Therapeutic combinations for movement disorders

Abstract

Therapeutic combinations, pharmaceutical compositions, and pharmaceutical kits containing bioactive molecules derived from fungi, plants, and algae are provided. In some embodiments, the fungus is from any psilocybin-producing fungus, such as a Psilocybe species fungus. In some embodiments, the plant is from either or both of the genera Cannabis and Dipteryx. In some embodiments, the algae may be marine algae, such as from the family Bangiaceae, including the genera Pyropia and Porphyra. Methods for producing the disclosed combinations, compositions, and kits are also provided, including by natural, biosynthetic, or synthetic means. Additionally, methods for using the disclosed combinations, compositions, and kits in the treatment of movement disorders, particularly Parkinson's disease, are provided, and the disclosed combinations are demonstrated to provide significant benefits in the treatment thereof.

Description

[Technical Field]

[0001] cross reference Priority is claimed under PCT Art. 8(1) and Rule 4.10 to U.S. Provisional Patent Application No. 63 / 405,430 (filed September 10, 2022), which is incorporated by reference for all purposes as if fully set forth herein.

[0002] FIELD OF THE INVENTION Provided are therapeutic combinations of bioactive molecules derived from fungi, plants, and algae, pharmaceutical compositions and kits containing such molecules, and methods for their use in medicine, particularly for treating movement disorders such as Parkinson's disease. [Background technology]

[0003] Nearly 40 million people in the United States suffer from movement disorders (Morishita, 2013). Most movement disorders are incurable, and treatments generally only attempt to alleviate symptoms or slow progression. Treatments typically fail to restore lost function and are insufficient to significantly slow the progression of most disorders. Current treatments, such as deep brain stimulation (DBS), which delivers electrical impulses to the brain using surgically implanted devices (Kringelbach et al., 2007), can also be invasive. Furthermore, current treatments cannot treat most non-motor symptoms of movement disorders, such as those related to thinking, memory, behavior, and mood. Therefore, there is a desperate need for new therapies that can reduce the severity of current symptoms, prevent the development of new symptoms, and broadly reverse the progression of the disease.

[0004] Provided herein are therapeutic combinations, pharmaceutical compositions and kits, and methods of their use, for treating movement disorders that meet these and other needs and have readily apparent advantages and improvements over prior art treatment options. Summary of the Invention

[0005] The following presents a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. This summary is not an extensive overview and is not intended to identify all key or critical elements of the invention or to delineate the full scope of the invention. Its sole purpose is to present some illustrative embodiments in a simplified form as a prelude to the more detailed description that follows.

[0006] In some embodiments, therapeutic combinations useful for preventing or treating movement disorders are disclosed, comprising a fungal part, a first plant part, optionally a second plant part, and an algal part. In some further embodiments, therapeutic combinations are disclosed, comprising a fungal part, a first plant part, a second plant part, and an algal part.

[0007] In some embodiments, the fungal portion is derived from a psilocybin-producing species. In some embodiments, the psilocybin-producing species is derived from any of the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In some embodiments, the psilocybin-producing species is derived from the genus Psilocybe. In some embodiments, the psilocybin-producing species from the genus Psilocybe is any of P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and P. liniformans. In some embodiments, the therapeutic combination comprises: a fungal part from a species of Psilocybe; a first plant part; a second plant part; and an algal part.

[0008] In some embodiments, the first plant part is from a Cannabis species. In some embodiments, the Cannabis species is Cannabis sativa, Cannabis indica, or Cannabis ruderalis. In some embodiments, the therapeutic combination comprises: a fungal part; a first plant part from a Cannabis species; a second plant part; and an algal part. In some embodiments, the therapeutic combination comprises: a fungal part from a Psilocybe species; a first plant part from a Cannabis species; a second plant part; and an algal part.

[0009] In some embodiments, the second plant part is from a species of the genus Dipteryx. In some embodiments, the Dipteryx species is Dipteryx odorata. In some embodiments, the therapeutic combination comprises a fungal part; a first plant part; a second plant part from a species of Dipteryx; and an algal part. In some embodiments, the therapeutic combination comprises: a fungal part from a species of Psilocybe; a first plant part from a species of Cannabis; a second plant part from a species of Dipteryx; and an algal part.

[0010] In some embodiments, the algae portion is from a seaweed species. In some embodiments, the seaweed species is from the family Bangiaceae. In some embodiments, the seaweed species is from the genera Pyropia and Porphyra. In some embodiments, the seaweed species is any of Pyropia yezoensis, Pyropia perforata, and Porphyra umbilicalis. In some embodiments, the therapeutic combination comprises a fungal portion; a first plant portion; a second plant portion; and an algae portion from a species of Pyropia or Porphyra. In some embodiments, the therapeutic combination comprises a fungal part from a Psilocybe species; a first plant part from a Cannabis species; a second plant part from a Dipteryx species; and an algal part from a Pyropia or Porphyra species.

[0011] In some embodiments, the fungal portion comprises a fungal extract from a psilocybin-producing species. In some embodiments, the fungal extract is derived from P. azurescens, P. bohemica, P. semilansata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weylii, P. hoogschagenii, P. stuntii, P. cyanofibrillosa, or P. liniformans. In some embodiments, the fungal extract is obtained by ultrasonic extraction or Soxhlet extraction. In some embodiments, the fungal extract comprises a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction.

[0012] In some embodiments, the first plant part comprises a cannabis plant extract derived from a species of the genus Cannabis. In some embodiments, the cannabis plant extract is derived from the species Cannabis sativa, Cannabis indica, or Cannabis ruderalis. In some embodiments, the cannabis plant extract is obtained by Soxhlet extraction.

[0013] In some embodiments, the second plant part comprises a Dipteryx plant extract from a species of the genus Dipteryx. In some embodiments, the Dipteryx plant extract is from Dipteryx odorata. In some embodiments, the Dipteryx plant extract is obtained by absolute ethanol extraction.

[0014] In some embodiments, the algae portion comprises an algae extract derived from a species of marine algae, such as Pyropia aezoensis, Pyropia perforata, or Porphyra umbilicalis. In some embodiments, the algae extract is obtained by ultrasonic extraction.

[0015] In some embodiments, the therapeutic combination comprises a fungal extract from Psilocybe species; a cannabis plant extract from Cannabis species; a Dipteryx plant extract from Dipteryx species; and an algae extract from Pyropia or Porphyra species.

[0016] In some embodiments, the therapeutic combination comprises a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction; a Cannabis plant extract obtained by Soxhlet extraction; a Dipteryx plant extract obtained by absolute ethanol extraction; and an algae extract obtained by ultrasonic extraction.

[0017] In some embodiments, the therapeutic combination comprises a fungal extract comprising psilocybin and psilocin; 9 -Cannabis plant extract containing THC (THC) and cannabidiol (CBD); Dipteryx plant extract containing coumarin; and algae extract containing porphyran.

[0018] In some embodiments, the therapeutic combination comprises a fungal portion comprising psilocybin and psilocin; 9-comprises a first plant part comprising THC (THC) and cannabidiol (CBD); a second plant part comprising coumarin; and an algal part comprising porphyran.

[0019] In some embodiments, the fungal portion comprises a fungal-derived bioactive molecule. In some embodiments, the fungal-derived bioactive molecule is a primary bioactive molecule from a psilocybin-producing species. In some embodiments, the primary bioactive molecule from a psilocybin-producing species is one or more tryptamines or one or more beta-carbolines. In some embodiments, the one or more tryptamines are psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aeruginascin. In some embodiments, the one or more tryptamines are psilocybin or psilocin. In some embodiments, the one or more tryptamines are psilocybin and psilocin. In some embodiments, the psilocybin and psilocin are in a weight ratio of about 5:3. In some embodiments, the one or more β-carbolines are harmane, harmine, harmol, pinoline, harmaline, cordysinin C, cordysinin D, norharmane, and perlolyrine. In some embodiments, the fungal-derived bioactive molecule is a secondary bioactive molecule from a psilocybin-producing species. In some embodiments, the secondary bioactive molecule from a psilocybin-producing species is a polysaccharide, a peptide, a terpene, a phenolic compound, a mineral, a vitamin, an amino acid, a lipid, choline, or a lactone.

[0020] In some embodiments, the first plant part comprises a bioactive molecule derived from Cannabis. In some embodiments, the bioactive molecule derived from Cannabis is a primary bioactive molecule derived from a Cannabis species. In some embodiments, the primary bioactive molecule derived from a Cannabis species is one or more cannabinoids. In some embodiments, the one or more cannabinoids are Δ 9 -THC-type cannabinoids, Δ 8 -THC-type cannabinoids, CBG-type cannabinoids, CBD-type cannabinoids, CBND-type cannabinoids, CBE-type cannabinoids, CBL-type cannabinoids, CBC-type cannabinoids, CBN-type cannabinoids, CBT-type cannabinoids, and mixed cannabinoids. In some embodiments, the one or more cannabinoids are Δ 9 In some embodiments, the one or more cannabinoids are THC and CBD. In some embodiments, the THC and CBD are in a weight ratio of about 1:1. In some embodiments, the cannabis-derived bioactive molecule is a secondary bioactive molecule derived from a cannabis species. In some embodiments, the secondary bioactive molecule derived from a cannabis species is any of a flavone or flavonoid, a terpene or terpenoid, a carbohydrate, a fatty acid or fatty acid ester, an amide, an amine, a phytosterol, and a phenolic compound.

[0021] In some embodiments, the second plant part comprises a bioactive molecule from Dipteryx. In some embodiments, the bioactive molecule from Dipteryx is a primary bioactive molecule from Dipteryx odorata. In some embodiments, the primary bioactive molecule from Dipteryx odorata is coumarin. In some embodiments, the bioactive molecule from Dipteryx is a secondary bioactive molecule from Dipteryx odorata. In some embodiments, the secondary bioactive molecule from Dipteryx odorata is selected from the group consisting of coumaric acid, coumarin derivatives, isoflavones, lupeol derivatives, fatty acid esters, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxyretsin-8-methyl ether, 5-methoxyxanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, betulin, butin, coumaric acid-β-glucoside, dipteryxin, and dipteryxic acid. , eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyllinolenic acid, methyloleic acid, O-coumaric acid, O-hydroxycoumaric acid, odoratin, P-hydroxybenzoic acid, retusin, retusin-8-methyl ether, sulfuretin, salicylic acid, afromisin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone.

[0022] In some embodiments, the algae portion comprises an algae-derived bioactive molecule. In some embodiments, the algae-derived bioactive molecule is a primary bioactive molecule from Pyropia or Porphyra. In some embodiments, the primary bioactive molecule from Pyropia or Porphyra is any of a porphyran, oligoporphyran, polysaccharide, oligopolysaccharide, monosaccharide, peptide, phycobiliprotein, mycosporine-like amino acid, essential amino acid, non-essential amino acid, carotene, intermediate carotenoid, glycoprotein, aminosulfonic acid, and taurine. In some embodiments, the primary bioactive molecule from Pyropia or Porphyra is a porphyran. In some embodiments, the algae-derived bioactive molecule is a secondary bioactive molecule from Pyropia or Porphyra. In some embodiments, the secondary bioactive molecule from Pyropia or Porphyra is any of a mineral, a vitamin, a lipid, a phenolic compound, and a phlorotannin.

[0023] In some embodiments, the therapeutic combination further comprises a flavoring or coloring agent. In some embodiments, the flavoring agent is ginger or bay leaf.

[0024] In some embodiments, the therapeutic combination further comprises an additional active agent, which in some embodiments is levodopa, carbidopa, carbidopa-levodopa, entacapone, carbidopa-levodopa-entacapone, tolcapone, opicapone, pramipexole, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, or the like. legiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, procyclidine, trihexyphenidyl, orphenadrine, and buntanetap.

[0025] In some embodiments, at least one of the fungal part, the first plant part, the second plant part, or the algal part further comprises a non-naturally occurring carrier, diluent, or excipient, hi some embodiments, at least two, at least three, or all four of the fungal part, the first plant part, the second plant part, and the algal part further comprise a non-naturally occurring carrier, diluent, or excipient.

[0026] In some embodiments, the therapeutic combination comprises a bioactive molecule from a Psilocybe species; a bioactive molecule from a Cannabis species; a bioactive molecule from a Dipteryx species; and a bioactive molecule from a Pyropia or Porphyra species.

[0027] In some embodiments, the therapeutic combination comprises a primary bioactive molecule from a species of the genus Psilocybe; a primary bioactive molecule from a species of the genus Cannabis; a primary bioactive molecule from a species of the genus Dipteryx; and a primary bioactive molecule from a species of the genus Pyropia or Porphyra.

[0028] In some embodiments, the therapeutic combination comprises one or more tryptamines from Psilocybe species; one or more cannabinoids from Cannabis species; a coumarin; and a porphyran.

[0029] In some embodiments, the therapeutic combination comprises psilocybin and psilocin; THC and CBD; coumarin; and porphyran.

[0030] In some embodiments, the therapeutic combination comprises psilocybin and psilocin in a 5:3 weight ratio; THC and CBD in a 1:1 weight ratio; coumarin; and porphyran.

[0031] In some embodiments, the therapeutic combination further comprises a second bioactive molecule from a Psilocybe species; a second bioactive molecule from a Cannabis species; a second bioactive molecule from a Dipteryx species; and a second bioactive molecule from a Pyropia or Porphyra species.

[0032] In some embodiments, one bioactive molecule, two bioactive molecules, three bioactive molecules, four bioactive molecules, five bioactive molecules, six bioactive molecules, at least one bioactive molecule, at least two bioactive molecules, at least three bioactive molecules, at least four bioactive molecules, at least five bioactive molecules, at least six bioactive molecules, all bioactive molecules, no more than six bioactive molecules, no more than five bioactive molecules, no more than four bioactive molecules, no more than three bioactive molecules, no more than two bioactive molecules are from the extract, contained in the extract, isolated molecules, pure molecules, substantially pure molecules, or synthetic molecules, or none of the bioactive molecules are from the extract, contained in the extract, isolated molecules, pure molecules, substantially pure molecules, or synthetic molecules.

[0033] In some embodiments, a single dose of the therapeutic combination comprises 250 μg of psilocybin; 150 μg of psilocin; 1 mg of CBD; 1 mg of THC; 1 mg of coumarin; 8 mg of Psilocybein extract, and, optionally, 8 mg of flavoring or coloring agent.

[0034] In some embodiments, the flavoring or coloring agent comprises ginger or bay leaf. In some embodiments, the flavoring or coloring agent comprises ginger and bay leaf.

[0035] In some embodiments, the therapeutic combination further comprises a diluent, hi some embodiments, the diluent is water.

[0036] In some embodiments, the fungal portion of the therapeutic combination comprises about 45% by volume of the total combination; the first plant part comprises about 15% by volume of the total combination; the second plant part comprises about 2% by volume of the total combination; the algae portion comprises about 15% by volume of the total combination; the flavoring or coloring agent comprises about 15% by volume of the total combination; and the diluent comprises the remainder of the total combination.

[0037] In some embodiments, the fungal portion of the therapeutic combination comprises a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction; the first plant portion comprises a Cannabis plant extract obtained by Soxhlet extraction; the second plant portion comprises a Dipteryx plant extract obtained by absolute ethanol extraction; the algae portion comprises an algae extract obtained by ultrasonic extraction; the flavoring or coloring agent comprises an ethanol infusion of ginger and bay leaves; and the diluent comprises water.

[0038] In some embodiments, the fungal portion of the therapeutic combination is a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction; the first plant part is a Cannabis plant extract obtained by Soxhlet extraction; the second plant part is a Dipteryx plant extract obtained by absolute ethanol extraction; the algae portion is an algae extract obtained by ultrasonic extraction; the flavoring or coloring agent is an ethanol infusion of ginger and bay leaves; and the diluent is water.

[0039] In some embodiments, the diluent comprises water and at least one non-naturally occurring diluent.

[0040] In some aspects, methods for preparing the disclosed therapeutic combinations are disclosed, the methods comprising the steps of obtaining a fungal extract by ultrasonic extraction and / or Soxhlet extraction; obtaining a Cannabis plant extract by Soxhlet extraction; obtaining a Dipteryx plant extract by absolute ethanol extraction; obtaining an algae extract by ultrasonic extraction; analyzing the concentration of at least one bioactive molecule in each extract; calculating a blending ratio for achieving a target dose for the at least one bioactive molecule in each extract; blending the calculated amount of each extract based on the blending ratio into a mixture; optionally homogenizing the mixture; optionally adding a flavoring or coloring agent; and optionally adding a diluent to obtain the target amount.

[0041] In some embodiments, the target dose of each of the at least one bioactive molecule in each extract comprises 250 μg of psilocybin; 150 μg of psilocin; 1 mg of CBD; 1 mg of THC; and 1 mg of coumarin.

[0042] In some embodiments, the calculated amount of each extract based on the blend ratio includes 45% by volume of the total blend for the fungal extract; 15% by volume of the total blend for the Cannabis plant extract; 2% by volume of the total blend for the Dipteryx plant extract; 15% by volume of the total blend for the algae extract; 15% by volume of the total blend for the flavoring or coloring agent; and 8% by volume of the total blend for the diluent.

[0043] In some aspects, pharmaceutical compositions are disclosed that include the disclosed therapeutic combinations and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is non-naturally occurring.

[0044] In some embodiments, the pharmaceutical composition is suitable for enteral or parenteral administration. In some embodiments, the pharmaceutical composition is prepared as a tincture, oral spray, oral mucosal spray, soft mist inhalation, vapor, tablet, divisible multiple-action tablet, capsule, capsule with added active agent, suspension, intravenous solution, injection solution, topical formulation for transdermal administration, cut matrix sublingual or buccal tablet, individually formed sublingual or buccal lozenge, or nasal delivery formulation. In some embodiments, the pharmaceutical composition is prepared as a tincture, oral spray, oral mucosal spray, or soft mist inhalation.

[0045] In some embodiments, the pharmaceutical composition is a formulation that includes 45% by volume of the total combination of fungal extract; 15% by volume of the total combination of cannabis plant extract; 2% by volume of the total combination of Dipteryx plant extract; 15% by volume of the total combination of algae extract; 15% by volume of the total combination of flavoring or coloring agent; and 8% by volume of the total combination of diluent.

[0046] In some embodiments, a single dose of the formulation contains 250 μg of psilocybin; 150 μg of psilocin; 1 mg of CBD; 1 mg of THC; 1 mg of coumarin; 8 mg of Psilocybein extract, and, optionally, 8 mg of flavoring or coloring agent.

[0047] In some embodiments, the single dose of psilocybin is between about 0.5 μg and about 200 mg, between about 5 μg and about 5 mg, or between about 100 μg and about 600 μg. In some embodiments, the single dose of psilocybin is 250 μg. In some embodiments, the single dose of psilocin is between about 0.5 μg and about 200 mg, between about 5 μg and about 5 mg, or between about 100 μg and about 600 μg. In some embodiments, the single dose of psilocin is 150 μg.

[0048] In some embodiments, the CBD dosage is between about 0.5 μg and about 200 mg, between about 0.01 mg and about 75 mg, or between about 0.5 mg and about 15 mg. In some embodiments, the CBD dosage is 1 mg. In some embodiments, the THC dosage is between about 0.5 μg and about 200 mg, between about 0.01 mg and about 75 mg, or between about 0.5 mg and about 15 mg. In some embodiments, the THC dosage is 1 mg.

[0049] In some embodiments, the single dose of coumarin is between about 0.5 μg and about 200 mg, between about 0.01 mg and about 75 mg, or between about 0.5 mg and about 15 mg, hi some embodiments, the single dose of coumarin is 1 mg.

[0050] In some embodiments, a single dose comprises about 0.5 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 20 mg of Pyropia aezoensis, Pyropia perforata, or Porphyra umbilicalis whole extract, hi some embodiments, a single dose comprises about 8 mg of Pyropia whole extract.

[0051] In some embodiments, a single dose comprises an ethanolic decoction of ginger and bay leaves in an amount of between about 0.5 mg and about 100 mg, between about 1 mg and about 50 mg, or between about 5 mg and about 20 mg, hi some embodiments, a single dose comprises an ethanolic decoction of ginger and bay leaves in an amount of 8 mg.

[0052] In some embodiments, a pharmaceutical kit is disclosed that includes a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition includes at least a portion of the therapeutic combination of claim 21 and a pharmaceutically acceptable carrier, diluent, or excipient; and the second pharmaceutical composition includes the remaining portion of the therapeutic combination of claim 21 and a pharmaceutically acceptable carrier, diluent, or excipient.

[0053] In some embodiments, the first pharmaceutical composition is formulated as a tincture, oral spray, oral mucosal spray, or soft mist inhalation formulation; and the second pharmaceutical composition is formulated as a tincture, oral spray, oral mucosal spray, or soft mist inhalation formulation.

[0054] In some aspects, methods of preventing or treating movement disorders are disclosed, the methods comprising administering to a patient in need thereof a disclosed therapeutic combination, a disclosed pharmaceutical composition, or a disclosed pharmaceutical kit.

[0055] In some embodiments, the movement disorder is any one or more of ataxia, ataxic disorders, certain defined movement disorders, cervical dystonia, chorea, choreiform disorders, dystonia, dystonic disorders, essential tremor, Friedreich's ataxia, functional movement disorders, hemifacial spasm, hereditary spastic paraplegia, Huntington's disease, L-dopa-induced dyskinesia, multiple system atrophy (MSA), myoclonus, myoclonic disorders, Parkinson's disease, atypical Parkinson's disease, parkinsonism, secondary parkinsonism, progressive supranuclear palsy (PSP), restless legs syndrome, Rett syndrome, sleep-related movement disorder, spasticity, tardive dyskinesia (TD), Tourette's syndrome, tic disorders, disorders associated with tremor, and Wilson's disease.

[0056] In some embodiments, the pharmaceutical composition is administered 1 to 8 times per day. In some embodiments, the patient experiences an improvement associated with the movement disorder. In some embodiments, the improvement is a decrease in the severity of at least one symptom of the movement disorder.

[0057] In some embodiments, at least one symptom of the movement disorder is a motor symptom. In some embodiments, the motor symptoms are any of the following: slouching posture, masked facial expression, leaning trunk, flexion of elbows and wrists, reduced arm swing, flexion of hips and knees, trembling of limbs, shuffling gait, walking with short steps, uncoordinated or awkward balance, altered speech, involuntary limb movements, irregular movements, long-lasting contractions, intermittent contractions of neck muscles, turning the head in different ways; repetitive, irregular, involuntary movements of the face, mouth, trunk, or limbs; twisting, repetitive movements; twitching, trembling, stiffness of a muscle or muscle group, finger tapping, toe tapping, poor posture, slow, reduced movement or imbalance; difficulty walking, irregular involuntary eye movements, involuntary eye blinking, involuntary grimacing, unpleasant or abnormal sensations in the limbs (which may be relieved by movement); involuntary vocalizations, rhythmic trembling of a part of the body (typically the hands and / or head). In some embodiments, the motor symptoms are any of the following: problems speaking; excessive saliva and drooling; problems chewing or swallowing; difficulty eating, dressing, maintaining proper hygiene, writing, or engaging in hobbies or other activities; difficulty rolling over in bed or getting out of a bed, car, or deep chair; difficulty walking or maintaining balance; experiencing tremors; or problems freezing in place.

[0058] In some embodiments, at least one symptom of movement disorder is a non-motor symptom.In some embodiments, the non-motor symptom is any of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, lethargy, characteristics of dopamine dysregulation syndrome, sleep disorder, daytime sleepiness, pain and other sensations, urinary disorder, constipation disorder, orthostatic dizziness, and fatigue.In some embodiments, the non-motor symptom is a mood symptom.In some embodiments, the mood symptom is any of depression, anxiety, irritability, mood swings, impaired judgment, loss of empathy, aggression, impulsivity, delusions, and paranoia.

[0059] In some embodiments, the reduction in severity of at least one symptom of the movement disorder occurs in less than about 75 days after the first administration of the pharmaceutical composition. In some embodiments, the reduction in severity of at least one symptom of the movement disorder occurs in less than about 35 days after the first administration of the pharmaceutical composition. In some embodiments, the reduction in severity of at least one symptom of the movement disorder lasts for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

[0060] In some embodiments, the improvement is improvement in motor control. In some embodiments, the improvement in motor control is improvement in any of balance, frequency of involuntary movements, amplitude of involuntary movements, muscle strength, endurance, and physical performance. In some embodiments, the improvement in motor control occurs in less than about 75 days after the first administration of the pharmaceutical composition. In some embodiments, the improvement in motor control occurs in less than about 35 days after the first administration of the pharmaceutical composition.

[0061] In some embodiments, the improvement is with respect to a clinical outcome assessment. In some embodiments, the clinical outcome assessment is a clinical outcome assessment such as the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS), the Corticobasal Ganglia Function Scale (SBFS), the Gastrointestinal Dysfunction Scale for Parkinson's Disease (GIDS-PD), the Expanded Wilson's Disease Rating Scale (GAS for WD), the Generalized Dystonia Severity Scale (GDS), the Bradypsychiatric Rating Scale-Revised (MBRS), the Non-Motor Symptom Questionnaire (NMSQ), the Parkinson's Disease Non-Motor Scale (NMSS), the Pantothenate Kinase-Associated Neurodegenerative Disorders Rating Scale (PKAN-DRS), the Progressive Supranuclear Palsy Clinical Deficits Scale (PSP ... Scale) (PSP-CDS), Essential Tremor Quality of Life Questionnaire, Psychogenic Movement Disorders Rating Scale, Rush Dyskinesia Rating Scale (RDRS), Rush Video-Based Tic Rating Scale (RVBTRS), Parkinson's Disease Outcome Assessment Scale - Autonomic Dysfunction (SCOPA-AUT), Parkinson's Disease Outcome Assessment Scale - Diary Card (SCOPA-DC), Parkinson's Disease Outcome Assessment Scale - Psychiatric Comorbidities (SCOPA-PC), Parkinson's Disease Outcome Assessment Scale - Psychosocial Functioning (SCOPA-PS), Parkinson's Disease Outcome Assessment Scale - Sleep ( In some embodiments, the clinical outcome assessment is any of the following: SCOPA-Sleep (SCOPA-S), Parkinson's Disease Outcome Assessment Scale-Cognitive (SCOPA-COG), Brief Parkinson's Disease Assessment Scale (SPES) / Parkinson's Disease Outcome Assessment Scale-Motor Function (SPES / SCOPA-Motor), Non-Motor Fluctuation Assessment (NoMoFA) questionnaire, UFMG Sydenham Chorea Rating Scale (USCRS), Unified Dyskinesia Rating Scale (UDysRS), Unified Dystonia Rating Scale (UDRS), Unified Multiple System Atrophy Rating Scale (UMSARS), and 8-item Unified Parkinson's Disease Rating Scale-8 (UPDRS-8). In some embodiments, the clinical outcome assessment is MDS-UPDRS, UPDRS, or UPDRS-8. In some embodiments, the clinical outcome assessment is MDS-UPDRS.

[0062] In some embodiments, the improvement in MDS-UPDRS is the improvement in nM-EDL.In some embodiments, the improvement in nM-EDL is for any of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, lethargy, characteristics of dopamine dysregulation syndrome, sleep disturbance, daytime sleepiness, pain and other sensations, urinary disturbance, constipation disturbance, orthostatic dizziness and fatigue.

[0063] In some embodiments, the improvement in the MDS-UPDRS is an improvement in the M-EDL, hi some embodiments, the improvement in the M-EDL is in any of speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, performing hobbies and other activities, turning in bed, tremor, getting out of bed, car, or deep chair, walking and balance, and solidifying.

[0064] In some embodiments, the improvement in the MDS-UPDRS is an improvement in a motor test, in some embodiments, the improvement in a motor test is for any of speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination, toe tapping, leg agility, chair rise, gait, gait stiffness, postural stability, posture, overall movement spontaneity (bradykinesia), hand postural tremor, hand kinetic tremor, resting tremor amplitude, resting tremor constancy, Hoehn and Yahr stage, time spent with dyskinesia, functional impact of dyskinesia, time spent in off-state, functional impact of fluctuations, complexity of motor fluctuations, and painful off-state dystonia.

[0065] In some embodiments, the improvement is a decrease in score, hi some embodiments, the decrease in score is at least 1 point, at least 2 points, at least 3 points, or at least 4 points.

[0066] In some embodiments, the improvement is an improvement in UPDRS.

[0067] In some embodiments, the improvement in UPDRS is an improvement in mental state, behavior, and mood. In some embodiments, the improvement in mental, behavior, and mood is any of intellectual disability, thought disorder, depression, and motivation / initiative.

