), carboxymethylcellulose (2 wt%), glycerin (0.23 wt%), and oleic acid (0.13 wt%). The nasal spray matrix was stirred at 1500 rpm for 30 minutes and subsequently high shear mixed at 12,000 rpm for 3 cycles of 60 seconds on followed by 60 seconds off. The coarse nasal spray matrix is then subjected to high-pressure homogenization for 4 cycles using the Z8 nozzle (0.2 mm aperture size) at a pressure of 15,000 -20,000 psi. The LNP is then incorporated into the stable nasal spray matrix in a ratio of 1 :1 v / v%. The LNP-NS is then vortexed to completely solubilize the LNP within the matrix and stored in transparent glass vials at 4 °C.

[0120] Extraction procedure: 50 - 100 mg of emulsion 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.

[0121] Sample acquisition and data analysis: Chromatographic analysis of supernatants from sample extraction was performed using an Agilent 1100 Liquid Chromatography system fitted with a photodiode array detector and using an Agilent Zorbax Eclipse Plus -C18 column (4.6 x 150mm, 3.5 pm). For data acquisition, the method reported by Cao (Cao, Wu et al 2019), was modified for proper and faster elution of the analyte, the disclosure of which is incorporated herein by reference. 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 18minutes 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 filtered with 0.20 pm filters before analysis.Standard dilutions of 5-MeO-DMT from 0.119 mg / mL to 0.001 mg / mL were 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 LNP-NS samples.

[0122] 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 liver cancer cell line, HepG2, 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% CO2 atmosphere with 95% humidity. The human glioblastoma cell, U251 , was purchased from Cytion and cultured in Minimal Essential Medium+ Earl’s Balanced Salts (MEM / EBSS, Hyclone, Logan, UT, USA), 10% FBS (Sigma-Aldrich), 1% penicillin / streptomycin (Sigma-Aldrich), and 1% Non-Essential Amino Acids (NEAA, Sigma-Aldrich) at 37 °C at 5% CO2 and 95% humidity. All the cell lines were sub-cultured when they got to 70% confluency.

[0123] The cytotoxicity of the LNP-NS was measured by the MTT assay on three different cell lines: L2 rat lung, HepG2 human liver cancer cells, and human glioblastoma U251 cells according to standard methods (Vistica, Skehan et al.1991). Briefly, the cells were seeded at 3x103cells / well for L2 cell,_2x103cells / well for HepG2, and 3x103cells / well for 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% CO2 with 95% humidity, cells were treated with 150 pL of the samples at four different concentrations (100, 1000, 10000, and 100000 dilution factor). After incubation for 48 h, the media was discarded and 100 pL of 0.5 mg-mL-1MTT stock solution was added to each well and the plates were incubated for an additional 4 hat 37 °C under 5% CO2 and 95% humidity. After discarding the MTT solution from wells, the obtained formazan crystals were solubilized with 100 pL / 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).

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Claims

CLAIMS:

1. A nanoemulsion composition comprising: lipid-based nanoparticles that comprise one or more psychedelic active ingredients that induce a psychedelic effect in a mammal.

2. A nanoemulsion composition as in claim 1 wherein said psychedelic active ingredient comprises 5-MeO-DMT, 4-MeO-DMT, 4-AcO-DMT (4-acetoxy-dimethyltrypamine), LSD, psilocybin, psilocin, mescaline, ibogaine, octanoyl bufotenin, and / or bufotenin.

3. A nasal spray composition that contains: (a) lipid-based nanoparticles that comprise one or more psychedelic active ingredients that induce a psychedelic effect in a mammal, and (b) a nasal spray matrix composition that comprises (i) a tonicity adjuster, (ii) a preservatives, (iii) a chelating agent, (iv) a suspending agent, (v) a humectant, (vi) a penetration enhancer, (vii) a surfactants, (viii) a co-solvent, (ix) a pH control agent, (x) a mucoadhesives, (xi) a ciliostatic or cilio-inhibiting agent, (xii) an aggregation inhibition agent, and / or (xiii) an enzyme inhibition agent.

4. A nasal spray composition as in claim 3 wherein said lipid-based nanoparticles are in a nanoemulsion.

5. A nasal spray composition as in claim 4 wherein said nanoemulsion composition comprises a self-nanoemulsifying drug delivery system.

6. A nasal spray composition according to claim 5 wherein said self-nanoemulsifying drug delivery system has an average droplet size containing a psychedelic drug or pro-drug encapsulated therein that is within a range from about 10 nm to less than 300 nm.

7. A nasal spray composition according to claim 6 wherein the average droplet size of said self-nanoemulsifying drug delivery system is within a range from about 10 nm to less than 150 nm.

8. A nasal spray composition according to claim 7 wherein the average droplet size of said self-nanoemulsifying drug delivery system is within a range from about 1 nm to less than 100 nm.

9. A nasal spray composition as in claim 3 wherein said psychedelic active ingredient comprises 5-MeO-DMT, 4-MeO-DMT, 4-AcO-DMT (4-acetoxy-dimethyltrypamine), LSD, psilocybin, psilocin, mescaline, ibogaine, octanoyl bufotenin, and / or bufotenin.

10. A nasal spray composition according to claim 9 wherein said psychedelic active ingredient further comprises ibogaine, octanoyl bufotenin, or 5-MeO-DMT.

11. A nasal spray composition according to claim 10 wherein said psychedelic active ingredient comprises 5-MeO-DMT.

12. A nasal spray composition according to claim 3 wherein said nasal spray matrix composition comprises a citrate buffer, sodium chloride, polyethylene glycol, disodium EDTA, carboxymethylcellulose, and glycerin.

13. A nasal spray composition according to claim 4 wherein said nanoemulsion is in liquid form and has a concentration of psychedelic active ingredients in an amount within a range from about 0.1-1000 mg / mL.

14. A nasal spray composition according to claim 13 wherein said concentration of psychedelic active ingredients in an amount within the range of 1-100 mg / mL.

15. A process for delivering a therapeutic amount of a psychedelic active ingredient to a human or mammal patient by administering to one or more nasal passages of said patient a measured dose of a nasal spray composition that comprises: (a) lipid-based nanoparticles containing one or more psychedelics in (b) a nasal spray matrix containing all or some of the following ingredients that behave as (i) tonicity adjusters, (ii) preservatives, (iii) chelating agents, (iv) suspending agents, (v) humectants, (vi) penetration enhancers, (vii) surfactants, (viii) co-solvents, (ix) buffer / pH control components, (x) mucoadhesives, (xi) ciliostatic or cilio-inhibiting agents, (xii) aggregation inhibitory agents, and (xiii) enzyme inhibitory agents.

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