[0068] In some embodiments, the improvement in UPDRS is an improvement in ADL. In some embodiments, the improvement in ADL is for any of the following complaints: speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning and adjusting bedding, falls, stiffness when walking, gait, tremor, and sensory impairments associated with parkinsonism.

[0069] In some embodiments, the improvement in the UPDRS is an improvement in motor tests. In some embodiments, the improvement in motor tests is in any of speech, facial expression, resting tremor, hand movement or postural tremor, rigidity, finger tapping, hand movement, rapid hand movements, leg agility, chair rising, posture, gait, postural stability, and bradykinesia and reduced motor function.

[0070] In some embodiments, the improvement in the UPDRS is an improvement in a complication of treatment, ie, an improvement in any of the following: daily duration of dyskinesias, severity of disability due to dyskinesias, painful dyskinesias, and the percentage of waking days in which the patient is "off" on average.

[0071] In some embodiments, the improvement is an improvement in score. In some embodiments, the improvement in score is at least 1 point, at least 2 points, at least 3 points, or at least 4 points. In some embodiments, the improvement in UPDRS is a reduction in stage on the Modified Hoehn and Yahr Staging Scale. In some embodiments, the reduction is a reduction of at least one stage. In some embodiments, the improvement in UPDRS is a reduction in Schwab and England ADL Scale percentage. In some embodiments, the reduction is a reduction of between about 10% and about 100%. In some embodiments, the improvement in UPDRS is a change in binary "yes" and "no" questions.

[0072] In some embodiments, the improvement occurs in less than about 75 days from the first administration of the pharmaceutical composition. In some embodiments, the improvement occurs in less than about 35 days from the first administration of the pharmaceutical composition. In some embodiments, the improvement lasts for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

[0073] The foregoing has outlined, in broad terms, some pertinent features of certain exemplary embodiments of the present disclosure in order that the detailed description that follows may be better understood, and that this contribution to the art may be more fully appreciated. Additional features of the present invention that form the subject matter of the claims follow. Those skilled in the art will appreciate that the particular formulations and methods disclosed may be readily utilized as a basis for modifying or designing other formulations and methods for carrying out the same purposes of the present disclosure. It will also be understood that such equivalent formulations and methods do not depart from the spirit and scope of the invention as claimed. This Summary is therefore intended to be a brief and general overview of only some aspects and embodiments herein, and is provided solely for the benefit and convenience of the reader, with the understanding that it is not intended in any way to limit the scope of the claims to which they are legally entitled or the scope of equivalents.

[0074] To further clarify various aspects of the present invention, a more particular description will be made by reference to certain exemplary embodiments which are illustrated in the drawings. It will be understood that these drawings depict only exemplary embodiments of the invention and should not be considered as limiting its scope. They are provided merely as illustrative illustrations of certain concepts of some embodiments of the invention. Certain aspects of the invention will therefore be described with further specificity and detail, which, again by way of example only, will be described with reference to the accompanying drawings in which: [Brief explanation of the drawings]

[0075] [Figure 1]

[0023] Figure 1 provides a summary and overview of certain recurring patterns of observed therapeutic activity and benefit by individuals utilizing the disclosed combinations. [Figure 2] FIG. 1 illustrates hand movement improvement through software-assisted motion tracking. [Figure 3]FIG. 1 summarizes certain observed data for the treatment of Parkinson's disease in terms of disease footprint using the Unified Parkinson's Disease Rating Scale, 8-item version (UPDRS-8) scoring (see, e.g., Hauser, Lyons, & Pahwa, 2012) before and after treatment with a composition referred to herein as ABS-108, and defined below, in studies conducted in accordance with some embodiments of the present invention. [Figure 4] FIG. 1 shows certain observed data regarding the treatment of Parkinson's disease in studies conducted according to some embodiments of the present invention, summarized by time to ABS-108 motor response versus disease progression. [Figure 5] FIG. 10 shows UPDRS-8 scoring estimates as change from baseline pre- and post-treatment with ABS-108 for patient A2 (described further below) for the non-motor symptom, motor symptom, and motor complication domains. [Figure 6] FIG. 1 shows estimated UPDRS-8 scoring for patient A3. [Figure 7] FIG. 1 shows estimated UPDRS-8 scoring for patient A4. [Figure 8] FIG. 1 shows estimated UPDRS-8 scoring for patient A5. [Figure 9] FIG. 1 shows estimated UPDRS-8 scoring for patient A6. [Figure 10] FIG. 1 shows estimated UPDRS-8 scoring for patient A9. [Figure 11] FIG. 1 shows estimated UPDRS-8 scoring for patient A10. [Figure 12] FIG. 1 shows estimated UPDRS-8 scoring for patient A11. [Figure 13] FIG. 1 shows estimated UPDRS-8 scoring for patient A12. [Figure 14] FIG. 1 shows estimated UPDRS-8 scoring for patient A13. [Figure 15]FIG. 1 shows estimated UPDRS-8 scoring for patient A14. [Figure 16] FIG. 1 shows estimated UPDRS-8 scoring for patient A16. [Figure 17] FIG. 1 shows estimated UPDRS-8 scoring for patient A17. [Figure 18] FIG. 1 shows estimated UPDRS-8 scoring for patient A18. [Figure 19] 1 is a spider chart showing UPDRS-8 scores for each of the eight items for patient A2 before and after treatment with ABS-108 according to the method of Example 16. [Figure 20] 1 is a spider chart of UPDRS-8 scores before and after treatment for patient A3. [Figure 21] 1 is a spider chart of UPDRS-8 scores before and after treatment for patient A4. [Figure 22] This is a spider chart of the UPDRS-8 scores of patient A5 before and after treatment. [Figure 23] This is a spider chart of the UPDRS-8 scores of patient A6 before and after treatment. [Figure 24] This is a spider chart of the UPDRS-8 scores of patient A9 before and after treatment. [Figure 25] This is a spider chart of the UPDRS-8 scores of patient A10 before and after treatment. [Figure 26] This is a spider chart of the UPDRS-8 scores of patient A11 before and after treatment. [Figure 27] This is a spider chart of the UPDRS-8 scores of patient A12 before and after treatment. [Figure 28] This is a spider chart of the UPDRS-8 scores of patient A13 before and after treatment. [Figure 29] This is a spider chart of the UPDRS-8 scores of patient A14 before and after treatment. [Figure 30] This is a spider chart of the UPDRS-8 scores of patient A16 before and after treatment. [Figure 31] This is a spider chart of the UPDRS-8 scores of patient A17 before and after treatment. [Figure 32] This is a spider chart of the UPDRS-8 scores of patient A18 before and after treatment. [Figure 33] FIG. 1 illustrates the production of an exemplary formulation by the method of certain described embodiments. [Figure 34] FIG. 1 shows an exemplary analysis of formulations by liquid chromatography-mass spectrometry (LC-MS) testing, including chromatograms showing various concentrations of bioactive molecules contained in the formulations with parameters disclosed in Table 6. [Figure 35] FIG. 1 shows an example H NMR spectrum of the disclosed composition having the parameters listed in Table 6. [Figure 36] Table 6 shows an example of the analysis of a formulation by multiple reaction monitoring (MRM) LC-MS study, including a chromatogram showing the concentration of bioactive molecules contained in the formulation with the parameters disclosed. [Figure 37] FIG. 1 shows the total antioxidant capacity of cannabis stocks as measured by the Folin-Ciocalteu assay, where the calculated gallic acid equivalents (GAE) of the cannabis stocks are plotted in milligrams (mg) per milliliter per liter (mL / L) of a given solution. [Figure 38] FIG. 1 shows the total antioxidant capacity of psilocybestock using the Folin-Ciocalteu assay. The calculated GAE of psilocybestock is plotted in mg per mL / L of a given solution. [Figure 39] FIG. 1 shows the total antioxidant capacity of Pyropia stoc using the Folin-Ciocalteu assay. The calculated GAE of Pyropia stoc is plotted in mg per mL / L of a given solution. [Figure 40] FIG. 1 shows the total antioxidant capacity of Tonka concentrates using the Folin-Ciocalteu assay. The calculated GAE of Tonka concentrates is plotted in mg per mL / L of a given solution. [Figure 41]Figure 41 shows the total antioxidant capacity of cannabis stock (Ca stock), psilocybe stock (Ps stock), and a cannabis / psilocybe binary blend (Ca / Ps) using the Folin-Ciocalteu assay (i.e., obtained by the Folin-Ciocalteu assay). Figure 41 shows the calculated GAE for the Ca stock, Ps stock, and Ca / Ps in mg per mL / L of solution utilized. The table below the graph in Figure 41 represents the statistical significance of the Ca stock vs. Ca / Ps and Ps stock vs. Ca / Ps, indicated by asterisks (* if P<0.10, * if P<0.05, and ** if P<0.01). The cannabis / psilocybe binary blend had a higher antioxidant capacity than either component alone, and this data suggested an additive effect of the two components contributing to the capacity of the binary blend. [Figure 42] Figure 42 shows the total antioxidant capacity of cannabis stock (Ca stock), Pyropia stock (Py stock), and a binary blend of cannabis / Pyropia (Ca / Py) obtained by the Folin-Ciocalteu assay. Figure 42 shows the calculated GAE for Ca stock, Py stock, and Ca / Py in mg per mL / L of solution utilized. The table below the graph in Figure 42 indicates the statistical significance of the Ca stock vs. Ca / Py and Py stock vs. Ca / Py, indicated by asterisks (* if P<0.10, * if P<0.05, and ** if P<0.01). The binary blend of cannabis and Pyropia had a higher antioxidant capacity than either component alone, and the data suggest a synergistic effect, as the antioxidant capacity of the binary blend was higher than that predicted by adding the values ​​of the two components together. [Figure 43]Figure 43 shows the total antioxidant capacity of cannabis stock (Ca stock), tonka stock (To stock), and a cannabis / tonka binary blend (Ca / To) as determined by the Folin-Ciocalteu assay. Figure 43 shows the calculated GAE for Ca stock, To stock, and Ca / To in mg per mL / L of solution utilized. The table below the graph in Figure 43 indicates the statistical significance of Ca stock vs. Ca / To and To stock vs. Ca / To, indicated by asterisks (P<0.10: (*), P<0.05: *, and P<0.01: **). The cannabis and tonka binary blend had antioxidant capacity comparable to the cannabis components. Tonka slightly improved antioxidant capacity despite its relatively low percentage in the blend. [Figure 44] Figure 44 shows the total antioxidant capacity of Psilocybe stock (Ps stock), Pyropia stock (Py stock), and the Psilocybe / Pyropia binary blend (Ps / Py) obtained by the Folin-Ciocalteu assay. Figure 44 shows the calculated GAE for Ps stock, Py stock, and Ps / Py in mg per mL / L of solution used. The table below the graph in Figure 44 indicates the statistical significance of Ps stock vs. Ps / Py and Py stock vs. Py / Py, indicated by asterisks (* if P<0.10, * if P<0.05, and ** if P<0.01). The Psilocybe / Pyropia binary blend had a slightly lower antioxidant capacity than Psilocybe alone. This suggests that compounds in the Pyropia stock solution interacted in a way that reduced antioxidant capacity, i.e., its ability to donate electrons to the chemical reactions in the assay. [Figure 45]Figure 45 shows the total antioxidant capacity of psilocybe stock (Ps stock), tonka stock (To stock), and a psilocybe / tonka binary blend (Ps / To) obtained by the Folin-Ciocalteu assay. Figure 45 shows the calculated GAE for Ps stock, To stock, and Ps / To in mg per mL / L of solution used. The table below the graph in Figure 45 indicates the statistical significance of the Ps stock vs. Ps / To and To stock vs. Ps / To, indicated by asterisks (P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The psilocybe / tonka binary blend had a lower antioxidant capacity than psilocybe alone. This suggests that compounds in tonka interacted with compounds in psilocybe in a way that reduced its antioxidant capacity, i.e., its ability to donate electrons to chemical reactions in the assay. [Figure 46] Figure 46 shows the total antioxidant capacity of Pyropia stock (Py stock), Tonka stock (To stock), and a Pyropia / Tonka binary blend (Py / To) using the Folin-Ciocalteu assay. Figure 46 shows the calculated GAE for Py stock, To stock, and Py / To in mg per mL / L of solution utilized. The table below the graph in Figure 46 represents the statistical significance of Py stock vs. Py / To and To stock vs. Py / To, indicated by asterisks (* if P<0.10, * if P<0.05, and ** if P<0.01). The Pyropia and Tonka binary blend had antioxidant capacity comparable to that of Pyropia alone. The effect of Tonka alone was undetectable within the dose range tested. [Figure 47]The total antioxidant capacity of the Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To) blend obtained by the Folin-Ciocalteu assay is shown compared to matched doses of Cannabis stock (Ca stock), Psilocybe stock (Ps stock), Pyropia stock (Py stock), and Tonka stock (To stock). Figure 47 shows the calculated GAE in mg per mL / L of solution utilized for Ca / Ps / Py / To, Ca stock, Ps stock, Py stock, and To stock. The table below the graph in Figure 47 shows the statistical significance of Ca / Ps / Py / To vs. Ca stock, Ca / Ps / Py / To vs. Ps stock, Ca / Ps / Py / To vs. Py stock, and Ca / Ps / Py / To vs. To stock, indicated by asterisks (* if P<0.10, * if P<0.05, and ** if P<0.01). [Figure 48] The total antioxidant capacity of the Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To) blend obtained by the Folin-Ciocalteu assay is shown compared to matched doses of each of the binary blends, including Cannabis / Psilocybe (Ca / Ps), Cannabis / Pyropia (Ca / Py), Cannabis / Tonka (Ca / To), Psilocybe / Pyropia (Ps / Py), Psilocybe / Tonka (Ps / To), and Pyropia / Tonka (Py / To). Figure 48 shows the calculated GAE in mg per mL / L of solution utilized for Ca / Ps / Py / To, Ca / Ps, Ca / Py, Ca / To, Ps / Py, Ps / To, and Py / To. The table below the graph in Figure 48 shows the statistical significance of Ca / Ps / Py / To vs. Ca / Ps, Ca / Ps / Py / To vs. Ca / Py, Ca / Ps / Py / To vs. Ca / To, Ca / Ps / Py / To vs. Ps / Py, Ca / Ps / Py / To vs. Ps / To, and Ca / Ps / Py / To vs. Py / To, indicated by asterisks (P<0.10: (*), P<0.05: *, and P<0.01: **). [Figure 49]Figure 49 shows the total antioxidant capacity of the Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To) quaternary blend compared to Applicant's "4+" blend (i.e., Applicant's final products disclosed herein as ABS-108 and NIM-01, and as the formulation in Example 1), as determined by the Folin-Ciocalteu assay. Figure 49 shows the calculated GAE for Ca / Ps / Py / To and the 4+ blend in mg per mL / L of solution utilized. Figure 49 presents data as the mean ± standard deviation of duplicate experimental data points for each dose. Figure 49 indicates statistical significance for Ca / Ps / Py / To versus the 4+ blend, indicated by asterisks (* if P<0.10, * if P<0.05, and ** if P<0.01). The 4+ blend exhibited higher antioxidant capacity than the Cannabis / Psilocybe / Pyropia / Tonka quaternary blend. This indicates that the additional components of the 4+ blend contribute to the antioxidant properties of the final product. DETAILED DESCRIPTION OF THE INVENTION

[0076] While various aspects and features of particular embodiments have been summarized above, the following detailed description exemplifies several exemplary embodiments in more detail to enable one of ordinary skill in the art to which this invention pertains (“ordinary art”) to implement such embodiments and to make and use the full scope of the invention as claimed.

[0077] Numerous modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention exemplified herein may be made by those skilled in the art without departing from the spirit of the invention or the scope of the invention as set forth in the appended claims, and the general principles defined herein can be applied to a wide range of aspects. Thus, the present invention is not intended to be limited to the aspects presented, but is to be accorded the widest scope consistent with the principles and features disclosed. The following description is intended to make such embodiments apparent to those skilled in the art in that they are readily recognizable and easily made without undue experimentation, using only the teachings herein together with general knowledge in the art.

[0078] Among the embodiments of the present invention are therapeutic combinations comprising bioactive molecules derived from fungi, plants, and / or algae. Other embodiments of the present invention are pharmaceutical compositions comprising the therapeutic combinations. Other embodiments include methods of using the therapeutic combinations and pharmaceutical compositions to treat movement disorders such as Parkinson's disease.

[0079] A. General Definitions and Terminology As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "excipient" includes a reference to a combination of one or more excipients, and a reference to a "bioactive molecule" includes a reference to a combination of one or more bioactive molecules. Similarly, a "bioactive molecule" includes a reference to a bioactive molecule within another substance, such as an extract, unless expressly or by context indicates that the bioactive molecule has been purified or isolated therefrom, and even in that case, the bioactive molecule may include another substance as long as the bioactive molecule is within the exemplary stated purity range.

[0080] The terms "comprising," "including," "such as," and "having" are intended to be inclusive and not exclusive (i.e., other elements may be present in addition to the referenced elements). Accordingly, as used herein, the term "including" means, and is used interchangeably with, the expression "including but not limited to." The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise. The specific use of the term "and / or" does not imply that any use of "or" is solely a conjunction; rather, such use merely highlights the possibility that the term "and / or" may be a conjunction in certain embodiments, but may otherwise be a conjunction like "or." The term "and" is understood to be conjunctive.

[0081] A composition "consisting of" particular bioactive molecules can include only the recited bioactive molecules, and a composition "consisting essentially of" particular bioactive molecules can include the recited bioactive molecules, optionally with additional compounds or other elements that do not materially affect the basic and novel characteristics of the claimed combination, composition, or method. Although the term "one or more" is sometimes used, its absence (or replacement with the singular) does not imply exclusiveness; rather, such use merely highlights the possibility of multiple agents or components in a particular embodiment.

[0082] When ranges are given herein, the invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other endpoint is excluded. Both endpoints should be assumed to be inclusive unless otherwise indicated. Also, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges are understood to be able to assume, in different embodiments, any specific value or subrange within the stated range, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. Furthermore, when a series of numerical values ​​is recited herein, it is understood that the invention includes embodiments related by analogy to any intervening value or range defined by any two values ​​in the series, with the minimum value taken as a minimum and the maximum value taken as a maximum. Numerical values ​​used herein include values ​​expressed as percentages. For embodiments in which numerical values ​​are preceded by "about" or "approximately," the invention includes embodiments in which the exact value is recited. For embodiments where a numerical value is not preceded by "about" or "approximately," the present invention includes embodiments in which the numerical value is preceded by "about." Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, concentrations, reaction conditions, and other properties, etc., used to describe and claim particular embodiments of the present invention are therefore understood to be modified, in some instances, by the term "about." "Approximately" or "about" is intended to encompass numerical values ​​that fall within a range that, in some embodiments, is within ±10% of the numerical value, in some embodiments, is within ±5% of the numerical value, in some embodiments, is within ±2% of the numerical value (including in some preferred embodiments), in some embodiments, is within ±1% of the numerical value, in some embodiments, is within ±0.5% of the numerical value, and in some embodiments, is within ±0.1% of the numerical value, unless otherwise stated or apparent from the context (except where such numerical value would impermissibly exceed 100% of a possible value).

[0083] In some embodiments, the numerical parameters set forth in the specification and claims are approximations that can vary depending on the desired properties sought to be obtained by a particular embodiment (and as would be understood by one of ordinary skill in the art). The term "substantially," when applied to modifying a feature or limitation herein, should be interpreted to provide an appropriate degree of certainty in light of the context of the invention and knowledge in the art, for example, by using art-recognized standards for measuring the meaning of "substantially" as a term of degree, or by grasping a range as would be understood by one of ordinary skill in the art. In some embodiments, numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as practicable. In some embodiments, the numerical values ​​set forth may necessarily contain certain errors resulting from the standard deviation found in their respective testing measurements.

[0084] A comprehensive list of abbreviations utilized by organic chemists of ordinary skill appears in the first issue of each volume of the Journal of Organic Chemistry; this list is usually presented in a table entitled "Standard List of Abbreviations." The most current list as of the filing date of this application is incorporated herein by reference as if fully set forth herein.

[0085] All technical and scientific terms in this specification have the meanings that are commonly understood by those skilled in the art unless expressly defined otherwise. Further definitions that may assist the reader in understanding the disclosed exemplary embodiments are provided below, but such definitions are not intended to limit the scope of the present invention, and it will be understood that they will be properly interpreted and understood (as well as any plain meaning known to those skilled in the art) by referring to the entire specification in light of the language used in the claims. The terms in this specification are only for describing specific embodiments and are not intended to be limiting.

[0086] Terms that have a specific meaning within the regulatory laws of the jurisdiction in which this application is filed or may be enacted should generally be given that meaning unless the context dictates otherwise. For example, "botanical drug substance" may refer to a term defined through FDA implementing rules and regulations and as set forth in the U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research's "Guidance for Industry Botanical Drug Products, December 2016 (Docket No. FDA-2000-D-0103)" (the "2016 FDA Botanical Drug Guidance"). The same applies to other terms, including "botanical drug" and "botanical material."

[0087] For the avoidance of doubt, although "botanical" is commonly used to mean "pertaining to plants," as used herein, "botanical" in "botanical" drug substance or drug product shall be understood to include compounds, substances, and products (e.g., extracts) obtained or derived from fungal material, such as psilocybin-containing or other fungi, as defined by the FDA. A "botanical" drug substance or drug product shall also be understood to include compounds, substances, and products (e.g., extracts) obtained or derived from algal material, where "algal material" refers broadly to any material from the polyphyletic group of diverse photosynthetic eukaryotic organisms referred to or understood in the art as "algae," particularly those portions that constitute a biologically active molecule of interest, as known to those skilled in the art.

[0088] Botanical drug substances and drugs, and compositions containing them, may be available by prescription or over the counter ("OTC"), or as dietary or nutraceutical supplements, or under other regulatory regimes, or may be unregulated (e.g., "natural products").

[0089] As used herein, the term "plant material" includes the entire plant and any portion thereof containing the desired bioactive molecule, such as the above-ground portion of the plant, isolated leaves, stems, flowers, fruits, roots, or any combination of the foregoing. In the case of cannabis plants, it will be understood that the portion primarily used is the flowering female inflorescence ("buds"), which generally contains the highest amount of bioactive molecules, such as terpenoids and cannabinoids. However, other plant parts may also be used in the disclosed compositions and methods, as will be understood by those skilled in the art.

[0090] Where fungal material is used (e.g., in an extraction process), it may be derived from fungal fruiting bodies ("mushrooms"), fungal sclerotia ("truffles"), as well as any part from mycelium or other fungal material (e.g., bioreactor biomass), unless the context indicates otherwise; any or all such parts, as well as combinations thereof, may be referred to as "fungal material."

[0091] Generally, the names used and procedures performed herein are those well known in the fields of biology, chemistry, natural product extraction, botany, mycology, phycology, pharmacology, medicine, or the like that are relevant to one aspect of this invention, and are those well known and commonly used in the art. Standard techniques and procedures are commonly performed according to conventional methods in the art.

[0092] It will be understood that the headings herein are used solely for ease of review by the reader and are not to be construed as limiting the invention in any manner.

[0093] B. Primary and Secondary Bioactive Molecules In some aspects, provided therapeutic combinations are useful for preventing or treating movement disorders such as Parkinson's disease (PD). In some embodiments, the therapeutic combination comprises a fungal part, a plant part, and an algal part. In some embodiments, the therapeutic combination comprises a fungal part, a first plant part, optionally a second plant part, and an algal part. In several embodiments, the therapeutic combination comprises a fungal part, a first plant part, a second plant part, and an algal part.

[0094] In some embodiments, the fungal parts, plant parts, or algal parts comprise an extract (i.e., a fungal extract, a plant extract, or an algal extract, respectively). In several embodiments, the therapeutic combination comprises a fungal extract, a plant part, and an algal part. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant part, optionally a second plant part, and an algal part. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant part, a second plant part, and an algal part. In some embodiments, the therapeutic combination comprises a fungal part, a first plant extract, optionally a second plant extract, and an algal part. In some embodiments, the therapeutic combination comprises a fungal part, a first plant extract, optionally a second plant extract, and an algal part. In some embodiments, the therapeutic combination comprises a fungal part, a first plant extract, a second plant extract, and an algal part. In some embodiments, the therapeutic combination comprises a fungal part, a first plant part, optionally a second plant part, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal part, a first plant part, optionally a second plant part, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, optionally a second plant extract, and an algal part. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, a second plant extract, and an algal part. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant part, optionally a second plant part, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant part, a second plant part, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal extract, a plant extract, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, optionally a second plant extract, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, optionally a second plant extract, and an algal extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, optionally a second plant extract, and an algal extract.

[0095] In some embodiments, the therapeutic combination comprises bioactive molecules derived from fungi, plants, and / or algae. In some embodiments, the therapeutic combination comprises a bioactive molecule derived from a fungus and a bioactive molecule derived from a plant. In some embodiments, the therapeutic combination comprises a bioactive molecule derived from a plant and a bioactive molecule derived from an algae. In some embodiments, the therapeutic combination comprises a bioactive molecule derived from a fungus, a bioactive molecule derived from a plant, and a bioactive molecule derived from an algae. In some embodiments, the therapeutic combination comprises a bioactive molecule derived from a fungus, a bioactive molecule derived from a plant, a bioactive molecule derived from an algae, and a bioactive molecule derived from a fungus, a plant, and / or algae. In some embodiments, the therapeutic combination comprises a bioactive molecule derived from a fungus, a first bioactive molecule derived from a plant, a second bioactive molecule derived from a plant, and a bioactive molecule derived from an algae.

[0096] In some embodiments, the therapeutic combination comprises a bioactive molecule from Psilocybe cubensis, a bioactive molecule from Cannabis sativa, a bioactive molecule from Pyropia yesoensis, and a bioactive molecule from Dipterix odorata. In some embodiments, the disclosed therapeutic combination is a botanical formulation, as prepared in embodiments herein, comprising a total extract of Psilocybe cubensis fungus, Cannabis sativa plant, Pyropia yesoensis algae, and Dipterix odorata bean. As will be further understood, the bioactive molecule may be provided in an extract, such as a total extract, a fraction or subfraction thereof, or may be provided as an isolated compound, a substantially purified compound, or a purified compound (including those produced by biosynthetic or synthetic means), and combinations thereof.

[0097] In some embodiments, the fungal-derived bioactive molecule is neither a plant-derived bioactive molecule nor an algae-derived bioactive molecule (i.e., the fungal-derived bioactive molecule is found only in fungi). In some embodiments, the plant-derived bioactive molecule is neither a fungal-derived bioactive molecule nor an algae-derived bioactive molecule (i.e., the plant-derived bioactive molecule is found only in plants). In some embodiments, the algae-derived bioactive molecule is neither any fungal-derived bioactive molecule nor any plant-derived bioactive molecule (i.e., the algae-derived bioactive molecule is found only in algae).

[0098] In some embodiments, the fungal-derived bioactive molecule is also either a plant-derived bioactive molecule or an algae-derived bioactive molecule (i.e., it is found in plants or algae, but not both). In some embodiments, the plant-derived bioactive molecule is also either any fungal-derived bioactive molecule or an algae-derived bioactive molecule (i.e., it is also found in fungi or algae, but not both). In some embodiments, the algae-derived bioactive molecule is also either any fungal-derived bioactive molecule or a plant-derived bioactive molecule (i.e., it is also found in fungi or plants, but not both).

[0099] In some embodiments, the fungal-derived bioactive molecule is also a plant-derived bioactive molecule or an algae-derived bioactive molecule (i.e., it is also found in plants or algae). In some embodiments, the plant-derived bioactive molecule is also a fungal-derived bioactive molecule or an algae-derived bioactive molecule (i.e., it is also found in fungi or algae). In some embodiments, the algae-derived bioactive molecule is also a fungal-derived bioactive molecule or a plant-derived bioactive molecule (i.e., it is also found in fungi or plants).

[0100] In some embodiments, the fungal-derived bioactive molecule is also a plant-derived bioactive molecule and an algae-derived bioactive molecule (i.e., it is also found in plants and algae). In some embodiments, the plant-derived bioactive molecule is both a fungal-derived bioactive molecule and an algae-derived bioactive molecule (i.e., it is also found in fungi and algae). In some embodiments, the algae-derived bioactive molecule is both a fungal-derived bioactive molecule and a plant-derived bioactive molecule (i.e., it is also found in fungi and plants).

[0101] The term "secondary," as in "secondary biological activity," is used herein to mean, and may be used interchangeably with, the terms "secondary" or "additional," and is not necessarily intended to imply a particular degree of priority compared to the term "primary," as in "primary biological activity," and therefore should not necessarily imply a lesser degree of importance or significance, such as importance or significance, in any particular composition or for any particular disclosed use.

[0102] a. Fungi Unlike plants, fungi do not contain chlorophyll and are saprophytic (feeding on dead plants and animals), parasitic (feeding on living hosts), or symbiotic (sharing mutually beneficial relationships with other organisms). Fungi reproduce both sexually and asexually by spores produced in a variety of ways. Representative fungi include phycomycetes, ascomycetes, and basidiomycetes. Fungi include what are commonly referred to as yeasts, rusts, smuts, mildews, molds, and mushrooms. As used herein, "fungi" should be understood to include both filamentous and non-filamentous species, and the term will be understood to include all forms of the word, including "mycota" and "fungi."

[0103] In some exemplary embodiments, the fungus is a psilocybin-producing fungus. A "psilocybin-producing" fungus (or psilocybin-producing fungi) is any fungus that produces or is capable of producing psilocybin. More than 100 species of fungi in the genus Psilocybe produce psilocybin. Numerous psilocybin-producing species are found in other genera, such as Ateria, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopylus, Inocybe, Mycena, Panaeolus, Phoriotina, and Pluteus. In some embodiments, the psilocybin-producing species is from any of these genera. In multiple embodiments, the psilocybin-producing species is from any of the genera Copelandia, Galerina, Gymnopylus, Inocybe, Panaeolus, Phoriotina, Pluteus, and Psilocybe. In embodiments, the psilocybin-producing species is derived from Psilocybe. Different species of psilocybin mushrooms, and different strains thereof, will be well known or readily identifiable to those skilled in the art.

[0104] In some embodiments, the psilocybin-producing fungus is a Psilocybe species fungus. In some embodiments, the Psilocybe species fungus is P. acutipilea, P. allenii, P. alutacea, P. angulospora, P. antioquiensis, P. araucariicola, P. atlantis, P. aquamarina, P. armandii (Mexicana), P. armandii (Mexicana), P. spp. exicana), P. aucklandiae, P. aztecorum, P. azurescens, P. baeocystis, P. banderillensis, P. bispora, P. brasiliensis, P. brunneocystidiata, P. caeruleoa nnulata, P. caerulescens, P. caerulescens, P. cyanofibrillosa, P. caerulipes, P. callosa, P. carbonaria, P. caribaea, P. chuxiongensis, P. collybioides, P. columbiana, P. congolensis, P. congolensis, P. cordispora, P. cubensis, P. cyanescens, P. cyanofibrillosa, P. dumontii, P. egonii, P. eximia, P. fagicola, P. farinacea, P. fimetaria, P. fuliginosa, P.fuliginosa), P.furtadoana, P.galindoi, P.gallaeciae, P.graveolens, P.guatapensis ), P. heimii, P. herrerae, P. hispanica, P. hoogshagenii, P. inconspicua, P. indi ca), P. isabelae, P. jacobsii, P. jalisca, P. lauraena, P. kumaenorum, P. laurae, P. lazoi, P. liniformans, P. mexicana, P. mairei, P. makarorae, P. mammillata, P. medullo sa), P. meridensis, P. meridionalis, P. mescaleroensis, P. moseri, P. muliercula, P. naematoliformis, P. natalensis, P. natarajanii, P. neorhombispora, P. neoxarapensis lapensis, P. ovoideocystidiata, P. papuana, P. paulensis, P. pelliculosa, P. pintonii, P. pleurocystidiosa, P. plutonia, P. portoricensis, P. pseudoaztecorum, P. puberulapuberula, P. quebecensis, P. rickii, P. rostrate, P. rzedowskii, P. samuiensis, P. schultesii, P. semilanceata, P. septentrionalis, P. serbica, P. sierrae, P. silvaci P. sylvatica, P. singinger, P. strictipes, P. stuntzii, P. subacutipilea, P. subaeruginascens, P. subaeruginosa, P. subcaerulipes, P. subcubensis, P. subpsilocybioides ioides, P. subtropicalis, P. tampanensis, P. thaicordispora, P. thaiaerugineomaculans, P. thaiduplicatocystidiata, P. uruguayensis, P. uxpanapensis, P. venenata nata, P. villarrealiae, P. weilii, P. weldenii, P. weraroa, P. wrightii, P. yungensis, P. zapotecoantillarum, P. zapotecocaribaea, or P. zapotecorum species, including strains thereof.

[0105] In some embodiments, the psilocybin-producing fungus is not a Psilocybe species fungus. Other psilocybin-producing fungi that are not of the Psilocybe genus will be readily apparent to those of skill in the art. Non-limiting examples include Conocybe siligineoides, Conocybe velutipes, Copelandia tropica, Inocybe aeruginascens, Inocybe caerulata, Inocybe coelestium, Inocybe corydalina, Inocybe haemacta, Inocybe tricolor, Galerina steglichii, Gymnopilus aeruginosus, and the like. aeruginosus, Gymnopilus braendlei, Gymnopilus cyanopalmicola, Gymnopilus dilepis, Gymnopilus dunensis, Gymnopilus intermedius, Gymnopilus lateritius, Gymnopilus luteofolius, Gymnopilus luteoviridis, Gymnopilus luteus, Gymnopilus palmicola palmicola, Gymnopilus purpuratus, Gymnopilus subpurpuratus, Gymnopilus subspectabilis, Gymnopilus validipesvalidipes, Gymnopilus viridans, Panaeolus venezolanus, Panaeolus tropicalis, Panaeolus tirunelveliensis, Panaeolus rubricaulis, Panaeolus olivaceus, Panaeolus moellerianus, Panaeolus microsporus, Panaeolus lentisporus, Panaeolus fimicola fimicola, Panaeolus cyanescens, Panaeolus cinctulus, Panaeolus chlorocystis, Panaeolus cambodginiensis, Panaeolus bisporus, Panaeolus axfordii, Panaeolus africanus, Panaeolus affinis, Pholiotina cyanopus, Pholiotina smithii, Pluteus albostipitatus albostipitatus, Pluteus americanus, Pluteus cyanopus, Pluteus glaucus, Pluteus glaucotinctus, Pluteus nigroviridis, Pluteus phaeocyanopusphaeocyanopus, Pluteus salicinus, Pluteus saupei, Pluteus velutinornatus, and Pluteus villosus.

[0106] In some aspects, the disclosed combinations, compositions, and methods comprising fungal parts, fungal extracts, or fungal-derived bioactive molecules affect CNS signaling capabilities. In some embodiments, the disclosed combinations, compositions, and methods comprising fungal parts, fungal extracts, or fungal-derived bioactive molecules (e.g., psilocybin and / or psilocin) increase extracellular dopamine and serotonin in animals, such as mammals, including humans, or in rodents, such as rats. In some embodiments, the disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or fungal-derived bioactive molecules (e.g., psilocybin and / or psilocin) increase synaptic density, for example, as measured by synaptic vesicle glycoprotein 2A (SV2A), in animal studies (Sakashita et al., 2015; and Raval et al., 2021). In some embodiments, the disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or fungal-derived bioactive molecules (e.g., psilocybin and / or psilocin) promote structural and functional plasticity, e.g., through 5-HT, mTOR, and various other pathways, which can be measured by known methods such as those shown in Ly et al., 2018.

[0107] In some aspects, the disclosed combinations, compositions, and methods comprising a fungus, a fungal part, a fungal extract, or a fungal-derived bioactive molecule modulate the inflammatory cycle. In some embodiments, the disclosed combinations, compositions, and methods comprising a fungus, a fungal part, a fungal extract, or a fungal-derived bioactive molecule (e.g., psilocybin and / or psilocin) reverse LPS-induced pro-inflammatory cytokines (e.g., TNF-α, IL-1β). In some embodiments, the disclosed combinations, compositions, and methods dose-dependently suppress the levels of LPS-induced pro-inflammatory cytokines (e.g., TNF-α, IL-1β). In some embodiments, the disclosed combinations, compositions, and methods comprising a fungus, a fungal part, a fungal extract, or a fungal-derived bioactive molecule (e.g., psilocybin and / or psilocin) reduce IL-6 and / or COX-2 levels without reducing the levels of anti-inflammatory IL-10, as described, for example, by Nkadimeng, Steinmann, and Eloff, 2021. In some embodiments, the disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or fungal-derived bioactive molecules (e.g., psilocybin and / or psilocin) exhibit a reduction in TNF-α, IL-1β, and ROS, as described, for example, by Nkadimeng, Steinmann, and Eloff, 2020.

[0108] ii. Fungal-derived primary and secondary bioactive molecules In some embodiments, the therapeutic combination comprises a fungal portion. In some embodiments, the fungal portion comprises a fungal extract. In some embodiments, the fungal portion comprises a bioactive molecule derived from a fungus. In some embodiments, the fungal extract comprises a bioactive molecule derived from a fungus. For example, in some embodiments, the fungal portion comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from a fungus. In some embodiments, the fungal extract comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from a fungus. Thus, in some embodiments, the disclosed therapeutic combinations comprise a primary bioactive molecule and / or a secondary bioactive molecule derived from a fungus.

[0109] In some embodiments (referred to herein equivalently and simply as shorthand "in embodiments"), the fungal portion is derived from a psilocybin-producing fungus. The fungus can be any psilocybin-producing fungus known or identifiable by those skilled in the art, including, by way of non-limiting example, specific species from the genera Ateria, Conocybe, Copelandia, Fibularizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Phoriotina, Pluteus, and Psilocybe. Different species of psilocybin-producing fungi, and different strains thereof, are described herein and are well known or readily identifiable by those skilled in the art.

[0110] In embodiments where a fungal portion is described as being "derived from" a fungus, it will be understood that the fungal portion includes, by way of non-limiting example, fungal material such as raw (i.e., unprocessed) fungal biomass, a fungal extract (e.g., an extract described herein, such as an aqueous and / or ethanolic extract), or a substance derived from a fungus that includes a molecule that is naturally present in a fungus (e.g., a primary or secondary bioactive molecule described in embodiments herein), whether or not the molecule is actually obtained by isolating the molecule from the fungus or whether it is obtained by another means (e.g., chemical synthesis).

[0111] In some embodiments, the fungal portion of the therapeutic combination is derived from a psilocybin-producing species. In some embodiments, the fungal portion of the therapeutic combination is derived from a species of the genera Ateria, Conocybe, Copelandia, Fibularizoctonia, Galerina, Gymnopylus, Inocybe, Mycena, Panaeolus, Phoriotina, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a fungal extract from a psilocybin-producing species. In some embodiments, the fungal portion comprises a fungal extract from a species of the genera Ateria, Conocybe, Copelandia, Fibularizoctonia, Galerina, Gymnopylus, Inocybe, Mycena, Panaeolus, Phoriotina, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a bioactive molecule from a psilocybin-producing species. In some embodiments, the fungal portion comprises a bioactive molecule from a species of the genera Ateria, Conocybe, Copelandia, Fibularizoctonia, Galerina, Gymnopylus, Inosybe, Mycena, Panaeolus, Horiotyna, Pluteus, and Psilocybe. In some embodiments, the fungal portion is from a species of the genera Copelandia, Galerina, Gymnopylus, Inosybe, Panaeolus, Horiotyna, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a fungal extract from a species of the genera Copelandia, Galerina, Gymnopylus, Inosybe, Panaeolus, Horiotyna, Pluteus, and Psilocybe. In embodiments, the fungal portion comprises a bioactive molecule from a species of Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Horiochina, Pluteus, and Psilocybe.

[0112] In some embodiments, the fungus is a Psilocybe species fungus. In some embodiments, the fungal portion is derived from a Psilocybe species fungus. In some embodiments, the fungal portion is derived from a P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weylii, P. hoogshagenii, P. stuntsii, P. cyanofibrillosa, and / or P. liniformans species. In some embodiments, the fungal portion comprises a fungal extract derived from a Psilocybe species fungus. In some embodiments, the fungal portion comprises a fungal extract from a P. azulescense, P. bohemica, P. semilansata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weihli, P. hoogschagenii, P. stuntsii, P. cyanofibrillosa, and / or P. liniformans species. In some embodiments, the fungal portion comprises a fungal extract from a Psilocybe species fungus. In multiple embodiments, the fungal portion comprises a bioactive molecule from a P. azulescense, P. bohemica, P. semilansata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weihli, P. hoogschagenii, P. stuntsii, P. cyanofibrillosa, and / or P. liniformans species.

[0113] In embodiments, the fungal portion comprises any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsirosin, and aeruginasin. In embodiments, the fungal portion comprises a fungal extract comprising any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsirosin, and aeruginasin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus selected from the group consisting of psilocybin, psilocin, baeocystin, norbaeocystin, norpsirosin, and aeruginasin. In embodiments, the fungal portion comprises psilocybin. In embodiments, the fungal portion comprises psilocin. In embodiments, the fungal portion comprises baeocystin. In embodiments, the fungal portion comprises norbaeocystin. In embodiments, the fungal portion comprises norpsirosin. In embodiments, the fungal portion comprises aeruginasin. In embodiments, the fungal portion comprises a fungal extract comprising psilocybin. In embodiments, the fungal portion comprises a fungal extract comprising psilocin. In embodiments, the fungal portion comprises a fungal extract comprising baeocystin. In embodiments, the fungal portion comprises a fungal extract comprising norbaeocystin. In embodiments, the fungal portion comprises a fungal extract comprising norpsirosin. In embodiments, the fungal portion comprises a fungal extract comprising aeruginasin. In embodiments, the fungal portion comprises a fungal-derived primary bioactive molecule, wherein the molecule is psilocybin. In embodiments, the fungal portion comprises a fungal-derived primary bioactive molecule, wherein the molecule is psirosin. In embodiments, the fungal portion comprises a fungal-derived primary bioactive molecule, wherein the molecule is baeocystin. In embodiments, the fungal portion comprises a fungal-derived primary bioactive molecule, wherein the molecule is norbaeocystin. In embodiments, the fungal portion comprises a fungal-derived primary bioactive molecule, wherein the molecule is norpsirosin. In embodiments, the fungal portion comprises a primary bioactive molecule derived from a fungus, wherein the molecule is an aeruginasin.

[0114] In some embodiments, the fungal portion comprises both psilocybin and psilocin. In some embodiments, the fungal portion comprises a fungal extract containing both psilocybin and psilocin. In some embodiments, the fungal portion comprises both psilocybin and psilocin as primary bioactive molecules from the fungus. In some embodiments, the fungal portion comprises both psilocybin and psilocin in a weight or molar ratio of between 100:1 and 1:100, between 50:1 and 1:50, between 10:1 and 1:10, between 5:1 and 1:5, between 2:1 and 1:2, between 5:3 and 3:5, or between 3:2 and 2:3 (all ranges inclusive). In some embodiments, the fungal portion comprises both psilocybin and psilocin in a weight or molar ratio of about 100:1, 50:1, 10:1, 5:1, 2:1, 5:3, 3:2, or 1:1. In some embodiments, the fungal portion contains both psilocybin and psilocin in a weight or molar ratio of about 1:100, 1:50, 1:10, 1:5, 1:2, 3:5, 2:3, or 1:1. In some embodiments, the fungal portion contains both psilocybin and psilocin in a weight or molar ratio of about 5:3, about 3:2, about 1:1, about 2:3, or about 3:5. In some embodiments, the fungal portion comprises a fungal extract containing both psilocybin and psilocin, including any of the above weight or molar ratios. In some embodiments, the fungal portion contains both psilocybin and psilocin as primary bioactive molecules derived from the fungus, including any of the above weight or molar ratios.

[0115] In some embodiments, the psilocybin and psilocin are in a ratio of about 5:3, about 3:2, or about 1:1. In embodiments, the psilocybin and psilocin are in a ratio of about 5:3 or a 5:3 ratio.

[0116] In some embodiments, the fungal portion comprises a β-carboline (beta-carboline). In some embodiments, the fungal portion comprises a fungal extract comprising a β-carboline. In some embodiments, the fungal portion comprises a primary bioactive molecule derived from a fungus, wherein the primary bioactive molecule is a β-carboline. In embodiments, the β-carboline is harmane, harmine, harmol, harmalol, harmaline, tetrahydroharmine, pinoline, cordysinin C, cordysinin D, norharmane, perloline, β-carboline (9H-pyrido[3,4-b]indole), or another L-tryptophan-derived β-carboline. Thus, while "β-carboline" can refer to both an individual compound and a class of related compounds, use of the term herein shall be understood to refer to the class of compounds (including, but not limited to, when described as "β-carboline") unless the context requires otherwise.

[0117] In embodiments, the fungal-derived secondary bioactive molecules are selected from the group consisting of polysaccharides (including α- and β-glucans and polysaccharide-protein complexes), peptides (including proteins such as lectins), terpenes or terpenoids (including diterpenes, triterpenoids, sterols, carotenoid pigments, including mono- and sesquiterpene oils), phenolic compounds (including phenolic acids, hydroxycinnamic acids, hydroxybenzoic acids, ligands, tannins, flavonoids, stilbenes, and oxidized polyphenols), minerals (potassium, phosphorus, sodium, calcium, magnesium ... The following nutrients are essential for healthy living: minerals (including potassium, phosphorus, sodium, calcium, magnesium, copper, selenium, iron, and zinc), vitamins (including ascorbic acid, vitamin D, riboflavin, folic acid, thiamine, pantothenic acid, and niacin), amino acids (including essential amino acids and histidine, isoleucine, leucine, lysine, methionine, phenylalanine, taurine, threonine, tryptophan, and valine), lipids (including saturated, monounsaturated, and polyunsaturated fatty acids, such as oleic acid, linoleic acid, and linolenic acid), choline, and lactones.

[0118] In several embodiments, the fungal-derived bioactive molecule is any of those described in Venturella, 2021; Anusiya et al., 2021; Thu et al., 2020; Muszynska, 2018; and Mishraki-Berkowitz et al., 2020.

[0119] b.Plant In some embodiments, the therapeutic combination comprises a plant part. In some embodiments, the plant part comprises a plant extract. In some embodiments, the plant part comprises a plant-derived bioactive molecule. In some embodiments, the fungal extract comprises a plant-derived bioactive molecule. For example, in some embodiments, the plant part comprises a plant-derived primary bioactive molecule and / or a plant-derived secondary bioactive molecule. In some embodiments, the plant extract comprises a plant-derived primary bioactive molecule and / or a plant-derived secondary bioactive molecule. Thus, in some embodiments, the disclosed therapeutic combination comprises a plant-derived primary bioactive molecule and / or a plant-derived secondary bioactive molecule.

[0120] In embodiments where a plant part is described as being "derived from" a plant, it will be understood that the plant part includes, by way of non-limiting example, plant material such as raw (i.e., unprocessed) plant biomass, plant extracts (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or plant-derived substances including molecules naturally occurring in the plant (e.g., primary or secondary bioactive molecules described in embodiments herein), whether said molecules are actually obtained by isolating the molecule from the plant or whether they are obtained by other means (e.g., chemical synthesis).

[0121] Plants are photosynthetic eukaryotes of the kingdom Plantae. In some embodiments, the therapeutic combination comprises a plant extract. In some embodiments, the therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from a plant. In some embodiments, the therapeutic combination comprises a Cannabis extract and / or a Dipteryx extract. In some embodiments, the therapeutic combination comprises a Cannabis extract. In some embodiments, the therapeutic combination comprises a Dipteryx extract. In some embodiments, the therapeutic combination comprises both a Cannabis extract and a Dipteryx extract. In some embodiments, the therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from a plant of the Cannabis and / or Dipteryx genus. In some embodiments, the therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from a plant of the Cannabis genus.

[0122] ii. Cannabis The genus Cannabis is a genus of flowering plants in the family Cannabaceae. The number of species in the genus is disputed; some recognize three separate species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis; others include C. ruderalis within C. sativa; others include C. sativa, C. indica, and C. ruderalis as subspecies of the single species C. sativa; and still others treat C. sativa L. as a single, unclassified species. As used herein, "cannabis" refers to all such encompassing species, subspecies, cultivars, varieties, strains, chemovarieties, etc., including the genus Cannabis, regardless of such terminology. As used herein, for shorthand purposes only, and without taking a position on the above controversy, the term "cannabis" refers to C. sativa, C. indica, and C. ridderalis, and further includes genetic crosses, self-crosses, and hybrids thereof.

[0123] In some embodiments, the plant parts of the therapeutic combination are derived from Cannabis. In embodiments where a plant part is described as being "derived from Cannabis," it will be understood that the plant part includes, by way of non-limiting example, Cannabis material such as raw (i.e., unprocessed) Cannabis biomass, Cannabis extracts (e.g., aqueous and / or ethanolic extracts described herein, such as water), or Cannabis-derived substances, including molecules naturally occurring in Cannabis (e.g., primary or secondary bioactive molecules described in embodiments herein), whether or not said molecules are actually obtained by isolating the molecule from Cannabis, or whether or not they are obtained by another means (e.g., chemical synthesis).

[0124] In some embodiments, the therapeutic combination includes a cannabis extract. In some embodiments, the therapeutic combination includes a first bioactive molecule derived from cannabis. In some embodiments, the combination includes a second bioactive molecule derived from cannabis.

[0125] a. Cannabis-derived primary and secondary bioactive molecules In some embodiments, the therapeutic combination includes primary and / or secondary bioactive molecules derived from Cannabis.

[0126] II. Primary Bioactive Molecules from Cannabis In some embodiments, the primary bioactive molecule derived from cannabis is a cannabinoid. Cannabinoids are a diverse class of small molecules grouped together due to their ability to act on cannabinoid receptors. Cannabinoid receptors are present throughout the brain and central and peripheral nervous systems of humans and other mammals. There are two main types of cannabinoid receptors, known as cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are primarily found in the central nervous system (i.e., brain and spinal cord) as well as in the lungs, liver, and kidneys. CB1 receptor-mediated signaling plays an important role in neural circuits mediating mood, motivation, and emotional behavior. CB2 receptors are primarily found in the immune system and hematopoietic stem and progenitor cells, and may also be present in neurons.

[0127] Cannabinoids have been shown to increase tyrosine hydroxylase activity and expression (Bonnin et al., 1996; Hernandez, et al., 1997). Consistent with this, Bloom (1982) and Maitre et al., (1970) have shown that THC increases dopamine synthesis. THC has also been shown to inhibit dopamine uptake (Banerjee et al., 1975). Szabo et al., (2002) also suggested that activation of CB1 receptors inhibits GABAergic neurotransmission in the VTA via a presynaptic mechanism. Suppression of GABAergic inhibitory effects on dopaminergic neurons may increase in vivo firing rate, resulting in increased dopamine in the NAc. Furthermore, cannabinoids regulate the release and uptake of various neurotransmitters, including acetylcholine, glutamate, noradrenaline, and GABA, via N- and P / Q-type calcium currents and potassium A currents ( Gifford et al., 2000 ).

[0128] Cannabinoids have also been shown to modulate the pro-inflammatory cycle. In an LPS-stimulated neuroinflammation assay, THC and CBD reduced IL-1β and IL-6, while CBD suppressed IL-1β secretion and inhibited the NF-kB signaling pathway (Kozela et al., 2010; Dos-Santos Pereira et al., 2020). CBD increased NRF2 expression, leading to a reduction in ROS, which may in part suppress NLRP3 inflammasome activation by lowering NF-kB levels (Jastrzab, Gegotek, and Skrzydlewska, 2019). In one study, CBD increased NRF2 expression while actively suppressing NF-kB through the p65 and p52 promoters (Jastrzab, Gegotek, and Skrzydlewska, 2019). CBD also activates the PPAR-γ network and directly inhibits NF-kB signaling via CB1 and CB2 receptors (Nichols and Kaplan, 2020).

[0129] Cannabinoids are known to those skilled in the art and are also reported and elucidated in part by Radwan et al., Cannabinoids, Phenolics, Terpenes and Alkaloids of Cannabis, Molecules, 26(9), 2774 (2021), which is incorporated by reference as if fully set forth herein. Without being bound by theory, cannabinoids according to the Radwan 2021 classification have a characteristic C21 terpene phenol skeleton and are divided into 11 cannabinoid subclasses, namely: cannabichromene (CBC) type, cannabidiol (CBD) type, cannabielsoin (CBE) type, cannabigerol (CBG) type, cannabicyclol (CBL) type, cannabinol (CBN) type, cannabinodiol (CBND) type, cannabitriol (CBT) type, (-)-Δ * -trans-tetrahydrocannabinol (Δ 8 -THC) type, (-)-Δ 9 -trans-tetrahydrocannabinol (Δ 9 -THC) type, and mixed cannabinoids. Non-limiting examples of such cannabinoids, all of which will be understood to be useful in the practice of the present invention, are known from the disclosure of Radwan 2021 and references below. In embodiments, the primary bioactive molecule derived from Cannabis is any such cannabinoid.

[0130] In embodiments, the Cannabis-derived primary bioactive molecule is Δ 9 -THC-type cannabinoids, Δ 8-A cannabinoid that is a THC-type cannabinoid, a CBG-type cannabinoid, a CBD-type cannabinoid, a CBND-type cannabinoid, a CBE-type cannabinoid, a CBL-type cannabinoid, a CBN-type cannabinoid, a CBC-type cannabinoid, a CBT-type cannabinoid, or a mixed cannabinoid.

[0131] Δ 9 Examples of -THC-type cannabinoids include Δ 9 -THC-C5, Δ 9 -THCAA-C5, Δ 9 -THCAB-C5, Δ 9 -THC-C4, Δ 9 -THCAA-C4, Δ 9 -THCV, Δ 9 -THCVAA, Δ 9 -THCO, Δ 9 -THCOAA, Δ 9 -THC-aldehyde, β-fenchyl(-)-Δ 9 -trans-tetrahydrocannabinolate, α-fenchyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, epi-bornyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, bornyl(-)-Δ 9 -trans-tetrahydrocannabinolate, α-terpenyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, 4-terpenyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, α-cadinyl(-)-Δ 9 -trans-tetrahydrocannabinolate, γ-eudesmyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, 8α-hydroxy-(-)-Δ 9 -trans-tetrahydro-cannabinol, 8β-hydroxy-(-)-Δ 9 -trans-Tetrahydrocannabinol, 11-acetoxy-(-)-Δ 9-trans-Tetrahydrocannabinolic acid A, 8-oxo-(-)-Δ 9 -trans-tetrahydrocannabinol, cannabisol, (-)-Δ 9 -trans-tetrahydrocannabiphorol, (-)-Δ 9 -trans-tetrahydrocannabihexol.

[0132] Δ 8 Examples of -THC-type cannabinoids include Δ 8 -THC, Δ 8 -THCA, 10α-OH-Δ 8 -THC, 10β-OH-Δ 8 -THC, 10a-α-hydroxy-10-oxo-Δ 8 -THC, etc.

[0133] In embodiments, CBG-type cannabinoids include (£)CBG, (£)CBGA, (£)CBGG, (£)CBGAM, (£)CBGV, (£)CBGVA, (Z)CBGA, 5-acetyl-4-hydroxycannabigerol, (±)-6,7-trans-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epoxycannabigerol, camagerol, and sesquicannabigerol.

[0134] Examples of CBD-type cannabinoids include CBD-C5, CBDA-C5, CBDM-C5, CBD-C4, CBDV, CBDVA, CBD-C1, CBDH, CBDP, and CBDD. Examples of CBND-type cannabinoids include CBND-C3 and CBND-C5. Examples of CBE-type cannabinoids include CBE-C5, CBEAA-C5, CBEAB-C5, CBE-C3, and CBEAB-C3. Examples of CBL-type cannabinoids include CBL, CBLA, and CBLV, and examples of CBC-type cannabinoids include CBC, CBCA, ±CBCV, +CBCV, CBCVA, 4-acetoxy-CBC, (±)-3"-hydroxy-Δ4"-cannabichromene, (-)-7-hydroxy-cannabichromene, and CBC-C3. Examples of CBN-type cannabinoids include CBN-C5, CBN-C5, CBN-C4, CBN-C3, CBN-C2, CBN-C1CBNM-C5, 8-OH-CBN, 8-OH-CBNA, 1'S-OH-CBN, and 4-terpenyl-cannabinolate. Examples of CBT-type cannabinoids include (-)-trans-CBT-C5, (+)-trans-CBT-C5, (±)-cis-CBT-C5, (±)-trans-CBT-C3, CBT-C3-homolog, (-)-trans-CBT-OEt-C5, (-)-trans-CBT-OEt-C3, 8,9-Di-OH-CBT-C5, CBDA-C5, and 9-OH-CBT-C5 ester.

[0135] Examples of mixed cannabinoids include DCBF-C5, CBF-C5, OH-iso-HHCV-C3OTHC, cannabicitran, and cis-Δ 9 -THC, CBCON-C5, CBR, CBTT, CBCN-C5, CBCN-C3, cis-iso-Δ 7 -THCV, trans-iso-Δ 7 -THCV, trans-iso-Δ 7-THC, CBCNB, CBCNC, CBCND, (-)-(7A)-cannabicoumarononic acid, 4-acetoxy-2-geranyl-5-hydroxy-3-w-pentylphenol, 2-geranyl-5-hydroxy-3-w-pentyl-1,4-benzoquinone, 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone, CBM, CBX, 10α-hydroxy-Δ 9,11 -Hexahydrocannabinol, 9β,10β-epoxyhexahydrocannabinol, 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexahydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10αR-hydroxyhexahydrocannabinol, and 9α-hydroxy-10-oxo-Δ 6α10α -THC is one example.

[0136] In embodiments, the Cannabis-derived primary bioactive molecule is Δ 9 -THC-C5, Δ 9 -THCAA-C5, Δ 9 -THCAB-C5, Δ 9 -THC-C4, Δ 9 -THCAA-C4, Δ 9 -THCV, Δ 9 -THCVAA, Δ 9 -THCO, Δ 9 -THCOAA, Δ 9 -THC-aldehyde, β-fenchyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, α-fenchyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, epi-bornyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, Bornyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, α-terpenyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, 4-terpenyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, α-cadinyl(-)-Δ 9-trans-Tetrahydrocannabinolate, γ-eudesmyl(-)-Δ 9 -trans-Tetrahydrocannabinolate, 8α-hydroxy(-)-Δ 9 -trans-Tetrahydrocannabinol, 8β-hydroxy-(-)-Δ 9 -trans-Tetrahydrocannabinol, 11-acetoxy-(-)-Δ 9 -trans-Tetrahydrocannabinolic acid A, 8-oxo-(-)-Δ 9 -trans-tetrahydrocannabinol, cannabidiol, (-)-Δ 9 -trans-tetrahydrocannabiphorol, (-)-Δ 9 -trans-trans-tetrahydrocannabihexol, Δ 8 -THC, Δ 8 -THCA, 10α-OH-Δ 8 -THC, 10β-OH-Δ 8 -THC, 10a-α-hydroxy-10-oxo-Δ 8-THC, (E)CBG, (E)CBGA, (E)CBGG, (E)CBGAM, (E)CBGV, (E)CBGVA, (Z)CBGA, 5-acetyl-4-hydroxy-cannabigerol, (±)-6,7-trans-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epoxycannabigerol, camagerol, sesquicannabigerol CBD-C5, CBDA-C5, CBDM-C5, CBD-C4, CBDV, CBDVA, CBD-C1, CBDH, CBDP, CBDD, CBND-C3, CBND-C5, CBE-C5, CBEAA-C5, CBEAB-C5, CBE-C3, CBEAB-C3, CBL, CBLA, CBLV, CBC, CBCA, ±CBCV, +CBCV, CBCVA, 4-acetoxy-CBC, (±)-3"-hydroxy-A4"-cannabichromene, (-)-7-hydroxy-cannabichroman, CBC-C3, CBN-C5, CBNA-C5, CBN-C4, CBN-C3, CBN-C2, CBN -C1, CBNM-C5, 8-OH-CBN, 8-OH-CBNA, 1'S-OH-CBN, 4-terpenyl-cannabinolate, (-)-trans-CBT-C5, (+)-trans-CBT-C5, (±)-cis-CBT-C5, (±)-trans-CBT-C3, CBT-C3-homolog, (-)-trans-CBT-OEt-C5, (-)-trans-CBT-OEt-C3, 8,9-di-OH-CBT-C5, and CBDA-C5, as well as 9-OH-CBT-C5 ester, DCBF-C5, CBF-C5, OH-iso-HHCV-C3OTHC, cannabiditran, cis-Δ 9 -THC, CBCON-C5, CBR, CBTT, CBCN-C5, CBCN-C3, cis-iso-Δ 7 -THCV, trans-iso-Δ 7 -THCV, trans-iso-Δ 7-THC, CBCNB, CBCNC, CBCND, (-)-(7R)-Cannabicoumaronate, 4-acetoxy-2-geranyl-5-hydroxy-3-n-pentylphenol, 2-geranyl-5-hydroxy-3-n-pentyl-1,4-benzoquinone, 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone, CBM, CBX, 10α-hydroxy-Δ 9 , 11 -Hexahydrocannabinol, 9β,10β-epoxyhexahydrocannabinol, 9α-hydroxyhexahydrocannabinol, 7-oxo-9α-hydroxyhexahydrocannabinol, 10α-hydroxyhexahydrocannabinol, 10αR-hydroxyhexahydrocannabinol, or 9α-hydroxy-10-oxo-Δ 6α,10α -THC. In embodiments, "cannabinoid" includes any of the cannabinoid carboxylic acids and their carboxylate salts (see U.S. Patent No. 9,376,367).

[0137] Each cannabinoid will also be understood to include its isomers, such as structural and stereoisomers (including enantiomers), -A and -B isomers of each cannabinoid, double bond isomers, and other such isomers known to those skilled in the art. Thus, "THC" will, in several embodiments, be understood to include THC-A and THC-B. Reference to a cannabinoid includes various alkyl chain lengths attached thereto, as exemplified by Cn, where "n" refers to the number of carbon atoms in each alkyl chain. Thus, "THC" also includes THC-C1, THC-C2, THC-C3, THC-C4, THC-C5, THC-C6, and THC-C7. Reference to a given cannabinoid also includes all possible isomers, such as its -A and -B isomers, along with all possible combinations of alkyl chain lengths, including chains consisting of 1, 2, 3, 4, 5, 6, or 7 carbon atoms, but is not limited to these. Thus, reference herein to "THC" includes THC-C1 A, THC-C1 B, THC-C2 A, THC-C2 B, THC-C3 A, THC-C3 B, THC-C4 A, THC-C4 B, THC-C5 A, THC-C5 B, THC-C6 A, THC-C6 B, THC-C7 A, and THC-C7 B. Those skilled in the art will appreciate that such logic applies to all cannabinoids disclosed herein; THC is used merely to illustrate such logic and should not be construed as limiting. In embodiments, the cannabinoid may further comprise additional chemical moieties substituted thereon, including methyl, alkyl, alkenyl, methoxy, alkoxy, acetyl, carboxyl, carbonyl, oxo, ester, hydroxyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, heterocyclylalkenyl, heteroarylalkenyl, arylalkenyl, heterocyclyl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, etc. In embodiments, the cannabinoid comprises a "synthetic cannabinoid."

[0138] In some embodiments, the plant parts contain both THC and CBD. In some embodiments, the plant parts include a plant extract containing both THC and CBD. In some embodiments, the plant parts contain both THC and CBD as primary bioactive molecules from a plant (e.g., cannabis). In some embodiments, the plant parts contain both THC and CBD in a weight or molar ratio of between 100:1 and 1:100, between 50:1 and 1:50, between 10:1 and 1:10, between 5:1 and 1:5, between 2:1 and 1:2, between 5:3 and 3:5, or between 3:2 and 2:3 (all ranges inclusive). In some embodiments, the plant parts contain both THC and CBD in a weight or molar ratio of about 100:1, 50:1, 10:1, 5:1, 2:1, 5:3, 3:2, or 1:1. In some embodiments, the plant parts contain THC and CBD in a weight or molar ratio of about 1:100, 1:50, 1:10, 1:5, 1:2, 3:5, 2:3, or 1:1. In several embodiments, the plant parts contain both THC and CBD in a weight or molar ratio of about 1:1. In several embodiments, the plant parts comprise a plant extract (e.g., a cannabis extract) containing both THC and CBD in any of the above weight or molar ratios. In several embodiments, the plant parts contain both THC and CBD as primary bioactive molecules derived from the plant in any of the above weight or molar ratios.

[0139] II. Cannabis-derived secondary bioactive molecules In some embodiments, the therapeutic combination includes a second bioactive molecule derived from Cannabis.

[0140] In some embodiments, the Cannabis-derived secondary bioactive molecule is a flavone and / or flavonoid, a terpene and / or terpenoid, a carbohydrate, a fatty acid or fatty acid ester, an amide, an amine, a phytosterol, or a phenolic compound.

[0141] Flavonoids are a broad class of water-soluble polyphenolic molecules (i.e., containing a phenyl group (-CH) linked to a hydroxyl group (-OH)), of which approximately 20 species are widely present in cannabis. Their primary function is to provide color to plants, particularly flowers. In cannabis, the deep purple color is due to the flavonoids anthocyanins and anthoxanthins. In addition to coloring, flavonoids have been shown to confer health benefits through regulating cell signaling pathways and through various anti-inflammatory, antioxidant, antifungal, and anticancer activities. For example, the cannabis flavonoid apigenin has potent anxiolytic, anti-inflammatory, and anticancer properties, and butin has been shown to reduce oxidative stress-related cellular dysfunction. Other bioactive flavonoids found in cannabis include cannaflavin, kaempferol, orientin, luteolin, quercetin, silymarin, and vitexin.

[0142] In embodiments, flavonoids include those broadly described in Radwan 2021, including orientin, vitexin, isovitexin, apigenin, luteolin, kaempferol, and quercetin flavonoids; in embodiments, these may be methylated, glycosylated, prenylated, or geranylated.

[0143] In embodiments, the flavonoid is orientin, orientin-O-glucoside, orientin-7-O-glucoside, orientin-7-O-rhamnoglucoside, vitexin, vitexin-O-glucoside, vitexin-7-O-glucoside, vitexin-7-O-rhamnoglucoside, cytisoside, cytisoside glucoside, isovitexin, isovitexin-O-glucoside, isovitexin-7-O-glucocarbinoside, isovitexin-7-O-rhamnoglucoside, apigenin-7-O-glucoside, apigenin-7-O-glucuronide, apigenin-7-O'P-coumaroylglucoside, 6-prenylated apigenin, or 6-prenylated apigenin. These include prenylapigenin, apigenin-6,8-di-gluco-pyranoside, luteolin-C-glucuronide, luteolin-7-O-glucuronide, canniflavin A, canniflavin B, canniflavin C, chrysoeriol, kaempferol-3-O-diglucoside, quercetin-3-O-glucoside, quercetin-3-O-diglucoside, kaempferol-3-O-sophoroside, quercetin-3-O-sophoroside, rutin, quercetin, naringenin, and naringin.

[0144] Terpenes are a large class of organic hydrocarbon compounds containing one or more repeating units of a five-carbon building block known as the isoprene unit (i.e., 2-methyl-1,3-butadiene, which has the molecular formula CH). As a group, terpenes, which are isoprene polymers, are often referred to as the "isoprenoid group." The isoprene units may be linked end-to-end to form linear chains or may be arranged to form rings (hence the molecular formula CH). nwhere n is the number of linked isoprene units. Terpenes are classified according to the number of isoprene units they contain: hemiterpenes (1 unit), monoterpenes (2 units), sesquiterpenes (3 units), diterpenes (4 units), sesterterpenes (5 units), triterpenes (6 units), sesquaterpenes (7 units), tetraterpenes (8 units), and polyterpenes (9 or more units).

[0145] Terpenes are sometimes referred to as "terpenoids" when they undergo oxidation and acquire additional oxygen-containing functional groups (e.g., after cannabis is cured and dried) or when they are modified by the addition or removal of functional groups (e.g., methyl groups (-CH3)). The presence and specific combinations of terpenes impart unique odors and flavors to different plants (and different cannabis strains). In cannabis, terpenes are the largest group of phytochemicals, with at least 120 molecules identified. Terpenes typically account for 10-20% of the total oil secreted by the resin glands of cannabis. Terpenes also account for the majority of chemicals in smoke from heated or vaporized cannabis flowers, often accounting for more than 50%, while cannabinoids typically account for 10-20%.

[0146] While cannabinoids are more commonly understood to be responsible for the psychosomatic effects of cannabis, terpenes also exhibit a wide range of such effects (see, e.g., Russo, 2011). For example, the terpene β-myrcene has sedative properties and is thought to produce a heavy "body high." β-Myrcene has also demonstrated the ability to reduce inflammation and inhibit liver carcinogenesis, and it acts as an analgesic and muscle relaxant. The terpenes linalool, nerolidol, and pulegone also exhibit sedative properties. Others, such as limonene and terpinolene, in contrast, exhibit stimulating properties. Other terpenes exhibit even more distinct effects. For example, α-humulene has appetite suppressant properties. Limonene has demonstrated anticancer, anxiolytic, and immunostimulatory properties, and nerolidol also possesses anticancer properties. β-Caryophyllene has anti-inflammatory and gastric cytoprotective properties. Pentacyclic triterpenes such as β-amyrin and cycloartenol exhibit antibacterial, antifungal, anti-inflammatory, and anticancer properties.

[0147] Terpenes readily cross the blood-brain barrier (BBB) ​​and may exert their effects by modulating neurotransmitters in the brain. For example, linalool has been shown to modulate glutamatergic and gabaminergic neurotransmitters, which may explain their analgesic, anxiolytic, anti-inflammatory, and anticonvulsant properties. α-Pinene is an acetylcholinesterase inhibitor, which may support memory. Phytol, a diterpene, increases gabaminergic expression. Other terpenes have been shown to affect serotonergic and dopaminergic neurotransmitters.

[0148] Some terpenes interact directly with the ECS. For example, β-caryophyllene selectively binds to CB2 receptors as a functional CB2 agonist, supporting its anxiolytic and antidepressant properties. Terpenes have also been shown to alter cell membrane permeability and modulate the effects of THC and other cannabinoids. Because terpenes are lipophilic, they interact with lipid membranes, ion channels, a variety of different receptors (including both G protein-coupled odorant receptors and neurotransmitter receptors), and enzymes. Through these and other mechanisms, terpenes in cannabis may not only elicit effects alone or in combination with other terpenes, but may also modulate the effects of the various cannabinoids present.

[0149] In embodiments, the cannabis-derived secondary bioactive molecule may be any of a hemiterpene, monoterpene, sesquiterpene, diterpene, sesterterpene, triterpene, sesquaterpene, tetraterpene, polyterpene, carbohydrate, fatty acid and its ester, amide, amine, phytosterol, or phenolic compound.

[0150] Examples of monoterpenes include myrcene, cis-β-ocimene, trans-β-ocimene, p-cymene, α-terpinene, β-phellandrene, γ-terpinene, α-terpinolene, α-phellandrene, 3-phenyl-2-methyl-prop-1-ene, α-pinene, β-pinene, camphene, Δ 3 -Karen, Δ 4-carene, sabinene, α-thujene, linalool, citral B, nerol, geraniol, ipsienol, citronellol, 2-methyl-2-hepten-6-one, geranylacetone, m-mentha-1,8-(9)-dien-5-ol, carvacrol, carvone arvone, α-terpineol, terpinen-4-ol, pulegone, dihydrocarvone, β-terpineol, dihydrocarbyl acetate, p-cymen-8-ol, β-cyclocitral, safranal, cis-linalool oxide, perylene, sabinol, thujil alcohol alcohol), linalool oxide, cis-carveol, cis-sabinene hydrate, sabinene hydrate, 8-cineole, 1,4-cineol, piperitone oxide, piperitenone oxide, fenchyl alcohol, fenchone, borneol, bornyl acetate, camphor, camphene hydrate, α-pinene oxide, pinocarveol, and pinocarvone.

[0151] Examples of sesquiterpenes include α-caryophyllene, β-caryophyllene, caryophyllene oxide, curcumene, α-trans-bergamotene, α-selinene, β-farnesene, longifolene, humulene epoxide I, humulene epoxide II, caryophyllene alcohol (caryophyllenol), β-bisabolene, and olene, allo-aromadendrene, calamenene, α-copaene, nerolidol, α-guijunene, iso-caryophyllene, β-selinene, selina-3,7(II)-diene, selina-4(14),7(II)-diene, α-bisabolo, α-cedrene, α-cubebene ne), δ-cadinene, epi-β-santalene, farnesol, γ-cadinene, γ-elemene, γ-eudesmol, guaiol, ledol, trans-trans-α-farnesene, (Z)-β-farnesene, farnesyl acetone, α-cadinene, α-cis-bergamotene, α-eudesmol, α-guaiol Examples of diterpenes include phytol and neophytadiene. Examples of triterpenes include friedelene and epifriedelanol.Examples of mixed terpenes include vomifoliol, dihydrovomifoliol, β-ionone, and dihydroactinidiolide.

[0152] Examples of phenolic compounds include, for example, lignans, spiroindanes, dihydrostilbenes, dihydrophenanthrene derivatives, stilbenoids, cannabispirans, denbinobin, catechin, chlorogenic acid, caffeic acid, epicatechin, luteolin-7-O-glucoside, p-coumaric acid, caffeoyl, tyramine, ferulic acid, quercetin-3-glucoside, kaempferol, apigenin-7-glucoside, luteolin, cannabisin, and apigenin, in addition to those disclosed as being part of the terpenes and flavonoids.

[0153] In embodiments, the cannabis-derived secondary bioactive molecule may be any of the following: orientin, orientin-O-glucoside, orientin-7-O-glucoside, orientin-7-O-rhamnoglucoside, vitexin, vitexin-O-glucoside, vitexin-7-O-glucoside, vitexin-7-O-rhamnoglucoside, citisoside, citisoside-glucoside, isovitexin, isovitexin-O-glucoside, isovitexin-7-O-glucocarbinoside, isovitexin-7-O-rhamnoglucoside, apigenin-7-O-glucoside, apigenin-7-O-glucuronide, apigenin-7-O'P-coumaroylglucoside, 6-prenylapigenin, apigenin-6, Flavonoids including 8-di-glucopyranoside, luteolin-C-glucuronide, luteolin-7-O-glucuronide, crabflavin A, crabflavin B, crabflavin C, chrysoeriol, kaempferol-3-O-diglucoside, quercetin-3-O-glucoside, quercetin-3-O-diglucoside, kaempferol-3-O-sophoroside, quercetin-3-O-sophoroside, rutin, quercetin, naringenin, and naringin; myrcene, cis-β-ocimene, trans-β-ocimene, p-cymene, α-terpinene, β-phellandrene, γ-terpinene, α-terpinolene, α-phellandrene, 3-phenyl-2-methyl-prop-1-ene, α-pinene, β-pinene, camphene, Δ 3 -Karen, Δ 4-Carene, sabinene, α-thujene, linalool, citral B, nerol, geraniol, epsilon, citronellol, 2-methyl-2-hepten-6-one, geranylacetone, m-mentha-1,8-(9)-dien-5-ol, carvacrol, carvone, α-terpineol, terpinen-4-ol, purugone, dihydrocarvone, β-terpineol, dihydrocarbyl acetate, p-cymen-8-ol, β-cyclocitral, safranal, cis-linalool oxide, perylene, sabinol, thujyl alcohol, linalool oxide, cis-carveol, cis-sabinene hydrate, sabinene hydrate, 8-cineole, 1,4-cineole, piperitone Oxide, piperitenone oxide, fenchyl alcohol, fenthion, borneol, bornyl acetate, camphor, camphene hydrate, α-pinene oxide, pinocarveol, pinocarvone, α-caryophyllene, β-caryophyllene, caryophyllene oxide, curcumene, α-trans-bergamotene, α-selinene, β-farnesene, longifolene, humulene epoxide I, humulene epoxide II, caryophyllene alcohol (caryophyllenol), β-bisabolene, allo-aromadendrene, calamenene, α-copaene, nerolidol, α-gurjunene, iso-caryophyllene, β-selinene, selina-3,7(11)-diene, selina-4(14),7(11)-Diene, α-Bisabolol, α-Cedrene, α-Cubebene, δ-Cadinene, Epi-β-Santalene, Farnesol, γ-Cadinene, γ-Elemene, γ-Eudesmol, Guaol, Ledol, Trans-Trans-α-Farnesene, (Z)-β-Farnesene, Farnesylacetone, α-Cadinene, α-Cis-Bergamotene, α-Eudesmol, α-Guaene, α-Longipinene, α-Ilangene, β-Elemene, β-Eudesmol, Epi-α-Bisabolol, γ-Cis-Bisabolene, γ-Curcumene, γ-Muolene, γ-Trans-Bisabolene, Viridiflorene, Germacrene-B, Clobandiol, Phytol, Neophytadiene , friedrin, epifreedelanol, vomifoliol, dihydrovomifoliol, β-ionone, dihydroactinidiolide, carbohydrates, fatty acids and their esters, amides, amines, phytosterols, and lignans, phenolic compounds including spiroindanes, dihydrostilbenes, and dihydrophenanthrene derivatives, stilbenoids, cannabispirans, denbinobin, catechin, chlorogenic acid, caffeic acid, epicatechin, luteolin-7-O-glucoside, p-coumaric acid, caffeoyl, tyramine, ferulic acid, quercetin-3-glucoside, kaempferol, apigenin-7-glucoside, luteolin, cannabidiol, and apigenin.

[0154] In several embodiments, cannabis-derived bioactive molecules further include those reviewed in Russo, 2011; Gertsch, Pertwee, and Di Marzo, 2010; Tahir et.al., 2021; Thomas and ElSohly, 2016; De Backer et.al., 2009; and Hazekamp et.al., 2004.

[0155] ii. Dipteryx In some embodiments, the plant part of the therapeutic combination is derived from Dipteryx. In embodiments where the plant part is described as being "derived from" Dipteryx, it will be understood that the plant part includes, by way of non-limiting example, Dipteryx material such as raw (i.e., unprocessed) Dipteryx biomass, a Dipteryx extract (e.g., an extract described herein, e.g., an aqueous extract such as an aqueous solution and / or an ethanolic extract), or a molecule naturally present in Dipteryx (e.g., a primary or secondary bioactive molecule described in embodiments herein), whether or not the molecule is actually obtained by isolating the molecule from Dipteryx or whether it is obtained by another means (e.g., chemical synthesis).

[0156] In some embodiments, the therapeutic combination comprises a Dipteryx extract. In some embodiments, the therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule from a species of the genus Dipteryx.

[0157] In some preferred embodiments, the primary bioactive molecule and / or the secondary bioactive molecule is from Dipteryx, while in other embodiments, the primary bioactive molecule and / or the secondary bioactive molecule is from another genus of the tribe Dipterigea, which further includes the genera Monopteryx, Pterodon, and Taralea.

[0158] In embodiments, the primary and / or secondary bioactive molecules are derived from Dipteryx, including D. odorata, also referred to herein as "cumar tree" or "cumar."

[0159] In some preferred embodiments, the bioactive molecule, such as coumarin, is derived from a plant of the Dipteryx genus, such as Dipteryx odorata, i.e., cumar, while in other embodiments, the bioactive molecule, such as coumarin, is derived from a plant of another genus, including any genera of the Amburana tribe, such as Amburana, Cordyla, Dupuya, Dussia, Mildbraediodendron, Myrocarpus, Myrospermum, Myroxylon, and Petaladenium. Thus, in some embodiments, species from such other genera, and extracts and bioactive molecules therefrom, are considered equivalents of similar extracts and bioactive molecules from Dipteryx.

[0160] Dipteryx is a genus of large trees in the family Fabaceae, native to South and Central America and the Caribbean, and was formerly known as Coumarouna.

[0161] In some embodiments, the therapeutic combination comprises a primary and / or secondary bioactive molecule derived from the species Dipteryx odorata.

[0162] Dipteryx odorata is known by many names, including coumarouna odorata, cumar tree (Brazil), tonka bean tree, Brazilian teak, Tonkin bean, rumara, cumar (Guyana), cumarzeiro (Portugal), Charapira (Peru), Charapira del Murcielago (Peru), Zihuahuaco (Peru), and Sarapia (Venezuela, Colombia), all of which may be used interchangeably or considered equivalent in accordance with the disclosure herein. Dipteryx odorata is a large tropical rainforest canopy tree growing up to 30 meters in height in the Amazon. It can be found in Brazil, Venezuela, Guyana, French Guiana, Suriname, Nigeria, Peru, and Colombia. Historically, the seeds and bark of Dipteryx odorata have been used by local Amazonian peoples. The seeds have been fermented in rum and used as a shampoo for snake bites, cuts, bruises, coughs, and rheumatism, the seed oil for earaches and ear infections, and the bark as a bath additive for fever sufferers.

[0163] The seeds (also called beans) from the kumaru tree (tonka bean) contain the bioactive molecule coumarin, which has a pleasant vanilla-like scent and has been used to flavor perfumes, soaps, food, and tobacco products. Coumarin is typically prepared by fermenting the beans in local rum and air-drying them, resulting in a dusting of coumarin crystals on the outside of the seeds, giving them a matte appearance.

[0164] In some embodiments, the disclosed combinations including bioactive molecules derived from Dipteryx, such as coumarin, can exhibit antispasmodic, emmenagogue, cardiotonic, and antiasthmatic effects.

[0165] In some aspects, the disclosed combinations including bioactive molecules derived from Dipteryx, such as coumarin, modulate serotonin, dopamine (including upregulating their synthesis and release), and / or modulate adrenergic receptors and may exhibit neuroprotective effects, as disclosed, for example, in Ostrowska, 2020 and Abdelhafez et al., 2011. In some embodiments, the disclosed combinations including bioactive molecules derived from Dipteryx, such as coumarin, inhibit MAO-B, thereby allowing dopamine to remain active, as disclosed, for example, in Huang et al., 2015.

[0166] In some embodiments, the disclosed combinations containing bioactive molecules derived from Dipterix, such as coumarin, dose-dependently reduce the production of nitric oxide (NO), tumor necrosis factor alpha (TNFα), and / or interleukin-1β (IL-1β). In some embodiments, the disclosed combinations containing bioactive molecules derived from Dipterix, such as coumarin, suppress LPS-induced protein and mRNA expression levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in RAW264.7 cells. In some embodiments, the disclosed combinations containing bioactive molecules derived from Dipterix, such as coumarin, activate PPAR-γ and counter-regulate inflammatory activity in a tissue-specific manner; the transcription factor NRf2 further regulates NF-kB activity, exerting a useful cytoprotective mechanism (e.g., as disclosed in Hassanein et al., 2020; and Di Stasi, 2021).

[0167] ii. Primary and secondary bioactive molecules derived from Dipteryx In embodiments, the therapeutic combination includes a first and / or second bioactive molecule derived from Dipteryx.

[0168] In embodiments, the primary bioactive molecule from Dipteryx is coumarin (2H-chromen-2-one; 2H-1-benzopyran-2-one), a colorless crystalline solid that gives tonka beans their characteristic vanilla-like odor and flavor and may also act as a chemical defense against predators.

[0169] Coumarins are obtained from Dipteryx and from numerous other plant species, including vanilla grass (Anthoxanthum odoratum), sweet woodruff (Galium odoratum), sweetgrass (Hierochloe odorata), sweet clover (Melilotus spp.), as well as cinnamon, including Ceylon cinnamon or "true cinnamon" (Cinnamomum verum), Chinese cinnamon or Chinese cassia (C. cassia), Indonesian cinnamon or Padang cassia (C. burmannii), Saigon cinnamon or Vietnamese cassia (C. loureiroi), Deatong (Carphephorus odoratissimus), and Tilo (Justicia Coumarins are obtained from Dipteryx (Pectoralis), Mullein (Verbascum spp.), many cherry trees in the Prunus genus, and in trace amounts from strawberries, black currants, apricots, and cherries (Ananthakrishnan et al., 2018; Wang et al., 2013; Khan and Ehab, 2010; Leri, Pinelli, and Romani, 2012; and National Center for Biotechnology Information, 2022). In some embodiments, coumarins are extracted, isolated, or otherwise obtained from any of these or other such species, but not from Dipteryx.

[0170] In some embodiments, the bioactive molecule is a compound derived from coumarin (e.g., a phenylpropanoid, coumarin, or coumarinoid) and may be used in the disclosed combinations, compositions, and methods; such compounds include, for example, the bioactive molecules umbelliferone, aesculetin, herniarin, psoralen, dicoumarol, imperatorin, brodifacoum, bromadiolone, difenacoum, auraptene, ensaculin, phenprocoumon, PSB-SB-487, PSB-SB-1202, scopoletin, and warfarin (e.g., Laposata, Van (See Cott and Lev, 2007; Syah et al., 2009).

[0171] In embodiments, the secondary bioactive molecule from Dipteryx is coumar, a coumarin derivative, an isoflavone, a lupeol derivative, a fatty acid ester, (±)-balanofonin, (-)-lariciresinol, 3'-hydroxyretsin-8-methyl ether, 5-methoxyxanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxy-isoflavone, betulin, butine, coumaric acid-β-glucoside, dipteryxin, dipteryxin. acid, eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyl-linolenic acid, methyl-oleic acid, O-coumaric acid, O-hydroxycoumaric acid, odoratin, p-hydroxybenzoic acid, lettucin, lettucin-8-methyl ether, sulfuretin, salicylic acid, afrormicin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone.

[0172] In several embodiments, the bioactive molecules derived from Dipteryx further include those of Trincone, 2019; Jofre et al., 2020; or Gomez-Zavaglia et al., 2019.

[0173] c.Algae In some embodiments, the therapeutic combination comprises an algae part. In some embodiments, the algae part comprises an algae extract. In some embodiments, the algae part comprises an algae-derived bioactive molecule. In some embodiments, the algae extract comprises an algae-derived bioactive molecule. For example, in some embodiments, the algae part comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from algae. In some embodiments, the algae extract comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from algae. Thus, in some embodiments, the disclosed therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule derived from algae.

[0174] In embodiments where the algae parts are described as being "derived" from algae, it will be understood that the algae parts include algae-derived materials, including, by way of non-limiting example, algae material such as raw (i.e., unprocessed) algae biomass, algae extracts (e.g., extracts described herein such as aqueous extracts and / or ethanolic extracts), or molecules naturally occurring in algae (e.g., primary or secondary bioactive molecules described in embodiments herein), whether said molecules are actually obtained by isolating the molecule from the algae or whether they are obtained by another means (e.g., chemical synthesis).

[0175] Algae, broadly defined, refers to a large, polyphyletic group of photosynthetic eukaryotic organisms. While there is no universally accepted definition of algae in general, one way to describe the multiple phyla encompassing "algae" is that they have chlorophyll as their primary photosynthetic pigment and lack a sterile cell envelope surrounding their reproductive cells (Lee, 2008). Algae include species that can live in freshwater and / or saltwater and generally include Euglenophyta (euglenoids), Chrysophyta (golden brown algae and diatoms), Pyrrophyta (fire algae), Chlorophyta (green algae), Rhodophyta (red algae), Phaeophyta (brown algae), and Xanthophyta (yellow-green algae) (Bailey, 2018).

[0176] In embodiments, the algae useful in the therapeutic combinations of the present invention are marine algae. In embodiments, the marine algae can be brown algae (Phaeophyta), green algae (Chlorophyta), and red algae (Rhodophyta). In embodiments, the marine algae is marine red algae. In embodiments, the marine red algae is from the family Bangiaceae. In embodiments, the marine red algae is from the genus Pyropia or Porphyra.

[0177] Culturally, Porphyra has been cultivated in East Asia and used to produce "nori" and other forms of edible seaweed, such as that used in sushi, and to bind and fix rice to other proteins, such as fish. Some species of Porphyra are also harvested in Western Europe to produce seaweed bread, eaten primarily in Wales as part of traditional local cuisine (Harford, n.d.).

[0178] In some embodiments, the red algae is Porphyra umbilicalis. Broadly speaking, umbilicalis is a membranous, monolamellar alga with irregularly lobed olive-to-brown leaves (up to 200 mm long) that split from a central holdfast, generally giving it a lettuce-like appearance. Texture-wise, umbilicalis is often smooth and gelatinous, not firm (Harford, n.d.). Like other Porphyra species, umbilicalis grows on rocks and sometimes mussels in mid-tide and splash zones, and is abundant from spring through summer. In some embodiments, the red algae is Pyropia perforata. Perforata is generally purple / green in color, has lobed blades, and can reach 30 cm in width and length. Perforata grows epiphytically on rocks or other algae. In some embodiments, the red algae is Pyropia ezogensis. ezoensis has a disc-shaped holdfast and a short stalk, with membranous, monochromatic, folded blades, and is colored red, brown, or dark green.

[0179] a. Primary and secondary bioactive molecules derived from algae In embodiments, the therapeutic combination includes a primary and / or secondary bioactive molecule derived from algae.

[0180] In some embodiments, the primary bioactive molecule derived from algae is a primary bioactive molecule derived from a genus of the family Bangiaceae. In some embodiments, the primary bioactive molecule derived from algae is a primary bioactive molecule derived from a species of the genus Pyropia or Porphyra. In some embodiments, the primary bioactive molecule derived from algae is a primary bioactive molecule derived from Porphyra umbilicalis. In some embodiments, the primary bioactive molecule derived from algae is a primary bioactive molecule derived from Pyropia aezoensis. In some embodiments, the primary bioactive molecule derived from algae is a primary bioactive molecule derived from Pyropia perforata.

[0181] In embodiments, the primary bioactive molecule from Pyropia or Porphyra is any of a porphyran and / or oligoporphyran, a polysaccharide, an oligopolysaccharide, and / or a monosaccharide; a peptide, a phycobiliprotein, a mycosporine-like amino acid, an essential amino acid, a non-essential amino acid, a carotene, an intermediate carotenoid, a glycoprotein, and an aminosulfonic acid such as taurine.

[0182] In some embodiments, the disclosed combinations, compositions, and methods including algae-derived bioactive molecules, such as oligosaccharides from Pyropia, will be shown to increase dopamine synthesis by inhibiting the loss of tyrosine hydroxylase, such as by the methods disclosed in Liu et al., 2019. In some embodiments, the disclosed combinations, compositions, and methods including algae-derived bioactive molecules, such as porphyrans, will be shown to provide neuroprotection. In some embodiments, the disclosed combinations, compositions, and methods including algae-derived bioactive molecules, such as taurine, will be shown to protect dopaminergic neurons and elevate dopamine, as shown in mouse models in the methods disclosed in Liu et al., 2018; Che et al., 2018; and Ericson et al., 2006.

[0183] In some embodiments, the disclosed combinations, compositions, and methods comprising algae-derived bioactive molecules such as taurine may be shown to reduce neurological damage through downregulation of NF-kB and activation of the Nrf2 signaling cascade. In some embodiments, taurine may be shown to reduce serum levels of IL-6 in TBI patients, according to the methods disclosed in Agca et al., 2014; and Vahdat et al., 2021. In multiple embodiments, taurine may be shown to biostabilize membranes, promote redox homeostasis, and remove oxidants, such as those disclosed in Yildirim et al., 2007; and Thirupathi et al., 2020.

[0184] In embodiments, phycobiliproteins include phycoerythrin, phycoerythrobilin, phycocyanin, and allophycocyanin. In embodiments, mycosporine-like amino acids include porphyra-334 and shinorine. In embodiments, amino acids include isoleucine, leucine, threonine, methionine, phenylalanine, lysine, histidine, valine, arginine, and cysteine. In embodiments, non-essential amino acids include aspartic acid, glutamic acid, glycine, tyrosine, serine, alanine, and proline. In embodiments, peptides include monopeptides, dipeptides, tripeptides, and proteins. In embodiments, carotenes include lutein, zeoxanthin, α-carotene, β-carotene, and astaxanthin, and in embodiments, intermediate carotenoids include α-cryptoxanthin, zeinoxanthin, and β-cryptoxanthin.

[0185] In embodiments, the primary bioactive molecule from Pyropia or Porphyra is any of: peptides, including porphyrans and / or oligoporphyrans, polysaccharides, monopeptides, dipeptides, tripeptides, and proteins; phycobiliproteins, including phycoerythrin, phycoerythrobilin, phycocyanin, and allophycocyanin; mycosporine amino acids, including Porphyra-334 and shinorine; essential amino acids, such as isoleucine, leucine, threonine, methionine, phenylalanine, lysine, histidine, valine, arginine, and cysteine; non-essential amino acids, such as aspartic acid, glutamic acid, glycine, tyrosine, serine, alanine, and proline; carotenes, such as lutein, zeoxanthin, α-carotene, β-carotene, and astaxanthin; intermediate carotenoids, such as α-cryptoxanthin, zeinoxanthin, and β-cryptoxanthin; and taurine.

[0186] In some embodiments, the therapeutic combination comprises a bioactive molecule derived from algae, and in some embodiments, the bioactive molecule is a secondary bioactive molecule derived from algae. In some embodiments, the secondary bioactive molecule derived from algae is a secondary bioactive molecule derived from a genus of the family Bangiaceae. In some embodiments, the secondary bioactive molecule derived from algae is a secondary bioactive molecule derived from a species of the genus Pyropia or Porphyra. In some embodiments, the secondary bioactive molecule derived from algae is a secondary bioactive molecule derived from Porphyra umbilicalis. In some embodiments, the secondary bioactive molecule derived from algae is a secondary bioactive molecule derived from Pyropia aezoensis.

[0187] In embodiments, the secondary bioactive molecule derived from Pyropia or Porphyra is any of a mineral, a vitamin, a lipid, a phenolic compound, and a phlorotannin.

[0188] In some embodiments, the minerals include potassium, phosphorus, magnesium, sodium, calcium, manganese, iron, copper, and zinc. In some embodiments, the vitamins include vitamin K, ascorbic acid, folic acid, and cobalamin. In some embodiments, the lipids include fatty acids such as eicosapentaenoic acid and palmitic acid. In some embodiments, the phlorotannin includes phlorotannin A.

[0189] In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is any of: minerals, including potassium, phosphorus, magnesium, sodium, calcium, manganese, iron, copper, and zinc; vitamins, including vitamin K, ascorbic acid, folic acid, and cobalamin; lipids, including fatty acids such as eicosapentaenoic acid and palmitic acid; phenolic compounds, and phlorotannins, including phlorotannin A.

[0190] C. Obtaining Bioactive Molecules In embodiments, the primary and secondary bioactive molecules disclosed herein may be obtained via any of the following, by way of non-limiting example: extraction methods, synthesis methods, biosynthesis methods, whole plants such as cannabis flowers or cannabis biomass, fruiting mycelia, fungal mycelium, fungal biomass produced in bioreactors, truffles (sclerotized fungal bodies), cumulus seeds, or whole, isolated, and / or collected fractions of Porphyra or Pyropia algae.

[0191] In some embodiments, the biologically active molecules of the therapeutic combination are commercially available and commercially sourced (e.g., Cayman Chemical Company, Ann Arbor, MI; Sigma-Aldrich, Burlington, MA).

[0192] While these methods are well known to those skilled in the art, exemplary means for obtaining the primary and secondary bioactive molecules are disclosed herein.

[0193] a. Extraction In some embodiments, the extracts (e.g., fungal extracts, plant extracts, or algal extracts) used in the disclosed therapeutic combinations are obtained by use of extraction techniques known to those of skill in the art, hi some embodiments, the disclosed primary and secondary bioactive molecules are provided in the form of extracts produced according to extraction techniques known to those of skill in the art.

[0194] Without being bound by theory, broadly, extraction systems function by introducing material, such as fungal, plant, and / or algal material (e.g., containing desired primary and / or secondary bioactive molecules), into a solvent capable of separating the desired primary and / or secondary bioactive molecules from the material to form a solution (extract) containing the solvent and the primary and / or secondary bioactive molecules.

[0195] The extracts can be used directly in the disclosed combinations, compositions, or methods, or can first be further processed, such as by further extraction, filtration, distillation, fractionation, sub-fractionation, isolation, and / or purification, and other such methods known in the art, including combinations thereof.

[0196] Various types of extraction systems exist, utilizing different methods and having different parameters (e.g., temperature, pressure, solvents), which can be tailored to the desired end product, e.g., the desired primary and / or secondary bioactive molecules. Such characteristics will be known to those skilled in the art. Without being bound by theory, for example, extraction systems generally follow the principle of "birds of a feather flock together." Thus, polar solvents are used to extract polar bioactive molecules, and non-polar solvents are used to extract non-polar bioactive molecules (Lowery and Richardson, 1987).

[0197] General methods for extracting primary and / or secondary bioactive molecules, creating plant and fungal extracts thereof, and producing purified products containing the desired compounds free of undesirable plant or fungal material, chemicals, and other impurities are known in the art, e.g., U.S. Pat. Nos. 6,403,126, 8,846,409, 8,895,078, and 10,059,684. , 10,239,808, 10,246,431, 10,300,494, 10,307,447, 10,406,453, 10,413,845, and 10,414,709, as well as U.S. Patent Application Publication Nos. 2003 / 0017216A1 and 2016 / 0038437A1, and the references cited therein, all of which are incorporated herein by reference.

[0198] The exemplary extraction methods and systems disclosed in such references and elsewhere herein should not be construed as limiting, and many variations will be appreciated by those skilled in the art. While exemplary extraction methods, including those described herein, are disclosed as a series of steps, other extraction methods useful in practicing the present invention and obtaining bioactive molecules may deviate from such steps, including altering, removing, adding, or rearranging such steps, as would be understood by one of ordinary skill in the art in light of this disclosure and general knowledge in the art.

[0199] As used herein, "extract" may refer to, for example, a botanical extract (e.g., a fungus, plant, Cannabis, Dipteryx, algae, or other extract containing the primary and / or secondary bioactive molecules disclosed herein) prepared from a botanical source ("botanical" as defined herein). In some embodiments, the extract undergoes further extraction, filtration, fractionation, sub-fractionation, partial purification, substantial purification, or complete purification, or other processing to obtain specific bioactive molecules separated from other components, and such bioactive molecules are found in filtrates, fractions, sub-fractions, partially purified products, substantially purified products, fully purified products, isolates, etc., and may, in some cases, be obtained as a single component or multiple single components separated from all other components. In some embodiments, the extract is obtained as a whole plant extract, whole fungal extract, or whole algae extract without fractionation, sub-fractionation, partial purification, substantial purification, or complete purification, or other processing to obtain specific bioactive molecules separated from other components, and may be referred to herein as a "whole extract." In alternative embodiments of any exemplary embodiment disclosed herein, the whole extract is replaced with a fraction, sub-fraction, partially purified, substantially purified, fully purified, isolated, etc., as well as a single biologically active molecule or molecules from the extract (including in the extract), or a molecule produced synthetically, such as by partial or complete chemical synthesis, or biosynthesis.

[0200] Thus, extracts may include purified extracts. As will be understood by those skilled in the art, "purified extract" may refer to a plant extract that has undergone further processing after preparation. In some exemplary embodiments, the purified extract may be produced, for example, by soaking or heating the preparation in water and / or alcohol (e.g., depending on whether and to what extent the desired bioactive molecule is water-soluble), stirring, cooling the resulting liquid, filtering, removing unwanted products (repeated as necessary), and then evaporating enough liquid solvent to obtain the desired concentration (or completely to obtain a crystalline precipitate), or by using a spray dryer to produce a purified dry powder. Other purification techniques are known to those skilled in the art, and generally, extraction and purification techniques for obtaining highly pure bioactive compounds will be known to those skilled in the art.

[0201] To maintain the purified dry powder as a flowable powder that is easy to work with during formulation, for example when adding the dry powder to a capsule, starch or other carriers may be added to the purified extract, but when referring to the weight of the "purified extract," such carriers, diluents, or excipients are excluded from the total amount.

[0202] In embodiments, the extract may be "standardized," which refers to an extract that contains a primary and / or secondary bioactive molecule at a particular concentration. Methods for producing a standardized extract will be known to those skilled in the art, such as quantifying the concentration of the extract and diluting the extract to a standardized concentration by adding a carrier, diluent, or excipient, or further concentrating the extract to increase the concentration.

[0203] "Natural" may refer to a material that is isolated, extracted, or otherwise obtained from a natural source, such as a fungus, plant, or algae. Thus, naturally occurring primary or secondary bioactive molecules, such as naturally occurring cannabinoids, may be isolated or extracted from the cannabis plant. Accordingly, in various disclosed embodiments, compositions are intended to be derived as extracts or by other means from botanical sources, including fungi, plants, and algae, and include botanical drug substances or cannabis-derived drug substances. In embodiments, such compositions are intended to include botanical drug products or cannabis-derived drug products. In other embodiments, such compositions are intended to include botanical drug products or cannabis-derived drug products that are substantially free of impurities.

[0204] In some embodiments, when the disclosed combinations or compositions include multiple extracts (e.g., fungal extracts, plant extracts, algae extracts), the concentrations of bioactive molecules contained therein are quantified (e.g., according to the methods disclosed herein and other methods known to those of skill in the art). The concentrations of bioactive molecules in the extracts may vary based on the concentrations of the bioactive molecules in the corresponding source material (e.g., live fungal, plant, or algae biomass). Therefore, the concentration of bioactive molecules in the disclosed compositions may vary from batch to batch based on the variability of the extracts between batches. In accordance with FDA regulations (2016, USHHS, FDA, CDER, Botanical Drug Development Guidance for Industry), bioactive molecules (e.g., the primary and / or secondary bioactive molecules disclosed herein) can be added to the extracts disclosed herein (e.g., fungal, plant, or algae extracts); or to the disclosed combinations or compositions containing the extracts. This can be done, for example, to standardize the disclosed combinations or compositions and ensure a consistent concentration of bioactive molecules between batches, even if the raw materials or their extracts may differ in the concentration of bioactive molecules.

[0205] i. Exemplary Extraction of Molecules from Fungi In embodiments, the therapeutic combination includes a first and / or second bioactive molecule from a fungus, hi embodiments, the first and / or second bioactive molecule is obtained by extraction of fungal material.

[0206] Without wishing to be bound by theory, fungal extraction methods can generally be described as follows: first, fungal material containing the desired primary and / or secondary bioactive molecules is obtained, optionally dried (e.g., using means such as a low temperature oven, a food dehydrator, and / or a commercial dryer), optionally ground, crushed, soaked, and / or milled to form a substantially fine powder, which is optionally sieved, for example, for consistency.

[0207] The fungal material is then combined with a solvent (e.g., methanol, ethanol, water, or a mixture thereof) capable of extracting the desired primary and / or secondary bioactive molecules to form a slurry, which is stirred for a predetermined period of time, e.g., about 24 hours, to promote extraction. The solvent is then filtered and collected. In some embodiments, the filter may include cheesecloth, filter paper, and / or a filtration system. If desired, the extract may be evaporated using any of several evaporation methods, including ambient temperature evaporation, rotary evaporation, vacuum evaporation, and evaporation methods that utilize heat, such as those utilizing ovens, to create more concentrated extracts. In some embodiments, the fungal material may be resaturated with the same or a different solvent after the initial filtration to complete secondary, tertiary, or further extractions. Extraction methods and variations thereof may be selected as appropriate by those skilled in the art.

[0208] In some embodiments, thermal extraction is utilized. In some embodiments, the thermal extraction generally follows the method described above, except, for example, that the solvent is heated, the stirring is completed in a heated environment, or the extraction is otherwise performed at an elevated temperature relative to ambient temperature. In some embodiments, the extraction is completed at a temperature at which psilocybin is substantially dephosphorylated to psilocin. In some embodiments, the thermal extraction is completed at a temperature greater than about 70°C. In some embodiments, the extraction is performed below a temperature at which substantial dephosphorylation of psilocybin occurs.

[0209] In several embodiments, ultrasonic extraction is utilized. In some embodiments, the mushrooms or other fungal material are dried, cut and / or crushed prior to ultrasonic extraction. In some embodiments, an ultrasonic extractor is utilized to expose fungal material to ultrasonic vibrations via an ultrasonic probe. In some embodiments, the ultrasonic probe vibrates at 20 kHz or higher. Without being bound by theory, as ultrasound propagates through a liquid, alternating cycles of high pressure (compression) and low pressure (rarefaction or expansion of the medium) occur (Hielscher, 2022). During the low-pressure vacuum cycles, tiny vacuum bubbles or cavities are generated in the liquid, which grow over several pressure cycles. During the compression phase of the liquid and bubbles, the pressure becomes positive, and during the rarefaction phase, a vacuum (negative pressure) occurs (Hielscher, 2022). During the compression-expansion cycles, the cavities in the liquid grow until they are too large to absorb any more energy, at which point they implode. The implosion of these cavities results in a variety of high-energy sonomechanical effects known as acoustic / ultrasonic cavitation ( Hielscher, 2022 ), during which gas bubbles are generated in the sonicated liquid, disrupting the cell walls of plant tissues and releasing intracellular compounds, including primary and / or secondary bioactive molecules.

[0210] In some embodiments, extraction is performed using a Soxhlet extractor. In some embodiments, Soxhlet extraction is performed using an ethanol and water solvent (e.g., 80% ethanol and 20% water). In some embodiments, the solvent is heated to reflux, and the solvent vapor rises up a distillation arm and flows into a chamber containing a thimble of fungal material. A condenser on top of the apparatus cools the solvent vapor and drips it into the chamber containing the fungus. As a result, the chamber containing the fungus slowly fills with warm solvent. When the Soxhlet chamber is nearly full, the chamber is emptied by a siphon, and the solvent is returned to the distillation flask. In some embodiments, Soxhlet extraction is performed for about 6 to about 10 hours, including about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours, using standard equipment known to those skilled in the art. In several embodiments, the Soxhlet extraction is performed for about 7 hours.

[0211] Extracts of fungal material (including primary and / or secondary bioactive molecules) produced according to different methods described herein or other methods known to those skilled in the art can be combined to provide various benefits. For example, fungal extracts produced according to different techniques may contain different concentrations of primary and / or secondary bioactive molecules, and combining such extracts in the disclosed therapeutic combinations can impart advantageous properties.

[0212] In some embodiments, the fungal portion of the disclosed therapeutic combination comprises a combination of fungal extracts. In some embodiments, the fungal portion of the disclosed therapeutic combination comprises an ultrasonic extract and a Soxhlet extract. In some embodiments, the combination comprises an ultrasonic:Soxhlet ratio (e.g., volume ratio (v / v) or weight ratio (w / w) of extract solutions, or a molar ratio, such as the molar ratio of constituent bioactive molecules in the extract) of ultrasonic extract and Soxhlet extract from about 0.5:1 to 10:1, including 0.5:1, 1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1, including ranges between these values. In some embodiments, the combination comprises an ultrasonic:Soxhlet volumetric ratio of about 0.5:1 to 10:1, including 0.5:1, 1:1, 1.25:1, 1.5:1, 1.75:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1, including ranges between these values. In some embodiments, the combination comprises an ultrasonic mixture of ultrasonic and Soxhlet extracts at an ultrasonic:Soxhlet ratio of about 2:1 (v / v).

[0213] Benefits of combining different fungal extracts in the disclosed combinations may include, for example, improved solution stability. For example, certain compositions disclosed herein include psilocin and / or psilocybin as components of the fungal parts. The solution instability of psilocybin, and particularly psilocin, has long been recognized, but the mechanism of degradation and the exact chemistry of the products remain a matter of ongoing research. Studies of injured psilocybin mushrooms that expose the alkaloids to environmental oxygen revealed that psilocybin is dephosphorylated to psilocin, and its hydroxyl group is oxidized to produce a 4-oxo degradant (Lenz et al., 2020). Research on possible solution degradation mechanisms revealed that oxidative dimerization may also contribute to psilocin's solution instability (Lenz et al., 2021). In some embodiments, combining fungal extracts (e.g., as in the disclosed combinations where the fungal parts include both ultrasonic and Soxhlet extracts) protects the resulting combination from oxidative degradation. Without being bound by theory, different levels of primary and / or secondary bioactive molecules in different fungal extracts, which may include naturally occurring stabilizers and antioxidants, may, in combination, produce additive or synergistic effects that stabilize the resulting formulation against degradative pathways such as oxidative dimerization. In some embodiments, oxidative degradation of the disclosed compositions can be monitored quantitatively (e.g., by chemical analytical methods such as those disclosed in Lenz et al., 2020 and Lenz et al., 2021; or otherwise known to those skilled in the art) or qualitatively (e.g., by visual monitoring of the characteristic "bluing" reaction of psilocybin- and / or psilocin-containing extracts and materials).

[0214] In some embodiments, the disclosed combinations, in which the fungal portion comprises multiple fungal extracts, may also have other advantageous properties, such as increased miscibility with other portions of the combination (e.g., plant and / or algal portions). As an example, certain compositions disclosed herein contain a component with high water solubility (e.g., a fungal extract containing psilocybin and / or psilocin, or a fungal extract containing these compounds) and a component with low water solubility (e.g., a plant part containing a cannabinoid or cannabis extract). During preparation and storage of such compositions, precipitation may occur due to mutual incompatibility between the primary and / or secondary bioactive molecules and the solvent system. Without being bound by theory, different levels of the primary and / or secondary bioactive molecules in different fungal extracts may result in additive or synergistic effects that stabilize the resulting formulation against precipitation.

[0215] In some embodiments, the disclosed combinations, in which the fungal portion comprises multiple different fungal extracts, have improved stability (e.g., against oxidation and / or precipitation) such that additional stabilizing excipients (e.g., antioxidants, stabilizers) are not required for the combination to be sufficiently stable under ambient conditions. Reducing or eliminating the need for such additional stabilizing excipients may provide additional benefits, such as improved bioavailability, as these components may inhibit absorption of the primary and / or secondary bioactive molecules.

[0216] a. Determining the concentration of primary and / or secondary bioactive molecules It will be appreciated that determining the concentration of primary and / or secondary bioactive molecules within an extract or within fungal, plant, and / or algal material is within the capabilities of one of ordinary skill in the art. Several such means are disclosed below and may be used in embodiments.

[0217] As a non-limiting example of such a means, the concentrations of primary bioactive molecules from various Psilocybe species are shown below in Table 1 (taken from Mahmood, 2013, and organized by psilocybin content; see also Stamets, 1996), which shows the w / w% of psilocybin, psilocin, and baeocystin in dried mushrooms (containing negligible water weight, or sometimes referred to as "cracker dry"), as further discussed herein: [Table 1]

[0218] Thus, 100 mg of P. cubensis extract may, in some embodiments, contain about 0.63 mg of psilocybin, and 275 mg of P. azurescens extract may, in some embodiments, contain about 4.895 mg.

[0219] It will be readily understood that the growth conditions of organisms such as fungi (as well as plants and algae) can affect the concentration of bioactive molecules found therein. Also, the concentration of bioactive molecules can vary depending on the part of the organism from which they are obtained (e.g., cap vs. stem or mycelium, flower vs. leaf or stem, etc.), as well as other variables known to those skilled in the art. Nevertheless, one will understand how to select such growth conditions, organism parts, etc., and how to determine the concentration of bioactive molecules using the disclosed methods or methods commonly known in the art.

[0220] In some embodiments, the concentrations of primary and / or secondary bioactive molecules in fungi, plants, and / or algae are determined using liquid chromatography, such as high-performance liquid chromatography (HPLC). Broadly, HPLC works by using a pump to pass a pressurized liquid solvent containing a sample mixture (in this case, a fungal extract) through a column filled with a solid adsorbent material. Individual components in the sample interact differently with the adsorbent, resulting in different flow rates for each component, which separates the components as they exit the column (Freshminds, 2021).

[0221] In some embodiments, the concentration of primary and / or secondary bioactive molecules in fungi, plants, and / or algae is determined using reversed-phase HPLC and single-wavelength detection, as disclosed in Samuelsson et al., incorporated herein by reference. Broadly, reversed-phase HPLC generally proceeds in the same manner as the exemplary HPLC methods disclosed above, but with a hydrophobic stationary phase rather than a hydrophilic one. That is, hydrophobic molecules adsorb to the column packing, and hydrophilic molecules are eluted and detected first (Mehta, 2012; Molnar and Horvath, 1976).

[0222] In several embodiments, the concentration of primary and / or secondary bioactive molecules in fungi, plants, and / or algae is determined using liquid chromatography and mass spectrometry (LC / MS), as exemplified by Oetjen et al., 2020, incorporated herein by reference.

[0223] In embodiments, the concentration of primary and / or secondary bioactive molecules in fungi, plants, and / or algae is determined using hydrophilic interaction liquid chromatography (HILIC), as described in Jiang et al., 2020, incorporated by reference. Broadly speaking, HILIC is a normal-phase HPLC technique that utilizes a reversed-phase type eluent. Thus, the column has a hydrophilic stationary phase, and the eluent contains water, a buffer, and a high concentration of a water-miscible organic solvent ("Hydrophilic Interaction Liquid Chromatography," 2022).

[0224] In several embodiments, the concentrations of primary and / or secondary bioactive molecules in fungi, plants, and / or algae are determined using rapid personal quantification tools that can be used to determine concentrations, such as the PSILO-QTest (Miraculix; Jena, Germany), which is useful for determining the concentration of psilocybin in fungi. The PSILO-QTest detects concentration using a chemical color reaction, with color intensity being proportional to the concentration of the bioactive molecule (Mandrake, 2021). In some embodiments, characterization of the fungal, plant, and / or algal parts of the disclosed combinations (e.g., characterization of the primary and / or secondary bioactive molecules) includes characterizing free and / or bound amino acids using known chromatographic techniques (e.g., LC-MS, HPLC). In some embodiments, characterization includes determining the concentration of taurine in the fungal, plant, and / or algal parts.

[0225] ii. Exemplary Extraction of Molecules from Cannabis In embodiments, the therapeutic combination comprises a primary and / or secondary bioactive molecule derived from a Cannabis species, hi embodiments, the primary and / or secondary bioactive molecule can be obtained via extraction of Cannabis plant material.

[0226] In embodiments, an exemplary extraction system is as follows: first, in embodiments, substantially dried cannabis plant material is obtained. In embodiments, the dried cannabis plant material may then be ground and optionally milled to obtain a fine powder, and optionally sieved. As elsewhere, milling and micronization may increase the surface area available for the solvent to interact with the material, thus increasing the yield of desired primary and / or secondary bioactive molecules within the material. In embodiments, the dried, optionally ground, and / or milled plant material is then placed into an extraction system that generally includes a loop through which chilled ethanol (maintained between -30°C and -40°C) is circulated. Evaporation is used to remove the solvent, followed by distillation and filtration to further concentrate the extract and remove impurities.

[0227] In such an exemplary extraction system, decarboxylation occurs at high temperature and pressure (which occurs at approximately 110°C at standard pressure). By way of example, if one does not want to obtain the intoxicating effects of THC, one may choose an extraction process with temperatures and pressures below the aforementioned thresholds. Similarly, column chromatography, for example, can be used to remove THC after extraction.

[0228] Although such extraction systems are disclosed as a series of steps, it will be understood that deviations from the steps are within the scope of the present invention, and that various steps may be altered, deleted, or added at any time during the extraction process.

[0229] Furthermore, ethanol extraction is only one extraction process that can produce extracts useful in therapeutic combinations. In embodiments, other extraction methods and solvents can be utilized, including, but not limited to, subcritical and supercritical CO2 extraction, hydrocarbon extraction such as using butane and / or propane, methanol extraction, isopropyl alcohol extraction, and other such extraction methods known to those skilled in the art. Any such extraction method may be utilized, although it should be understood that particular extraction methods may offer particular advantages depending on the desired composition of the extract.

[0230] For example, supercritical extraction, such as supercritical CO2 extraction, is useful for extracting cannabinoids and preserving terpenoids. Hot alcohol extraction is useful for extracting and decarboxylating cannabinoids, but also extracts various pigments and impurities; on the other hand, hydrocarbon extraction, including butane and propane extraction, is effective at reducing impurities and pigments in the extract and is more efficient than cold alcohol extraction.

[0231] Cannabis-derived primary and / or secondary bioactive molecules may be obtained by extraction of the cannabis plant and used to prepare cannabis-derived drug substances and cannabis-derived medicines.

[0232] "Cannabis-derived active pharmaceutical ingredients" may refer to botanical pharmaceutical ingredients derived from the cannabis plant (including plant parts, plant part biomass, and plant exudates), and may include, by way of non-limiting and purely illustrative examples, primary extracts prepared by processes including maceration, percolation, extraction with solvents such as C1-C5 alcohols (e.g., ethanol), hydrocarbons (e.g., propane, butane), and sub- or supercritical carbon dioxide.

[0233] "Cannabis-derived medicinal products" may refer to primary cannabis extracts that have been further purified, for example, by distillation or chromatography. Those skilled in the art will recognize that when certain solvents are used to prepare the primary extract, the resulting extract may contain non-specific lipid-soluble materials. Those skilled in the art will recognize that such impurities can be removed by various processes, including winterization (e.g., cooling to -20°C, followed by filtration to remove waxy ballast), further extraction or filtration, and distillation.

[0234] iii. Exemplary Extraction of Molecules from Dipteryx In embodiments, the therapeutic combination comprises a first and / or second bioactive molecule derived from Dipteryx, hi embodiments, the first and / or second bioactive molecule is obtained via extraction of Kumaru (Tonka) beans.

[0235] As previously mentioned, the primary bioactive molecule in Dipteryx is coumarin, which in embodiments can be extracted from coumarin beans via extraction with polar solvents such as, but not limited to, water, alcohols, including ethanol and methanol; and various ethers. An exemplary extraction system utilizing ethanol is described below.

[0236] In embodiments, ethanol extraction may be utilized to extract coumarin from coumarine beans. In embodiments, the ethanol extraction may be ethanol percolation, in embodiments using absolute ethanol. In embodiments, the ethanol percolation extraction system functions by first crushing the coumarine beans to allow the ethanol solvent to enter and exit the beans. Preferably, the seeds are sufficiently crushed to increase surface area for extraction and form a plant mass. The seeds are then placed in a filter placed over a collection device. Ethanol is then poured over the seed material, passed through the filter, and collected in the collection device. In embodiments, this is complete only when the color of the ethanol indicates that substantially no additional bioactive molecules have been collected.

[0237] If necessary, excess ethanol is then evaporated, which can be accomplished by applying heat to the resulting solution or by utilizing ambient evaporation.

[0238] Other extraction methods may be used, as known to those skilled in the art. Additionally, although coumarin is directly mentioned, it should be readily understood that secondary bioactive molecules derived from coumarin, for example, may also be extracted using the same or similar methods and may be present in the extract when the exemplary ethanol extraction method is utilized. Additionally, the concentrations of the primary and / or secondary bioactive molecules may be determined as disclosed herein.

[0239] b.Synthesis In embodiments, the primary and secondary bioactive molecules disclosed herein may be synthetic, where "synthetic," as used herein, can refer to substances produced in a laboratory by chemical synthesis (e.g., by a series of chemical steps or reactions using chemical substrates, reagents, and optionally catalysts), or by biosynthesis as discussed herein (e.g., including compounds from bioengineered organisms, and thus also referred to as including "biosynthesis" or "synthetic biology" or "synbio").

[0240] Generally, methods for chemical synthesis are well known in the art, including the bioactive molecules disclosed herein.Therefore, the synthesis method of bioactive molecules and / or starting materials will be readily apparent to those skilled in the art, taking into account the general literature known in the art (see, for example, Greene et al., 1991; "Harrison et al., 1971-1996; "Beilstein Handbook of Organic Chemistry", Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., 1967-1994; Trost et al., 1991; "Theilheimer's Synthetic Methods of Organic Chemistry", 1991; March, 1991; Larock, 1989; Paquette, 1995), and can be used to synthesize bioactive molecules when they cannot be obtained by other methods, such as extraction. Generally, such modifications are known and understood by those skilled in the art with respect to techniques used for analogous compounds (Shulgin & Shulgin, 1992; Shulgin & Shulgin, 1997; Glennon et al., 1986; Nichols et al., 1991; Kedrowski et al., 2007; Heravi & Zadsirjan, 2016; Keri et al., 2017; Perez-Silanes et al., 2001; and references therein).

[0241] In embodiments, the disclosed first and second bioactive molecules are obtained by biosynthesis. Biosynthesis refers to the production of molecules, such as the first and / or second bioactive molecules utilized in a therapeutic combination, within a cell or a cell-free system. In embodiments, the first and / or second bioactive molecules useful in a therapeutic combination may be produced via biosynthesis.

[0242] Methods for the biosynthesis of bioactive molecules will be readily apparent to those of skill in the art in light of the general literature known in the art (see, e.g., WO 2021 / 052989, WO 2019 / 173797, WO 2021 / 086513, and WO 2019 / 180309). Non-limiting examples of biosynthetic pathways known in the art include pathways for cannabinoids, flavonoids, carotenoids, psilocybin, psilocin, and other indole alkaloids (such as primary and secondary bioactive molecules found in fungi), amino acids, and peptides (including monopeptides, dipeptides, tripeptides, and proteins).

[0243] In embodiments, the fungal-derived primary and / or secondary bioactive molecules are produced biosynthetically. In embodiments, the plant-derived primary and / or secondary bioactive molecules are produced biosynthetically. In embodiments, the algae-derived primary and / or secondary bioactive molecules are produced biosynthetically.

[0244] c. Separation, fractionation, and purification In embodiments, the first and / or second bioactive molecules are obtained via fractionation, separation, and / or purification. Fractionation refers to a separation process in which a volume of a mixture is divided into several smaller portions, called fractions, during a phase transition, the composition of which varies along a gradient.

[0245] In embodiments, fractions containing target primary and / or secondary bioactive molecules may be obtained via fractional distillation, column chromatography, fractional crystallization, fractional freezing, and bioassay-guided fractionation.

[0246] In some embodiments, the separation of the primary and / or secondary bioactive molecules from the extract containing the primary and / or secondary bioactive molecules can be completed. Many means for separating compounds from extracts are known to those skilled in the art. However, exemplary means include thin layer chromatography, column chromatography, flash chromatography, Sephadex chromatography, and high performance liquid chromatography (Sasidharan et al., 2011).

[0247] In some embodiments, the extract may be further purified to isolate specific primary and / or secondary bioactive molecules. In some embodiments, such purification techniques are known to those skilled in the art and may include HPLC and centrifugal partition chromatography (CPC).

[0248] d.Compound In several embodiments, the disclosed primary and / or secondary bioactive molecules are pure or substantially pure. As used herein, the terms "pure" or "substantially pure" refer to a material that is substantially or essentially free from components that normally accompany the material when it is synthesized, manufactured, or otherwise produced. A "pure" or "substantially pure" preparation of a primary and / or secondary bioactive molecule is therefore defined as a preparation having a chromatographic purity (of the desired bioactive molecule) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, and most preferably greater than 99.9%, as determined by area normalization of HPLC profiles or other similar detection methods. Preferably, the pure or substantially pure primary and / or secondary bioactive molecules used in the present invention are substantially free of other active compounds not intended for administration to a subject. In this context, "substantially free" means that no active compounds other than the primary and / or secondary biologically active molecules intended for administration to a subject are detectable by HPLC or other similar detection methods, or are below the desired detection threshold as defined above.

[0249] The disclosed primary and / or secondary biologically active molecules may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomers. The present invention includes all such possible isomers, including racemic and optically pure forms, as well as mixtures thereof. Optically active isomers can be prepared using chiral synthons or chiral reagents or separated using conventional techniques. Various methods for preparing optically active forms and determining activity are known in the art.

[0250] The present invention also includes primary and / or secondary bioactive molecules that have at least one desired isotopic substitution of an atom at or above the natural abundance of that isotope, i.e., are isotopically enriched. Isotopes are atoms with the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. An example is deuterium ( 2 H) and tritium ( 3 Any isotope of hydrogen, including H, may be used anywhere within the depicted structures to achieve the desired result. Alternatively, or in addition, any isotope of carbon, e.g. 13 C and 14 C may also be used. Isotopic substitution, e.g., deuterium substitution, may be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced with deuterium. In embodiments, the isotope is enriched to at least 60%, 70%, 80%, 90%, 95%, or 99% or more at any desired position. In one embodiment, deuterium is enriched to 90%, 95%, or 99% at the desired position.

[0251] The first and / or second biologically active molecules of the therapeutic combination will be understood to also include pharmaceutically acceptable salts of such molecules. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, which can be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these agents with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of the two; non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are generally preferred. For therapeutic use, salts of compounds are those in which the counterion is pharmaceutically acceptable. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefirate, acetate, adipate, alginate, aminosalicylate, ammonium salt, anthonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, tartrate, borate, butyrate, calcium edetate, calcium carbonate, camphor carbon dioxide, and the like. Acid salts: camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecyl sulfate, edetate, editate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furoate, fusidate, galactarate (mucoate), galacturonate, gallate, gentate, gluceptate Glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycolylsanilate, hemisulfinate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hibenzoate, hydrabamate, hydrobromide, hydrobromide / hydrobromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, hydroiodide, isethionate, isothionate, 1-aspartate, 1-camsylate, 1-lactate, lactate, lactobionate, laurate, laurylsulfonate, lithium, magnesium, malate, maleateMalonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphaterdiphosphinate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, sodium, stearate These include acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teocrine, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, and zinc (see Berge et al., 1977).

[0252] . It will be understood that prodrugs of the primary and / or secondary biologically active molecules are also within the scope of the present invention. The term "prodrug" refers to a precursor of a biologically active agent. A prodrug undergoes chemical or metabolic transformation to become a biologically active agent, such as the conversion of the prodrug psilocybin to the active metabolite psilocin.

[0253] In the case of solid compositions, it is understood that the disclosed primary and / or secondary bioactive molecules may exist in different forms. For example, the primary and / or secondary bioactive molecules may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms, and nanoparticulate forms, all of which are intended to be within the scope of the present invention. Furthermore, the primary and / or secondary bioactive molecules may include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a bioactive molecule. Polymorphs typically differ in X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, solubility, etc. Various factors such as recrystallization solvent, crystallization rate, and storage temperature may result in the predominance of single crystals.

[0254] It should be understood that the substitution of any of the disclosed primary and / or secondary bioactive molecules with their ions, free bases, salt forms, polymorphs, hydrate or solvate forms, co-crystals, or isomerically or enantiomerically enriched mixtures provides merely alternative embodiments within the scope of the invention (including formulation and dosage modifications, as necessary or desired, made in accordance with the teachings herein and ordinary skill in the art). Furthermore, compositions within the scope of the invention should be understood to be open-ended and may include additional primary and / or secondary bioactive molecules, active or inactive agents, and ingredients.

[0255] In some embodiments, the disclosed primary and / or secondary bioactive molecules, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, are manufactured and tested in accordance with Good Laboratory Practice (GLP) or Good Manufacturing Practice (GMP) requirements, and / or their equivalents, and any related practices, e.g., in Canada, when referring to the cannabis plant, the Good Manufacturing Practices (GPP) of Cannabis Regulations.

[0256] D. Therapeutic Combinations In some embodiments, the therapeutic combination includes primary and / or secondary bioactive molecules derived from fungi, plants, and / or algae.

[0257] In embodiments, therapeutic combinations comprising fungal-derived primary and / or secondary bioactive molecules and plant-derived primary and / or secondary bioactive molecules will be synergistic or will have a synergistic effect. In embodiments, therapeutic combinations comprising fungal-derived primary and / or secondary bioactive molecules and plant-derived primary and / or secondary bioactive molecules will be synergistic or will have a synergistic effect. In embodiments, therapeutic combinations comprising fungal-derived primary and / or secondary bioactive molecules and algae-derived primary and / or secondary bioactive molecules will be synergistic or will have a synergistic effect. In embodiments, therapeutic combinations comprising fungal-derived primary and / or secondary bioactive molecules and algae-derived primary and / or secondary bioactive molecules will be synergistic or will have a synergistic effect. In embodiments, therapeutic combinations comprising fungal-derived primary and / or secondary bioactive molecules, plant-derived primary and / or secondary bioactive molecules, and algae-derived primary and / or secondary bioactive molecules will be synergistic or will have a synergistic effect.

[0258] E. Synergy and Synergistic Effects In several embodiments, "synergy" can refer to a combination that is more effective than the additive effect of any two or more single primary and / or secondary bioactive molecules. Synergy, for example, allows for the effective treatment of a disease using lower amounts (doses) of each individual therapy. This can include lower doses of the first primary and / or secondary bioactive molecule or the second primary and / or secondary bioactive molecule ("apparent one-way synergy"), or lower doses of both the primary and / or secondary bioactive molecules ("two-way synergy") than would normally be required if either primary and / or secondary bioactive molecule were used alone. In effect, lower doses can reduce toxicity without reducing efficacy. Synergy can also result in improved efficacy, including improved disease avoidance or mitigation, compared to single therapies. "Synergistic effect" will also be understood to include an increase in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects) that is greater than the additive contribution of the components acting alone and / or greater than the contribution of the isolated primary and / or secondary bioactive molecules alone.

[0259] Numerous methods known to those skilled in the art exist for determining whether synergy exists for a particular effect, i.e., whether the effect of two or more components when mixed together is greater than the sum of the effects of the individual components applied alone, thereby resulting in "1 + 1 > 2." Suitable methods include isobologram (or contour) analysis (Huang et al., 2019) or the Loewe additivity equation (Loewe & Muischnek, 1926). Synergy can also be calculated using methods such as the sigmoid-Emax equation (Holford & Scheiner, 1981) or the median effect equation (Chou & Talalay, 1984). The graphs corresponding to the above equations are the concentration-effect curve and the combination index curve, respectively. Each of the above equations can be applied to experimental data to generate corresponding graphs that can be used to evaluate the effect of drug combinations.

[0260] In some embodiments, the combination comprises a primary and / or secondary bioactive molecule derived from a psilocybin-producing fungus and a primary and / or secondary bioactive molecule derived from cannabis. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0261] In some embodiments, the combination comprises a primary and / or secondary bioactive molecule from a psilocybin-producing fungus and a primary and / or secondary bioactive molecule from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0262] In some embodiments, the combination includes a primary and / or secondary bioactive molecule from a psilocybin-producing fungus and a primary and / or secondary bioactive molecule from a Pyropia or Porphyra fungus. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0263] In some embodiments, the combination comprises a primary and / or secondary bioactive molecule derived from Cannabis and a primary and / or secondary bioactive molecule derived from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0264] In some embodiments, the combination comprises a primary and / or secondary bioactive molecule derived from Cannabis and a primary and / or secondary bioactive molecule derived from Pyropia or Porphyra, hi some embodiments, the combination will be synergistic or have a synergistic effect.

[0265] In some embodiments, a combination includes a primary and / or secondary bioactive molecule from Dipteryx with a primary and / or secondary bioactive molecule from Pyropia or Porphyra, hi some embodiments, the combination will be synergistic or have a synergistic effect.

[0266] In some embodiments, the combination includes a primary and / or secondary bioactive molecule from a psilocybin-producing fungus, a primary and / or secondary bioactive molecule from Cannabis, and a primary and / or secondary bioactive molecule from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0267] In some embodiments, the combination includes a primary and / or secondary bioactive molecule from a psilocybin-producing fungus, a primary and / or secondary bioactive molecule from Cannabis, and a primary and / or secondary bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination is synergistic or will have a synergistic effect.

[0268] In some embodiments, the combination includes a primary and / or secondary bioactive molecule from a psilocybin-producing fungus, a primary and / or secondary bioactive molecule from Dipteryx, and a primary and / or secondary bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination is synergistic or will have a synergistic effect.

[0269] In some embodiments, the combination includes a primary and / or secondary bioactive molecule from Cannabis, a primary and / or secondary bioactive molecule from Pyropia or Porphyra, and a primary and / or secondary bioactive molecule from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0270] In some embodiments, the combination includes a primary and / or secondary bioactive molecule from a psilocybin-producing fungus, a primary and / or secondary bioactive molecule from Cannabis, a primary and / or secondary bioactive molecule from Dipteryx, and a primary and / or secondary bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0271] In some embodiments, the disclosed therapeutic combinations are botanical formulations containing minimal or low doses of whole extracts of C. sativa plants, P. cubensis fungi, P. yezoensis algae, and D. odorata beans compared to doses that would otherwise be understood or predicted in the art, and the synergistic effect is the ability of these given dosages to provide efficacy. Because the disclosed combinations, compositions, and methods synergistically enable the effective use of surprisingly low doses of one or more bioactive molecules, in some embodiments, these low doses avoid receptor depletion, avoid activation of autoregulatory compensatory measures, or avoid induced compensatory neurological responses.

[0272] F. Additional Activators Therapeutic combinations can also be used with additional active agents that, for example, contribute or provide an additive therapeutic effect or that can contribute or provide a synergistic effect.

[0273] In embodiments, the additional active agent is a drug useful in the treatment of Parkinson's disease, such as carbidopa-levodopa, carbidopa-levodopa (controlled release), carbidopa-levodopa (orally disintegrating tablet), carbidopa-levodopa (extended release capsule), carbidopa-levodopa (oral suspension), carbidopa-levodopa-entacapone (enteral suspension), levodopa, levodopa (inhalation powder), total plant extract versions of levodopa, e.g., from Mucuna pruriens or broad bean, entacapone, tolcapone, opicapone, pramipex In some embodiments, the additional active agent may be administered in a separate dosage form or in a single dosage form comprising the first and / or second bioactive molecule according to the present invention in combination with the additional active agent.

[0274] In some embodiments, the additional active agent is a serotonergic agent. In some embodiments, "serotonergic agent" refers to any compound that binds to, blocks, or otherwise affects the activity of a serotonin receptor, including any serotonin receptor subtype (e.g., via an allosteric response). In some embodiments, a serotonergic agent binds to a serotonin receptor. In some embodiments, a serotonergic agent indirectly affects a serotonin receptor, e.g., via an interaction that affects the responsiveness of other molecules at the serotonin receptor. In some embodiments, a serotonergic agent is an agonist, e.g., a compound that activates a serotonin receptor. In some embodiments, a serotonergic agent is an antagonist, e.g., a compound that binds to but does not activate a serotonin receptor, e.g., blocks the receptor. In some embodiments, a serotonergic agent is an effector molecule, e.g., a compound that binds to an enzyme for allosteric modulation. In some embodiments, serotonergic agents act (directly or indirectly) on several types of receptors, including receptors other than serotonergic receptors or other monoaminergic receptors. In some embodiments, serotonergic agents block the serotonin transporter (SERT), resulting in increased synaptic concentrations of serotonin and increased neurotransmission. In some embodiments, serotonergic agents are serotonin uptake or reuptake inhibitors. In some embodiments, serotonergic agents act as reuptake modulators, inhibiting plasma membrane transporter-mediated reuptake of serotonin from synapses to presynaptic neurons, resulting in increased extracellular concentrations of serotonin and increased neurotransmission. In some embodiments, serotonergic agents inhibit the activity of one or both monoamine oxidases, resulting in increased concentrations of serotonin and increased neurotransmission. In embodiments, the serotonergic agent is an antidepressant or anxiolytic, such as an SSRI, a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), or an atypical antidepressant. In other embodiments, the serotonergic agent is selected from the group consisting of: (1) serotonin transport inhibitors; (2) serotonin receptor modulators; (3) serotonin reuptake inhibitors; (4) serotonin and norepinephrine reuptake inhibitors; (5) serotonin dopamine antagonists; (6) monoamine reuptake inhibitors; (7) pyridazinone aldose reductase inhibitors; (8) serotonin receptor stimulants; (9) serotonin synthesis stimulants; (10) serotonin receptor agonists; (11) serotonin receptor antagonists; and (12) serotonin metabolites.

[0275] In embodiments, the additional active agent may be one or more of phenolic compounds, terpenes, polysaccharides, polyphenols, lipids, organic acids, polyunsaturated fatty acids (PUFAs), and tocopherols extracted from fungi, algae, or plants. In embodiments, the additional active agent may be extracted from any of the genera including Cheirolophus, Rhaponticoides, Volutaria, Zingiber, Rosmarinus, Salvia, Thymus, Origanum, Ocimum, Melissa, Mentha, Origanum, Satureja, Hyssopus, Taurus, Bacopa, Bupleurum, Camellia, Berberis, and Lathyrus. In embodiments, the additional active agent is derived from the Zingiber genus, e.g., Zingiber officinale. In embodiments, the additional active agent is derived from the rhizome of Zingiber officinale. In embodiments, the additional active agent is derived from the Taurus genus, e.g., Taurus nobilis. In embodiments, the additional active agent is derived from Taurus nobilis leaves. In embodiments, the disclosed compositions include an additional active agent derived from Zingiber, such as from the rhizome of Zingiber officinale, and an additional active agent derived from Taurus, such as from Taurus nobilis leaves.

[0276] In embodiments, the additional active agent may be any one or more of amino acids, antioxidants, anti-inflammatory agents, analgesics, anti-neuropathic and anti-nociceptive agents, anti-migraine agents, anti-anxiety agents, anti-depressants, anti-schizophrenia drugs, anti-PTSD agents, cannabinoids, NMDA antagonists, dissociative agents, immunostimulants, anti-cancer agents, antiemetics, appetite stimulants, anti-ulcer agents, antihistamines, anti-hypertensive agents, anti-convulsants, anti-epileptic agents, bronchodilators, neuroprotective agents, nootropics, hallucinogens, entactogens and empathogens, psychedelics, monoamine oxidase inhibitors (including RIMAs), tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins. These agents may be in ionic, free base, or salt form, and may be isomers, prodrugs, derivatives (preferably physiologically functional derivatives), or analogs.

[0277] G. Pharmaceutical Compositions In some aspects, pharmaceutical compositions comprising the therapeutic combination are disclosed. A "pharmaceutical composition" (and, unless the context indicates otherwise, includes the shorthand "composition") comprises a quantity of the therapeutic combination (e.g., in unit dosage form) together with a pharmaceutically acceptable carrier, diluent, or excipient. It will be understood that some embodiments include not a single carrier, diluent, or excipient alone, but multiple carriers, diluents, and / or excipients.

[0278] In some embodiments, the disclosed combinations or compositions include non-naturally occurring carriers, diluents, or excipients, examples of which will be known to those of skill in the art. In some embodiments, "non-naturally occurring" refers to a carrier, diluent, or excipient used in the disclosed combinations or compositions that does not naturally occur in the fungi, plants, and / or algae, or in the same fungi, plants, and / or algae from which the extracts and / or bioactive molecules of the combination or composition are or may be derived.

[0279] Compositions can be prepared by standard pharmaceutical formulation techniques such as those disclosed in Remington: Science and Practice of Pharmacy, 2005; The Merck Index, 1996; Pharm. Principles of Solid Dosage Forms 1993; Ansel and Stoklosa, 2001; and Poznansky et al., 1980. "Pharmaceutically acceptable," as used in reference to an agent, means that the agent is generally safe and, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and other animals without undue toxicity, irritation, allergic response, or complications, and is commensurate with a reasonable risk / benefit ratio.

[0280] The compositions comprising the therapeutic combination can be formulated into any suitable dosage form, such as aqueous oral dispersions, aqueous oral suspensions, solid dosage forms including oral solid dosage forms, aerosols, controlled release dosage forms, fast melt dosage forms, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, patches, inhalants, nebulizers, pulsatile release formulations, multiparticulate formulations, immediate release formulations, controlled release formulations, sustained release formulations, extended release formulations, and modified release formulations, as well as mixed immediate release and controlled release formulations.

[0281] In several embodiments, the pharmaceutical composition is formulated in a unit dosage form. A "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for a patient to be treated, containing a predetermined amount of a biologically active molecule calculated to produce a desired therapeutic effect, together with a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are often used for ease of administration and uniformity of dosage. A unit dosage form can contain a single or individual dose or unit, sub-dose, or an appropriate fraction thereof (e.g., one-half of a "total amount") of the pharmaceutical composition to be administered. Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampoules, and vials, which may contain a freeze-dried or lyophilized composition; for example, a sterile liquid carrier may be added prior to administration or in vivo delivery. Unit dosage forms include ampoules and vials into which a liquid composition is disposed. Unit dosage forms include compounds for transdermal administration, such as "patches" that are in contact with the patient's epidermis for prolonged or brief periods.

[0282] In embodiments, the pharmaceutical compositions are formulated into pharmaceutically acceptable oral dosage forms, including oral solid dosage forms and oral liquid dosage forms.

[0283] In some embodiments, the compositions are formulated as pharmaceutically acceptable oral solid dosage forms, including lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, capsules, pills, and / or any combination thereof. The oral solid dosage forms may be formulated as immediate release, controlled release, extended release, sustained release, or modified release. In some embodiments, the solid dosage forms may include pharmaceutically acceptable excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersants, suspending agents, disintegrants, thickeners, film-forming agents, granulation aids, flavoring agents, sweeteners, coating agents, solubilizers, and combinations thereof. In some embodiments, the solid dosage form may contain pharmaceutically acceptable additives, such as compatible carriers, complexing agents, ionic dispersion modifiers, disintegrants, surfactants, lubricants, colorants, wetting agents, plasticizers, stabilizers, humectants, and antifoaming agents, alone or in combination, and may further contain auxiliary active agents, including preservatives, antioxidants, and probiotics, such as antibacterial agents, including biocides, antiviral agents, and antifungal agents. Preservatives can be used to inhibit microbial growth or enhance the stability of active ingredients to extend the shelf life of pharmaceutical compositions, and include EDTA, EGTA, benzalkonium chloride, and benzoates, such as benzoic acid or sodium benzoate. Antioxidants include compounds such as vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and alpha-lipoic acid (ALA).

[0284] In some embodiments, the compositions are formulated as pharmaceutically acceptable oral liquid dosage forms. Non-limiting examples of oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions. In some embodiments, oral liquid dosage forms can be formulated using any pharmaceutically acceptable excipient known to those skilled in the art for preparing liquid dosage forms, as well as solvents, diluents, carriers, excipients, and the like, selected appropriately depending on the solubility and other properties of the primary and / or secondary bioactive molecules and other components disclosed herein. Non-limiting examples of solvents include, for example, water, glycerin, simple syrup, alcohol, medium-chain triglycerides (MCTs), and combinations thereof.

[0285] In some embodiments, oral liquid dosage forms may be monophasic or biphasic, the former being a substantially homogeneous solution dissolved in water or a non-aqueous solvent, and the latter referring to an oral liquid dosage form in which the bioactive molecule is not completely dissolved in the common solvent. In some embodiments, solid particles (i.e., bioactive molecules) within the oral liquid dosage form may form a sediment at the bottom of the container over time, requiring vigorous shaking to redisperse the bioactive molecules. Non-limiting examples of monophasic liquid dosage forms include syrups, lycates, spirits / essences, elixirs, and fluid extracts. Non-limiting examples of biphasic liquid forms include oral suspensions, oral emulsions, and mixtures.

[0286] Liquid dosage forms for oral administration can be prepared as liquid suspensions or solutions using sterile liquids, such as, but not limited to, oils, water, alcohol, pharmaceutically suitable surfactants, suspending agents, and emulsifying agents. In some embodiments, liquid formulations can also be prepared as single-dose or multi-dose beverages. In some embodiments, the suspension can contain oil. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. Suitable oils also include carrier oils such as MCT and long-chain triglyceride (LCT) oil. In some embodiments, the suspension can contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. In some embodiments, the suspension can contain alcohols, such as ethanol, isopropyl alcohol, and hexadecyl alcohol; glycerol, and propylene glycol. In some embodiments, ethers, such as polyethylene glycol; petroleum hydrocarbons, such as mineral oil and petrolatum; and water can also be used in suspension formulations. In embodiments, suspensions may therefore comprise an aqueous liquid or a non-aqueous liquid, an oil-in-water liquid emulsion, or a water-in-oil emulsion.

[0287] In addition to the primary and / or secondary bioactive molecules, the liquid dosage form may contain additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) preservatives, (e) thickeners, (f) sweeteners, and / or (g) flavoring agents. In addition to the above additives, in embodiments, the liquid formulations of the present invention may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, emulsifiers, flavoring agents, and / or sweeteners. In embodiments, cosolvents and adjuvants may also be added to the formulation.

[0288] In embodiments of modified release formulations, the plasma half-life compared to the plasma half-life of an immediate release formulation is at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 50%, at least 75%, at least 100%, or any value therebetween. In embodiments of modified release formulations, the formulations are designed to provide equivalent area under the curve (AUCO-24) and similar safety and efficacy profiles, but with a lag time to peak concentration (tmax) of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 50%, at least 75%, at least 100%, or any value therebetween. In embodiments, the formulations are designed to result in a product having a specific time course based on an optimal therapeutic window, for example, less than about 30 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, and more than 4 hours (including periods in between).

[0289] In embodiments, a formulation is selected based on its absorption surface area. In embodiments, a tincture, such as those described in the formulation examples below, may be selected based on its pre-digestive absorption by epithelial tissue.

[0290] In some embodiments, multiple formulations are combined, and thus the therapeutic combination comprises two or more pharmaceutical compositions together, which may be provided as a single pharmaceutical kit. In some embodiments, one or more portions of the therapeutic combination are provided as an inhalable formulation, such as for a soft mist inhaler, and the remaining portions of the combination are provided as a tincture. In some embodiments, one or more portions of the therapeutic combination are provided as an inhalable formulation, and the remaining portions of the combination are provided as orally dissolving strips. In some embodiments, one or more portions of the therapeutic combination are provided as a tincture, and the remaining portions of the combination are provided as orally dissolving strips. In some embodiments, one or more portions of the therapeutic combination are provided as an inhalable formulation, and the remaining portions of the combination are provided as an oral spray, such as an oromucosal spray. In some embodiments, one or more portions of the therapeutic combination are provided as a tincture, and the remaining portions of the combination are provided as an oral spray. In some embodiments, two or more separate formulations are combined, and thus the therapeutic combination comprises two or more pharmaceutical compositions together, which may be provided as a single pharmaceutical kit. In some embodiments, three or more, four or more, five or more, or six or more separate formulations are combined, and thus the therapeutic combination comprises two or more, three or more, four or more, five or more, or six or more pharmaceutical compositions together, which may be provided as a single pharmaceutical kit.

[0291] In some embodiments, the pharmaceutical composition is formulated as an inhalation formulation. Non-limiting examples of inhalation formulations include soft mist inhalation formulations, dry powder aerosol formulations, and vaporization formulations. In some embodiments, the inhalation formulation is a soft mist inhalation formulation ("soft mist" formulation). Soft mist formulations can be produced by combining a liquid containing the biologically active molecule in a cartridge or syringe. The cartridge or syringe is then placed in a soft mist inhalation device, such as those described in International Publication No. 2020 / 167893 and U.S. Patent No. 9,108,011. One may also choose to include a solubilizer (e.g., polysorbate 80, also known as TWEEN®-80) to aid in homogenization of the formulation. In some embodiments, the liquid containing the biologically active molecule may be a liquid extract obtained via the methods disclosed herein, with or without a solubilizer. In some embodiments, the inhalation formulation may be a dry powder aerosol formulation, in which the biologically active molecule is obtained as a powder and aerosolized by an inhaler device, such as a metered-dose inhaler (MDI).

[0292] In some embodiments, the inhalation formulation is a vaporizable formulation. The vaporizable formulation may be vape juice, e-liquid, e-juice, or the like. In some embodiments, the vaporizable formulation may be liquid (e.g., including oils) and / or solid (e.g., including wax or dry powder). In some embodiments, the vaporizable formulation may be produced by combining bioactive molecules in a suitable liquid, referred to as a "base liquid," and the resulting formulation can be vaporized by an internal heating element (such as those found in vape pens, e-cigarettes, e-pipes, and other such electronic smoking devices). Examples of suitable liquids include propylene glycol (PG), vegetable glycerin (VG), and polyethylene glycol (PEG). In some embodiments, the base liquid may also include a low-viscosity liquid that acts as a diluent, including water and / or ethanol (which may be an alcoholic beverage or distilled spirit, including vodka). In some embodiments, the vaporizable formulation may further include a flavoring, which may be any flavor concentrate known to those skilled in the art.

[0293] In embodiments, the pharmaceutical composition is formulated as an effervescent powder.

[0294] In some embodiments, the pharmaceutical composition is formulated into a pharmaceutically acceptable transdermal application that can be administered transdermally. Non-limiting examples of transdermal formulations include ointments, creams, suspensions, lotions, pastes, gels, sprays, foams, oils, and the like, and any combination thereof.

[0295] In embodiments, the pharmaceutical compositions are formulated for subcutaneous, intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, or intracerebroventricular injection ("injectable formulations"). In embodiments, the injectable formulations may be prepared by dissolving, suspending, or emulsifying the first and / or second bioactive molecules in an aqueous or non-aqueous solvent, non-limiting examples of which include oils such as vegetable oils, synthetic aliphatic acid glycerides, and esters of higher aliphatic acids or propylene glycol; and may also include additives such as solubilizers, stabilizers, and suspending agents, preservatives, wetting agents, emulsifiers, dispersing agents, and isotonic agents.

[0296] In some embodiments, compositions are formulated for specific tissues or for specific routes of administration other than oral gastrointestinal administration, e.g., mucosal (e.g., sublingual, buccal, rectal, nasal), intramuscular, subcutaneous, dermal, intranasal, inhalation, etc. Such administration may result in reduced side effects, reduced toxicity, increased efficacy, improved selectivity, increased bioavailability, and minimized drug-drug interactions.

[0297] Injectable formulations may contain additives such as preservatives, wetting agents, emulsifiers, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, and sorbic acid, and isotonicity agents, such as sugars and sodium chloride, may also be included. Prolonged drug absorption from injectable dosage forms can be achieved by the use of absorption delaying agents, such as aluminum monostearate and gelatin. Injectable formulations designed for sustained release via SC or IM injection can avoid first-pass metabolism and require lower doses of the primary and / or secondary bioactive molecules to maintain desired plasma levels. In such formulations, the particle size and particle size range of the primary and / or secondary bioactive molecules can be used to control the release of the primary and / or secondary bioactive molecules by controlling their dissolution rate in fat or muscle.

[0298] In embodiments, the composition is formulated into a pharmaceutically acceptable nanostructured formulation, such as a nanoemulsion, nanocapsule, nanoparticle conjugate, or nanoencapsulated oral, sublingual, buccal, or nasal spray. In embodiments, the nanostructured formulation is prepared with reference to the general knowledge in the art (see, e.g., Jaiswal 2015).

[0299] In some preferred embodiments, when a therapeutic combination, pharmaceutical composition, or other formulation includes a natural compound or a compound found in nature, at least one of the carriers, diluents, and / or excipients used in the combination, composition, or formulation is non-natural or non-naturally occurring, or other agents, such as additional active agents, in the disclosed combination, composition, or formulation are non-natural or non-naturally occurring, i.e., a natural compound is combined with a non-natural component such that the combination, composition, or formulation includes at least one non-natural component.

[0300] By way of non-limiting, merely suggestive example, the following formulations can be prepared and used in the methods of the present invention.

[0301] In all exemplary formulation embodiments disclosed below, the formulation may comprise solely fungal-derived bioactive molecules and solely plant-derived bioactive molecules ("may comprise solely" means not comprising additional disclosed bioactive molecules, but the formulation may further comprise one or more carriers, diluents, or excipients, other inactive ingredients, and / or, in some embodiments, additional active agents disclosed herein). In several embodiments, the formulation may comprise solely fungal-derived bioactive molecules and solely plant-derived bioactive molecules (i.e., when the molecules are extracted, isolated, derived, or otherwise obtained from a single genus, and not necessarily only found in one genus). In several embodiments, the formulation may comprise solely fungal-derived bioactive molecules and solely plant-derived bioactive molecules (i.e., when the molecules are extracted, isolated, derived, or otherwise obtained from a single species, and not necessarily only found in a single species). In several embodiments, the formulation may comprise solely one fungal-derived bioactive molecule and one plant-derived bioactive molecule.

[0302] In some embodiments, a formulation may contain a bioactive molecule derived from a psilocybin-producing species and a bioactive molecule derived from a cannabis plant, independently. In several embodiments, a formulation may contain a bioactive molecule derived from a species such as Psilocybe azurescens, Psilocybe bohemica, Psilocybe semilanceata, Psilocybe baeocystis, Psilocybe cyanescens, Psilocybe tampanensis, Psilocybe cubensis, Psilocybe weilii, Psilocybe hoogshagenii, Psilocybe stantii, Psilocybe cyanofibrillosa, or Psilocybe liniformans, independently, and a bioactive molecule derived from a cannabis plant. In several embodiments, a formulation may contain one bioactive molecule derived from a psilocybin-producing species and one bioactive molecule derived from a cannabis plant, independently. In some embodiments, the formulation may comprise one bioactive molecule derived from the species Psilocybe azurescens, Psilocybe bohemica, Psilocybe semilanceata, Psilocybe baeocystis, Psilocybe cyanescens, Psilocybe tampanensis, Psilocybe cubensis, Psilocybe weilii, Psilocybe hoogshagenii, Psilocybe stantii, Psilocybe cyanofibrillosa, or Psilocybe liniformans, and a cannabis plant, alone. In some embodiments, the formulation may comprise one bioactive molecule derived from a Psilocybe fungus and one bioactive molecule derived from a cannabis plant, alone. "Psilocybe fungus" refers to the Psilocybe species fungus. In some embodiments, the formulation may comprise one bioactive molecule derived from a Psilocybe fungus and one bioactive molecule derived from a cannabis plant, alone.

[0303] For example, the following embodiments may optionally use psilocybin (or psilocin) alone or both; CBD (or THC) alone or both; and coumarin, whole Pyropia extract, ethanol, and ginger (and any other disclosed active or inactive ingredients), i.e., some embodiments may not include any one or more of coumarin, whole Pyropia extract, and ethanol, and flavorings and / or colorings such as ginger (and any other disclosed active or inactive ingredients). Thus, in some embodiments, exemplary formulations include psilocybin and CBD alone. In some embodiments, exemplary formulations include psilocin and CBD alone. In some embodiments, exemplary formulations include psilocybin, psilocin, and CBD alone. In some embodiments, exemplary formulations include psilocybin, THC, and CBD alone. In some embodiments, exemplary formulations include psilocin, THC, and CBD alone. In embodiments, exemplary formulations comprise psilocybin, psilocin, and THC alone. In embodiments, exemplary formulations comprise psilocybin and THC alone. In embodiments, exemplary formulations comprise psilocybin and THC alone. As noted above, "comprising solely" means not comprising additional disclosed bioactive molecules, although the formulation may further comprise one or more carriers, diluents, or excipients disclosed herein, other inactive ingredients, and / or, in some embodiments, additional active agents, or active agents suitable for other formulations, such as those known in the art.

[0304] In some embodiments, any one or more of psilocybin, psilocin, THC, and CBD can be substituted with another bioactive molecule, for example, another bioactive molecule from the same fungus or plant. In some embodiments, flavorings and / or colors (equivalent but abbreviated as "flavorings / colorings") are optional. Thus, any of the following examples that do not include flavorings / colorings are additional embodiments. In some preferred embodiments, the exemplary "flavorings / colorings" are ethanol and ginger. In some embodiments, the formulations include additional active agents. In the absence of active and / or inactive ingredients from the disclosed exemplary formulations, the formulations are prepared as described, with modifications understood by those of ordinary skill in the art, using common skill and knowledge in the art. Where ingredients can be provided as solids or liquids, those skilled in the art will understand how to convert between mass amounts and volume amounts, including alternative or variable concentrations of ingredients, whether solid or liquid.

[0305] Example 1: Tincture Prepare a tincture in the following proportions: [Table 2]

[0306] The solution is prepared by mixing bioactive molecules derived from fungi, plants, and algae, and / or extracts containing them ("bioactive molecules and / or extracts containing them") with flavoring agents and a solvent. In embodiments, amounts or proportions of ingredients, such as when expressed by weight or percentage, include the term "about." In some embodiments, "about" a weight or proportion refers to a range of ±2%, including when the term "about" is implied by context. Thus, for example, in embodiments where psilocybin extract is 45% of the formulation, the amount in the embodiment refers to "about" 45% psilocybin extract; in some such embodiments, an amount of "about" 45% will be understood to refer to an amount of 45% ±2%, i.e., between 43% and 47% psilocybin extract. In some other embodiments, an amount expressed by weight or percentage also refers to "about" that amount, with "about" having the meaning described elsewhere.

[0307] In some embodiments, the fungal extract comprises about 45% of each dose and contains about 400 μg of combined psilocybin and psilocin per dose; the cannabis extract comprises about 15% of each dose and contains about 1 mg of CBD and about 1 mg of THC per dose; the coumarin extract comprises about 2% of each dose and contains about 1 mg of coumarin per dose; the algae extract (in embodiments, Pyropia extract) comprises about 15% of each dose; the flavoring and / or coloring (in some preferred embodiments, an ethanol infusion of ginger and bay leaves, or in some embodiments, another flavoring and / or coloring that may be in ethanol, water, or another diluent) comprises about 15% of each dose; and the added water comprises about 8% of each dose. In some embodiments, the tinctures or other liquid formulations herein further comprise a solubilizing agent, such as cyclodextrin, lecithin, propylene glycol, xanthan gum, or a combination thereof.

[0308] Tinctures can be prepared by exposing fungi, plants and / or algae to solvents capable of extracting the desired primary and / or secondary bioactive molecules, combining the extracts, and then optionally adding flavors and / or colors.

[0309] In some embodiments, the solvent is alcohol. In embodiments, the alcohol may be, for example, 40% to 60% alcohol, or 80% to 90% alcohol, and then diluted to 40% to 60% alcohol. In some embodiments, the solvent is water. In some embodiments, the solvent may be an acid, such as acetic acid.

[0310] As an example, food coloring may be added to a tincture to give the solution a certain appearance, and may contain additional compounds sufficient to improve the taste of the tincture. In embodiments, the food coloring may include compounds that improve the biological activity of the primary and / or secondary bioactive molecules. Examples of food colorings suitable for use with the disclosed extracts, compositions, and tinctures include turmeric extract, cinnamon extract, beetroot extract, carrot extract, caramel, blueberry extract, blackberry extract, and ginger extract.

[0311] In some embodiments, the patient is administered one dose of a tincture having the amounts of ingredients as prescribed above, two doses of a tincture in the amounts as prescribed above, three such doses, four such doses, five such doses, or more than five such doses daily. In some preferred embodiments, the daily dose is four.

[0312] Example 2: Oral spray and oral mucosal spray formulations An oral spray can be prepared containing the same ingredients, amounts (units) of ingredients, and overall proportions as in Example 1. When the oral spray is formulated for oral mucosal (e.g., sublingual or buccal) administration, it may further contain a penetration enhancer and / or a mucoadhesive polymer.

[0313] Example 3: Soft mist inhalation formulation A soft mist inhalation formulation is prepared as follows: The soft mist inhalation formulation contains the same ingredients, amounts (units) of ingredients, and overall proportions as in Example 1 above: a solution is prepared by combining bioactive molecules from fungi, plants, and algae, and / or extracts containing same, with flavors / colors and a solvent.

[0314] The bioactive molecules and / or the extracts containing them are mixed and combined.Then, the combined bioactive molecules and / or the extracts containing them can be combined with ethanol and / or water, and optionally added preservatives, such as benzalkonium chloride, to a volume of, for example, 15 mL.Can refer to Anderson, 2006, and Dalby, Eicher, and Zierenberg, 2011, all of which are incorporated herein by reference in their entirety.

[0315] Example 4: Vapor Formulation A vaporization formulation containing 500 μg of psilocybin, 300 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 16 mg of whole P. thaliana extract, 16 mg of flavors / colors, and 10 mL of a 50:50 base liquid (50% PG, 50% VG) is prepared as follows: the bioactive molecules and / or extracts containing them are mixed and combined (in solid form and / or as part of one or more liquid extracts) with a 50:50 base liquid prepared for use in any liquid vaporization device or apparatus, such as an e-liquid vaporizer, e-cigarette, mod, or vape pen. Optionally, flavors / colors (including, for example, ginger and / or bay) may be added. This formulation can also be prepared for any oil, thin oil, e-juice, or e-liquid vaporizer, according to those skilled in the art.

[0316] Example 5: Tablet and Divisible Multi-Act Tablet Formulations The tablets, containing 500 μg of psilocybin, 300 μg of psilocin, 1 mg of CBD, 1 mg of THC, 1 mg of coumarin, 16 mg of whole psilocybin extract, 170 mg of microcrystalline cellulose, 10 mg of colloidal silicon dioxide, and 7.5 mg of stearic acid, are prepared by blending the bioactive molecules and / or extracts containing them with other ingredients and compressing them to form tablets.

[0317] Divisible, multi-action tablets containing 1000 μg of psilocybin, 600 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 32 mg of whole Psilocybean extract, 35 mg of microcrystalline cellulose, 45 mg of starch, 4.5 mg of sodium carboxymethyl starch, 0.5 mg of magnesium stearate, 1 mg of talc, and 4 mg of polyvinylpyrrolidone (PVP) (as a 10% solution in water) are prepared as follows: The bioactive molecules and / or extracts containing them, starch, and cellulose are passed through a 20-mesh US sieve and thoroughly mixed. The PVP solution is mixed with the resulting powder, which is then passed through a 16-mesh US sieve. The resulting granules are dried at 50-60°C and passed through a 16-mesh US sieve. Sodium carboxymethyl starch, magnesium stearate, and talc are passed through a 30-mesh US sieve and added to the granules. After mixing, the granules are compressed on a tablet machine to give tablets. The tablets are scored to allow equal dosing of half the dose.

[0318] Example 6: Capsule formulation Capsules containing 500 μg of psilocybin, 300 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 16 mg of whole Pyropia extract, 119 mg of cellulose and / or starch, and 1 mg of magnesium stearate are prepared by blending these and other bioactive molecules and / or extracts with the cellulose and / or starch and magnesium stearate, passing the mixture through a No. 20 mesh U.S. sieve, and filling it into hard or soft gelatin capsules.

[0319] Example 7: Alternative capsule formulations optionally containing additional active agents Capsules containing 1000 μg of psilocybin, 600 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 16 mg of whole Pyropia extract, 100 mg of cellulose and / or starch, and 1 mg of magnesium stearate are prepared as follows: the bioactive molecules and / or extracts containing them, the cellulose and / or starch, and the magnesium stearate are blended, passed through a 20-mesh US sieve, and filled into hard or soft gelatin capsules. Optionally, additional active agents may be added during blending. In some embodiments, the additional active agent is a serotonergic agent, such as an antidepressant or an anxiolytic. In some embodiments, the additional active agent is an anti-Parkinson's drug, e.g., levodopa, amantadine, a dopaminergic anti-Parkinson's drug (e.g., a dopamine agonist), an anticholinergic anti-Parkinson's drug, or another anti-Parkinson's drug, e.g., an adenosine A2A antagonist, a COMT inhibitor, an MAO-B inhibitor, or another such anti-Parkinson's drug described herein or generally known in the art.

[0320] Example 8: Suspension formulation A suspension formulation containing 250 μg of psilocybin, 150 μg of psilocin, 1 mg of CBD, 1 mg of THC, 1 mg of coumarin, 8 mg of total psilocybin extract, and 25–50 mg of levodopa is prepared as follows: The bioactive molecules and / or their constituent extracts are mixed with 1.75 g of sucrose and 4 mg of xanthan gum, passed through a 10-mesh US sieve, and mixed with a solution of 50 mg of sodium carboxymethylcellulose (11%) and 50 mg of microcrystalline cellulose (89%) in water. 10 mg of sodium benzoate and flavoring / coloring (see section) are diluted with a portion of water and added with stirring. Levodopa may be added at 5–10 mg / mL. Then, add enough water to make 5 mL.

[0321] Example 9: Intravenous Solution Formulation An intravenous formulation containing 250 μg of psilocybin, 150 μg of psilocin, 1 mg of CBD, 1 mg of THC, 1 mg of coumarin, 8 mg of whole Pyropia extract, and 1000 mL of isotonic saline can be prepared as follows: the bioactive molecules and / or extracts containing them are dissolved in a suitable solvent, such as isotonic saline or another suitable solvent; additional active or inactive ingredients, such as solubilizers and preservatives, can be added as described above and within the scope of common knowledge in the art. It will be understood that the amount of each bioactive molecule and / or extract can be adjusted accordingly to achieve the desired mg / mL.

[0322] Example 10: Injection formulation An injectable formulation containing 250 μg of psilocybin, 150 μg of psilocin, 1 mg of CBD, 1 mg of THC, 1 mg of coumarin, 8 mg of whole P. thaliana extract, and 5 mL of isotonic saline can be prepared as follows: the bioactive molecules and / or extracts containing them are dissolved in an appropriate solvent, such as isotonic saline or other suitable solvent; additional active or inactive ingredients, such as preservatives, can be added as described above and within the knowledge of the art. It will be understood that the amount of each bioactive molecule and / or extract can be adjusted accordingly to achieve the desired mg / mL.

[0323] Example 11: Topical formulation for transdermal administration A topical formulation containing 400 μg of psilocybin, 250 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 8 mg of whole P. psilocybin extract, 30 mg of emulsifying wax, and 20 mg of liquid paraffin in a total amount equal to 100 g of white soft paraffin can be prepared as follows: Heat the white soft paraffin until melted. Add the liquid paraffin and emulsifying wax and stir until dissolved. Add the bioactive molecules and / or extracts containing them and continue stirring until dispersed. Then, cool the mixture until solid.

[0324] Example 12: Cut Matrix Sublingual or Buccal Tablet Formulation Sublingual or buccal tablets containing 500 μg of psilocybin, 300 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 8 mg of whole Psilocybean extract, 210.5 mg of glycerol, 143 mg of water, 4.5 mg of sodium citrate, 26.5 mg of polyvinyl alcohol, and 15.5 mg of polyvinylpyrrolidone (PVP) are prepared as follows: glycerol, water, sodium citrate, polyvinyl alcohol, and PVP are mixed by continuous stirring while maintaining a temperature of approximately 90°C. Once the polymers are in solution, the solution is cooled to approximately 50-55°C, and the bioactive molecules and / or extracts containing them are slowly mixed in. The homogenous mixture is poured into a mold made of inert material to create a drug-containing diffusion matrix approximately 2-4 mm thick. The diffusion matrix is ​​then cut to form individual tablets of appropriate size.

[0325] Example 13: Individually Formed Sublingual or Buccal Lozenge Formulations Sublingual or buccal lozenges containing 500 μg of psilocybin, 300 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 8 mg of whole Psilocybean extract, 350 mg of silica gel powder, 400 mg of citric acid powder, 600 mg of acacia powder, 1 g of polyethylene glycol (PEG), and optionally 100 mg of flavoring / coloring are prepared as follows: The silica gel powder, citric acid powder, acacia powder, optional flavoring / coloring, and PEG are mixed with continuous stirring at a temperature of approximately 90°C. Once the PEG has melted and the other ingredients have gone into solution, the solution is cooled to approximately 50-55°C and the bioactive molecules and / or extracts containing them are slowly mixed in. The homogeneous mixture is poured into separate molds and allowed to cool. See also U.S. Patent No. 10,034,832 and its Examples.

[0326] Example 14: Intranasal Delivery Formulations A nasal spray formulation for intranasal delivery containing 250 μg of psilocybin, 150 μg of psilocin, 1 mg of CBD, 1 mg of THC, 1 mg of coumarin, 8 mg of whole Pyropia extract, 50 μL of DMSO, and 5 mL of MCT in saline (1% cremophor) to a total volume of 10 mL can be prepared as follows: a solution of approximately 1 mg / mL of bioactive molecules and / or extracts containing same is prepared in 49.5% MCT, 49.5% saline, 0.5% DMSO, and 0.5% cremophor for use in a nasal spray device. In other embodiments, the nasal formulation can be prepared as a dry powder for inhalation, for example, by combining the bioactive molecules and / or extracts containing same with lactose and blending for use in a dry powder inhaler, or as described in U.S. Patent Application Publication No. 2015 / 0367091 A1 and the references cited therein.

[0327] In some exemplary embodiments, the disclosed therapeutic combinations or pharmaceutical compositions comprise the primary biologically active molecules in the table below from each listed component of the combination or composition, and such combinations or compositions may be formulated according to any of the examples herein, or in many other exemplary formulations according to this disclosure and general knowledge in the art: [Table 3] JPEG2025530301000005.jpg33159

[0328] It should be noted that while certain primary and / or secondary bioactive molecules, and certain extracts containing them, are disclosed above, this should not be construed as limiting the invention or limiting the formulation of Example 1 to the primary and / or secondary bioactive molecules disclosed above. Thus, in embodiments, the formulation of Example 1 (or other examples herein) contains additional or fewer primary and / or secondary bioactive molecules than those disclosed; including any of the primary and / or secondary bioactive molecules disclosed herein for each of the fungal extract, cannabis extract, cumar extract, and algae extract.

[0329] In some alternative embodiments of this example, the formulation comprises at least one bioactive molecule derived from a fungus and at least one bioactive molecule derived from a plant, wherein the fungal bioactive molecule comprises one derived from a psilocybin-producing species, such as Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Phoriotina, and Pluteus, and the plant bioactive molecule comprises one derived from a cannabinoid-producing species, such as Cannabis. In some such alternative embodiments, the formulation further does not comprise any fungal bioactive molecules or plant bioactive molecules, other than those derived from psilocybin-containing species and cannabinoid-producing species. In some alternative embodiments, the formulation further does not contain bioactive molecules derived from fungi and plants, excluding those from the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Horiochina, and Pluteus, and those from the genus Cannabis. In some alternative embodiments, the formulation does not contain bioactive molecules derived from the genus Dipteryx. In some alternative embodiments, the formulation does not contain bioactive molecules derived from algae, seaweed, the family Bangiae, or the genera Pyropia and Porphyra. In some alternative embodiments, the only bioactive molecules are psilocybin, psilocin, CBD, and THC. In some alternative embodiments, the only bioactive molecules are psilocybin, CBD, and THC. In some alternative embodiments, the only bioactive molecules are psilocybin and CBD. In some alternative embodiments, the only bioactive molecules are psilocybin and THC. In some such alternative embodiments, the only biologically active molecules are psilocybin, CBD, and THC. In some such alternative embodiments, the only biologically active molecules are psilocin and CBD. In some such alternative embodiments, the only biologically active molecules are psilocin and THC.

[0330] It will be readily understood that the above formulation examples are exemplary only. Any of the primary and / or secondary bioactive molecules disclosed herein may be utilized in the above formulation examples, and in the dosage ranges applicable to said primary and / or secondary bioactive molecules. Reference to specific primary and / or secondary bioactive molecules is exemplary only, and it will be understood that the bioactive molecules of any example may be substituted with other primary and / or secondary bioactive molecules disclosed herein.

[0331] Furthermore, it will be readily understood that the disclosed compositions are not limited to combinations of a single primary and / or secondary bioactive molecule, or (when formulated as a pharmaceutical composition) limited to only a single carrier, diluent, and / or excipient, but may also include combinations of multiple primary and / or secondary bioactive molecules (including additional bioactive molecules), and / or multiple carriers, diluents, and excipients. Thus, the pharmaceutical compositions of the present invention may include any of the primary and / or secondary bioactive molecules disclosed above. That is, in embodiments, the disclosed compositions include fungal, plant, and algae-derived primary and / or secondary bioactive molecules, optionally in combination with one or more other bioactive molecules (or derivatives and analogs thereof), along with one or more pharmaceutically acceptable carriers, diluents, and / or excipients, and further along with one or more other active agents.

[0332] In embodiments, the disclosed compositions are formulated to augment an existing therapeutic effect, to provide an additional therapeutic effect, to increase adherence or ease of use, to increase a desired property such as stability or shelf life, to reduce an undesirable effect or property, to alter a property in a desired manner (such as pharmacokinetics or pharmacodynamics), to modulate a desired system or pathway (e.g., a neurotransmitter system), or to provide a synergistic effect.

[0333] "Therapeutic effects" that may be increased or added in embodiments of the present invention include, but are not limited to, antioxidant, anti-inflammatory, analgesic, anti-neuropathic, anti-nociceptive, anti-migraine, anti-anxiety, anti-depressant, anti-psychotic, anti-PTSD, dissociative, immunostimulatory, anti-cancer, anti-emetic, appetite stimulant, anti-ulcer, antihistamine, anti-hypertensive, anti-convulsant, anti-epileptic, bronchodilator, neuroprotective, cerebral function improving, empathogenic, psychedelic, sedative, or stimulant effects, as well as known effects that improve symptoms caused by movement disorders.

[0334] The goals of augmenting an existing therapeutic effect, providing an additional therapeutic effect, increasing adherence or ease of use, increasing a desired property such as stability or shelf life, decreasing an undesirable effect or property, altering a property in a desired manner (such as pharmacokinetics or pharmacodynamics), modulating a desired system or pathway (e.g., a neurotransmitter system), or inducing a synergistic effect are achieved in several embodiments by including an additional active agent.

[0335] The type of formulation employed for administration of the disclosed primary and / or secondary bioactive molecules employed in the disclosed methods will generally be determined by the primary and / or secondary bioactive molecules employed, the route of administration and the type of pharmacokinetic profile desired from the primary and / or secondary bioactive molecules, and the condition of the patient. It will be readily understood that any of the above embodiments and types of embodiments can be combined to form additional embodiments.

[0336] a. Route of administration The disclosed pharmaceutical compositions are suitable for administration by various routes, including, but not limited to, enteral administration, such as oral, sublingual, buccal, and rectal administration, bolus injection or continuous infusion, parenteral administration, including intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, intravaginal, intraocular, intranasal, intradermal, topical, auricular, intraocular, transdermal, and subcutaneous administration.

[0337] In embodiments, the pharmaceutical compositions are administered as oral solid and liquid dosage forms; as sublingual or buccal administration; as injections, including intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, and intracerebroventricular administration; rectally, vaginally, ocularly, nasally, dermally, topically, otically, transdermally, and subcutaneously.

[0338] In embodiments where administration is enteral, parenteral, or both, an effective amount of the first and / or second bioactive molecules is administered systemically to the subject. In embodiments, an effective amount of the first and / or second bioactive molecules is administered orally to the subject. In embodiments, an effective amount of the first and / or second bioactive molecules is administered intravenously to the subject. In embodiments, an effective amount of the first and / or second bioactive molecules is administered to the subject by inhalation. In embodiments, an effective amount of the first and / or second bioactive molecules is administered nasally to the subject. In embodiments, an effective amount of the first and / or second bioactive molecules is administered to the subject by injection. In embodiments, an effective amount of the first and / or second bioactive molecules is administered topically (transdermally) to the subject. In embodiments, an effective amount of the first and / or second bioactive molecules is administered to the subject by ophthalmic administration. In embodiments, an effective amount of the first and / or second bioactive molecules is administered rectally to the subject. In embodiments, the primary and / or secondary bioactive molecules disclosed herein and employed in the methods described herein are effectively administered to a subject via other means and are prepared in any acceptable composition known to those of skill in the art. In embodiments, such compositions can be prepared by any method known in the pharmaceutical arts that includes at least one bioactive molecule (Sheth, 1980).

[0339] In embodiments, the primary and / or secondary bioactive molecules disclosed herein are administered by multiple routes, which may vary between subjects, such as patients, according to subject preferences, comorbidities, side effect profiles, pharmacokinetic and pharmacodynamic considerations, and other factors. In embodiments, other substances are present with the primary and / or secondary bioactive molecules, such as those known to those of skill in the art, to enhance absorption via various routes (e.g., gastrointestinal, transdermal, etc.), prolong the effect of the drug, and / or achieve higher or stable serum levels, or modifications in the preparation to enhance the therapeutic effect of the primary and / or secondary bioactive molecules disclosed herein.

[0340] In embodiments, the pharmaceutical compositions are suitable as oral solid or liquid dosage forms administered sublingually, bucally, rectally, vaginally, ocularly, otically, nasally, intradermally, topically, and transdermally; or as intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intrathecal, intracerebroventricular, and subcutaneous injections, including physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0341] In embodiments, the pharmaceutical compositions may be administered via enteral or parenteral means, where enteral means include, but are not limited to, oral solid and liquid dosage forms, sublingual and buccal administration, and rectal administration; and parenteral means of administration include, but are not limited to, bolus injection or continuous infusion, intravenous, intraarterial, intraperitoneal, intraperitoneal, intramuscular, intrathecal, intraventricular, intravaginal, intraocular, intranasal, intradermal, topical, auricular, transdermal, and subcutaneous administration; as well as other equivalent means known to those skilled in the art.

[0342] Enteral administration includes administration through any part of the digestive tract. Non-limiting examples include oral (oral), including oral solid and liquid dosage forms, and rectal, which may, in some embodiments, preferably be formulated as a tincture. Parenteral administration refers to administration by any means that does not involve the digestive tract, including intravenous (into a vein), intraarterial (into an artery), intraosseous injection (into the bone marrow), intramuscular (into a muscle), intracerebral (into the brain parenchyma), intraventricular (into the ventricular system), intrathecal (injection into the spinal canal), auricular (through the ear), ocular (through the eye), vaginal (intravaginal), and subcutaneous (subcutaneous). In some embodiments, parenteral administration may include sublingual and / or buccal administration. In some embodiments, the pharmaceutical composition may be administered to a subject via injection. In embodiments, the pharmaceutical composition may be administered to a subject via the nasal system or mouth, for example, in an oral solid dosage form and / or an oral liquid dosage form; inhaled via a nasal spray or oral inhaler; sprayed from a nebulizer, such as a machine that atomizes liquid medicine; or via buccal / sublingual administration. In embodiments, the pharmaceutical composition may be administered to a subject via a combination of administration means. In embodiments, the pharmaceutical composition may be administered to a subject via enteral administration means. In embodiments, the pharmaceutical composition may be administered to a subject via parenteral administration means. In embodiments, the composition may be administered to a subject via at least one enteral administration means and at least one parenteral administration means. In embodiments, equivalent routes of administration known to those skilled in the art are utilized.

[0343] In some embodiments, the therapeutic combination may be administered via multiple routes of administration. For example, in some embodiments, the fungal portion of the disclosed combination is administered via one route of administration, and the plant and algal portions are administered via different routes of administration. In some embodiments, the plant portion of the disclosed combination is administered via one route of administration, and the fungal and algal portions are administered via different routes of administration. In some embodiments, the algal portion of the disclosed combination is administered via one route of administration, and the plant and fungal portions are administered via different routes of administration.

[0344] Administering different (fungal, plant, or algal) parts of the disclosed combinations to different tissues may maximize the therapeutic effect of the combination, reduce side effects, reduce patient discomfort, and / or increase bioavailability. In one exemplary embodiment, the disclosed combinations consist of plant parts containing a cannabinoid (e.g., THC) or cannabis extract, which are administered to the oral mucosa via a spray; while the remaining components (e.g., fungal, plant, and / or algal parts) are delivered to pulmonary epithelial cells via a soft-mist inhaler. In some embodiments, administration according to this exemplary procedure results in reduced pharyngeal irritation (e.g., in individuals sensitive to inhaled cannabis or cannabinoids), maximizes the bioavailability of the remaining components (e.g., fungal, plant, and / or algal parts), and improves the pharmacokinetic profile of the components of the therapeutic combination, e.g., by promoting uptake of longer-lasting plant parts (e.g., THC or cannabis extract) while mitigating uptake of shorter-lasting parts.

[0345] In another example, the disclosed combination includes an algae portion containing Pyropia or Pyropia extract, which is administered to the oral mucosa via an oral spray, while the remaining components (e.g., fungal, plant, and / or algal portions) are delivered to pulmonary epithelial cells via a soft mist inhaler. In some embodiments, administration according to this exemplary procedure results in reduced pharyngeal irritation, maximizes the bioavailability of the components (e.g., fungal, plant, and / or algal portions), and improves the pharmacokinetic profile of the therapeutic combination components; for example, by facilitating uptake of the shorter-acting algae portion (e.g., Pyropia or Pyropia extract) while facilitating uptake of the longer-acting portion.

[0346] B. Administration Method In some embodiments, methods for administering the primary and / or secondary bioactive molecules disclosed herein are provided. As used herein, the terms "subject," "user," "patient," and "individual" are used interchangeably and refer to any mammal, preferably a human. These terms will be understood to include anyone with an indication for which the combinations, compositions, or methods described herein may be effective, or who may otherwise benefit from the invention. In general, it will be understood that all of the combinations, compositions, and methods of the present invention will work for all individuals, although individual differences are to be expected.

[0347] The present invention provides methods of using a therapeutically effective amount of a pharmaceutical composition of the present invention comprising a first and / or second bioactive molecule disclosed herein in a mammal, preferably a human, including methods for treating movement disorders, including in healthy individuals.

[0348] Administration of a pharmaceutical composition in an "effective amount," "therapeutically effective amount," "therapeutically effective dose," or "pharmacologically effective amount" refers to an amount of the primary and / or secondary bioactive molecule sufficient to produce the desired therapeutic effect, e.g., relief to some extent of one or more symptoms of the disease or condition being treated. That result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. A "therapeutically effective amount" includes, for example, a prophylactically effective amount.

[0349] An "effective amount" of a primary and / or secondary bioactive molecule disclosed herein is an amount effective to achieve a desired pharmacological effect or meaningful therapeutic improvement. It is understood that an "effective amount" or "therapeutically effective amount" may vary from subject to subject due to variations in metabolism of compounds such as the primary and / or secondary bioactive molecules disclosed herein, variations in age, weight, and the general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. The effective amount will vary depending on the subject and the disease state or health benefit being treated, the subject's weight and age, the severity of the disease state or the extent of the health benefit being sought, the method of administration, etc., all of which can be readily determined by one of ordinary skill in the art. Additionally, pharmacogenomic information about a particular patient (such as the influence of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic agent) may influence the dosage used.

[0350] As used herein, "therapeutic effect" or "therapeutic efficacy" refers to a response in a mammal, preferably a human, following treatment that is deemed to be a desirable and beneficial treatment. Accordingly, these responses will vary depending on the disorder being treated or the improvement in physiological or psychological function desired, and on the specific components in the compositions of the present invention considered, as would be readily understood by one of ordinary skill in the art. For example, in some embodiments, "therapeutic effect" may refer to the effect caused by the disclosed compositions or their use in the methods of the present invention, such as treating movement disorders, as disclosed herein.

[0351] A "therapeutically effective dose" refers to the dose required to elicit a desired result in the patient receiving treatment. Thus, in embodiments, a therapeutically effective dose may refer to the dose of a pharmaceutical composition or therapeutic combination required to deliver a measurable, patient-specific biological effect in the treatment or prevention of a condition or disorder. A "therapeutically effective dose" may be used interchangeably with a "therapeutically effective amount" or an "effective amount."

[0352] H. Medication It will be readily understood that dosages may vary depending on whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability or susceptibility of the condition being treated, the desired clinical endpoint, previous, concurrent or subsequent treatments, the general health, age, sex, and race of the subject, bioavailability, potential adverse systemic, local or regional side effects, the presence of other disorders or diseases in the subject, and other factors that will be appreciated by one of skill in the art (e.g., medical history or family history).

[0353] In embodiments where the combination and / or composition includes a first and / or second bioactive molecule derived from a fungus, the first and / or second bioactive molecule may be present in an amount such that a single dose (whether or not such dose is present in a unit dosage form) is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose may be greater than 75 mg, including 100 mg, 150 mg, 200 mg, or more than 200 mg.

[0354] In all embodiments herein that include a dosage of less than about 1 mg, it will be understood that such dosage includes the additional specific dosages of about 0.5 mg or less, about 0.25 mg or less, about 0.1 mg or less, about 0.05 mg or less, about 0.005 mg or less, about 0.001 mg or less, and about 0.0005 mg or less.

[0355] In all embodiments herein, including doses of at least about 1 mg or more, up to about 75 mg, such doses may be further expressed in terms of the specific doses (all such milligram doses being understood to be accompanied by the modifier "about"): 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, g, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, and amounts within these ranges.

[0356] In all embodiments herein including a 75 mg dose, as well as doses greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg, such doses may be 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 150 mg, 200 mg, or greater than 200 mg. mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 119mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 133mg, 134mg, 135 mg, 136mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170 It will be understood that the above-mentioned dosage amounts include the additional specific dosage amounts of 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, and 200 mg. Such dosage amounts will be further understood to include amounts within these ranges, and in all such embodiments, a single dosage may further exceed 200 mg, including 225 mg, 250 mg, or amounts greater than 250 mg.

[0357] In embodiments, when a combination and / or composition includes a first and / or second bioactive molecule derived from a fungus, the first and / or second bioactive molecule may be present in an amount such that a single dosage (whether or not such dosage is present in a unit dosage form) is about 100 μg or less (including 95 μg, 90 μg, 85 μg, 80 μg, 75 μg, 70 μg, 65 μg, 60 μg, 55 μg, 50 μg, 45 μg, 40 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg or less), or is at least about 100 μg, or more, and greater than 1,000 μg, including 1,500 μg, 2,000 μg, up to and including 5,000 μg, and in some embodiments, greater than 5,000 μg.

[0358] For all embodiments herein that include a dosage of about 100 μg or less, it will be understood that such embodiments include further specific dosage amounts, including about 95 μg, about 90 μg, about 85 μg, about 80 μg, about 75 μg, about 70 μg, about 65 μg, about 60 μg, about 55 μg, about 50 μg, about 45 μg, about 40 μg, about 35 μg, about 30 μg, about 25 μg, about 20 μg, about 15 μg, about 10 μg, about 5 μg, and about 5 μg or less.

[0359] In all embodiments herein, including dosages of at least about 100 μg or more, and greater than 1,000 μg, including 1,500 μg, 2,000 μg, and up to 5,000 μg, dosages of 110 μg, 120 μg, 130 μg, 140 μg, 150 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg, 600 μg, 610 μg, 620 μg, 630 μg, 640 μg, 650 μg, 660 μg, 670 μg, 680 μg, 690 μg, 700 μg, 710 μg, 720 μg, 730 μg, 74 0μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg, 310μg, 320μg, 330μg, 340μg, 350μg, 360μg, 370μg, 380μg g, 390μg, 400μg, 410μg, 420μg, 430μg, 440μg, 450μg, 460μg, 470μg, 480μg, 490μg, 500μg, 510μg, 520μg, 530μg, 540μg, 550μg, 560μg, 570μg, 580μg, 590μg, 600μg, 610μg, 620μg, 630μg, 640μg, 650μg, 660μg, 6 70μg, 680μg, 680μg, 700μg, 710μg, 720μg, 730μg, 740μg, 750μg, 760μg, 770μg, 780μg, 790μg, 800μg, 810 μg, 820 μg, 830 μg, 840 μg, 850 μg, 860 μg, 870 μg, 880 μg, 890 μg, 900 μg, 910 μg, 920 μg, 930 μg, 940 μg, 950 μg, 960 μg, 970 μg, 980 μg, 990 μg, and 1000 μg, and in some embodiments will further be understood to include certain dosage amounts greater than 5,000 μg.

[0360] In some embodiments, the fungal-derived primary bioactive molecule is any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, airauginasin, or a β-carboline, which may be present in an amount such that a single dose (whether or not such dose is present in a unit dosage form) is about 100 μg or less, at least about 100 μg or more, and 1,000 μg or more, including 1,500 μg, 2,000 μg, up to and including 5,000 μg.

[0361] In embodiments, when the fungal-derived secondary bioactive molecule is a polysaccharide, peptide, terpene or terpenoid, phenolic compound, mineral, vitamin, amino acid, lipid, choline, or lactone, it may be present in a single dose (whether or not such dose is present in a unit dosage form) in an amount of less than about 1 mg, about 1 mg, up to about 75 mg, and greater than about 1 mg, including 75 mg. In embodiments, a single dose may be greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0362] In embodiments where the combination and / or composition includes a plant-derived primary and / or secondary bioactive molecule, the primary and / or secondary bioactive molecule may be present in an amount such that a single dose (whether or not such dose is present in a unit dosage form) is less than about 1 mg, about 1 mg, or up to and including about 75 mg, in embodiments, a single dose may be greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0363] For example, the primary bioactive molecule from a plant may be cannabinoid, THC, CBD, flavone or flavonoid, terpene or terpenoid, carbohydrate, fatty acid or fatty acid ester (FAE), amide, amine, phytosterol, phenolic compound, coumarin, compound derived from coumarin (e.g., phenylpropanoid, coumarin, or coumarinoid), coumaric acid, isoflavone, lupeol derivative, fatty acid ester, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxyretsin-8-methyl-ether, 5-methoxyxanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, betulin, butin, coumaric acid-β-glucan, ... In some embodiments, lucoside, dipteryxin, dipterixic acid, eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyl linolenic acid, methyl oleic acid, O-coumaric acid, O-hydroxycoumaric acid, odoratin, P-hydroxybenzoic acid, retsucin, retsucin-8-methyl-ether, sulfuretin, salicylic acid, afrormicin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone may be present in an amount such that a single dosage (whether or not such dosage is present in a unit dosage form) is less than, about, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose may be greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0364] In embodiments where the combination and / or composition includes a primary and / or secondary bioactive molecule derived from algae, the primary and / or secondary bioactive molecule may be present in an amount such that a single dose (whether or not such dose is present in a unit dosage form) is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose may be greater than 75 mg, including 100 mg, 150 mg, 200 mg, or more than 200 mg.

[0365] For example, in some embodiments where the algae-derived primary bioactive molecule is a porphyran or oligoporphyran, a polysaccharide, an oligopolysaccharide, a monosaccharide, a peptide, a phycobiliprotein, a mycosporine-like amic acid, an essential amino acid, a non-essential amino acid, a carotene or intermediate carotenoid, a glycoprotein, an aminosulfonic acid (such as taurine), a mineral, a vitamin, a lipid, a phenolic compound, or a phlorotannin, a single dose (whether or not such a dose is present in a unit dosage form) can be present in an amount less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose can be greater than 75 mg, including 100 mg, 150 mg, 200 mg, or more than 200 mg.

[0366] In some embodiments, the disclosed therapeutic combinations (i.e., particularly the disclosed therapeutic combinations comprising a fungal-derived bioactive molecule and a plant-derived bioactive molecule) are administered in a total daily dose of between about 50 mg and 1 g. In embodiments, the total daily dose is between about 50 mg and 1 g, between 100 mg and 500 mg, and preferably between 100 mg and 400 mg. In embodiments, each individual dose of the disclosed therapeutic combination is between 5 mg and 500 mg, or between 10 mg and 400 mg, or preferably between 10 mg and 100 mg.

[0367] In several embodiments, the patient is administered a therapeutically effective dose of the first and / or second bioactive molecules on a regular or chronic basis, wherein the patient receives the first and / or second bioactive molecules daily, several times per day (at least once, at least twice, at least three times, at least four times, or more than four times per day); on a set repeating schedule, such that the patient receives a therapeutically effective amount of the first and / or second bioactive molecules every other day, every two days, every three days, every four days, every five days, every sixth day, or more frequently than every sixth day; or, in some embodiments, on a varying schedule consisting of multiple days "on" (when a therapeutically effective dose of the first and / or second bioactive molecules is administered) and multiple days "off" (when no administration occurs), e.g., 1 day administered and 2 days not administered, 2 days administered and 3 days not administered, 3 days administered and 4 days not administered, etc., or other such schedules that would be apparent to one of skill in the art (see, e.g., what are known as microdosing protocols of Paul Stamets or James Fadiman).

[0368] It is understood that in several embodiments, the actual dose administered will be determined by the physician in light of the relevant circumstances, the method of delivery, the patient's age, the patient's weight, whether the patient has co-morbidities, other medications the patient is taking (routinely or currently), and any patient-specific aspects that may affect how the primary and / or secondary bioactive molecules interact with the patient, such as metabolic variability, variability in patient response, etc., and therefore the dosage ranges disclosed herein are not intended to limit the scope of the invention. In some cases, dosage levels below the lower end of the disclosed ranges may be more than adequate, while in other embodiments, doses above the ranges may be employed without causing adverse side effects, provided, for example, that such larger doses may also be divided into several smaller doses for administration, either together or separately.

[0369] In such embodiments, the primary and / or secondary bioactive molecules may be administered and dosed in accordance with principles of good medical practice, taking into account the method and schedule of administration, pre-existing and concomitant medications and supplements, the individual patient's clinical condition and the severity of the underlying disease, the patient's age, sex, weight, tolerance, and other such factors relevant to the healthcare professional, as well as their knowledge of the specific compounds used. Dosages may vary from patient to patient, from individual to individual, and for different combinations and formulations, but are determinable by those of ordinary skill in the art. Determining the appropriate dosage includes not only determining the single dose, but also determining the route of administration, the number and timing of administrations, and the preferred time of day or time during a psychotherapy session for administration.

[0370] In embodiments, the patient may self-administer the dose, which may be on a dosing schedule as described above. In embodiments, the combination and / or disclosed compositions may be prescribed to the patient, who obtains a therapeutically effective dose from a pharmacy or healthcare provider.

[0371] The dosage, frequency, or duration of administration may be increased or decreased as indicated by the desired clinical results, the state of the disease or condition, the side effects of the treatment or therapy, or the concomitant medication. The concentration or concentration ratio of the components of the disclosed combinations and compositions may also be varied as indicated by the desired clinical results, the state of the disease or condition, the side effects of the treatment or therapy, or the concomitant medication. For example, in some embodiments, the disclosed combinations include tryptamine (e.g., psilocin and / or psilocybin, e.g., as a component of a fungal part, such as a fungal extract from a psilocin- and / or psilocybin-containing fungus). In some such embodiments, a patient taking a monoamine oxidase inhibitor (MAOI) may be administered a composition with a reduced concentration of tryptamine (e.g., psilocin and / or psilocybin), since MAOIs are expected to reduce the metabolic excretion of tryptamine, thereby affecting the ratio and synergistic effect of the bioactive molecules upon administration of the disclosed compositions. In another example, the proportions of components of the disclosed compositions may be increased or decreased depending on an individual's tolerance. For example, individuals who frequently consume cannabis products often develop tolerance to the effects of cannabinoids. Thus, in some embodiments, individuals with significant tolerance to cannabis or cannabinoids (e.g., THC) may be administered compositions with increased concentrations of THC to account for such tolerance. In yet another example, individuals with certain medical conditions may be particularly sensitive or resistant to the effects of the disclosed compositions. By way of example only, in some embodiments, an individual with Lewy Body Dementia (LBD) may be administered a disclosed composition with a reduced concentration of cannabinoids (e.g., THC) or cannabis extract, for example, if there is a reasonable suspicion (e.g., at the discretion of a physician or other healthcare professional) that the cannabinoid or cannabis extract may worsen the cognitive or psychiatric symptoms of LBD and / or increase the patient's sensitivity to the composition or any of its components.In another merely illustrative example, an individual with clinical depression may be administered the disclosed compositions having increased concentrations of tryptamine (e.g., psilocin and / or psilocybin, e.g., as a component of the fungal portion, such as a fungal extract from a psilocin- and / or psilocybin-containing fungus), which may provide clinical benefits such as promoting serotonin modulation, neuroplasticity, and connectivity.

[0372] One of ordinary skill in the art having the benefit of this disclosure will understand the factors that can affect the dosage, frequency, and timing necessary to provide a sufficient or effective amount to provide a therapeutic effect or benefit, and to do so depending on the type of therapeutic effect desired, as well as to avoid or minimize side effects.

[0373] In other embodiments, appropriate doses for achieving a therapeutic effect, including the upper and lower limits of any dose range, can be determined by individuals, including non-clinicians, by reference to available public information and knowledge and by reference to subjective considerations regarding desired outcomes and effects.

[0374] In some embodiments, rather than being formulated as a single composition, the biologically active molecules in the therapeutic combination are administered to the patient separately, sequentially, or simultaneously. In some embodiments, the biologically active molecules in the therapeutic combination may be formulated individually as pharmaceutical compositions and then administered to the patient separately, sequentially, or simultaneously.

[0375] In some embodiments, sequential administration refers to administration of one combination agent shortly after administration of another combination agent (e.g., within about 5 minutes of administration of the first combination agent), simultaneous administration refers to administration of each combination agent substantially simultaneously, and separate administration refers to administration with a time lapse between administrations. In some embodiments in which the combination agents are administered separately, such administration can include an lapse of time between each administration of about 5 to about 30 minutes, about 10 to about 60 minutes, about 30 to about 180 minutes, about 180 to about 360 minutes, or more than 360 minutes, e.g., 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 5 days, 7 days, 10 days, 14 days, 21 days, 30 days, and any such time period therebetween that would be readily apparent to one of skill in the art.

[0376] The time lapse between doses should not be confused with the frequency with which the doses are administered. As will be understood by one of skill in the art, the frequency of administration can depend on the disease and condition being treated and the administration of the first and / or second bioactive molecules disclosed herein. By way of non-limiting example, it may be desirable to administer the combination agent between about 1 and about 8 times per day, including once daily, twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, and eight times daily; in some embodiments, one of the combination agents (i.e., one of the bioactive compounds in the combination) may be administered twice daily or three times daily, while another combination agent is administered once daily or twice daily, and any additional combination agents are administered according to the appropriate dosing schedule applicable thereto.

[0377] Additionally, the dosing schedule can be 1 to 7 days, including days 14, 21, 28, 29, 30, 31, 35, 42, 49, 60, 75, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, and 700; The same or altered pattern may continue for a particular period of time greater than 7 days, and the manner in which administration is completed (i.e., by separate, sequential, or simultaneous administration) may be adjusted as necessary so that the overall administration schedule may include only sequential, simultaneous, or separate administration, or may include a combination of two of sequential, simultaneous, or separate administration, or may include all of sequential, simultaneous, or separate administration. Thus, in embodiments, the frequency of administration and the period of time that lapses between doses will depend on the particular first and / or second bioactive molecules utilized and the condition being treated.

[0378] In embodiments, depending on the desired therapeutic effect, administration may include separate, sequential, or simultaneous oral, sublingual, buccal, intravenous, intraarterial, intraperitoneal, intramedullary, intramuscular, intrathecal, intracerebroventricular, rectal, vaginal, ocular, nasal, dermal, topical, otic, transdermal, or combinations thereof, as will be apparent to one of skill in the art. Furthermore, as noted above, in embodiments, a patient receives the combination agent in multiple administrations, where each administration is not by the same means of administration. As disclosed herein, this may be advantageous in situations where the first and / or second biologically active molecules have varying durations of action and maximum plasma concentrations.

[0379] In some embodiments, the first and / or second bioactive molecules disclosed herein are administered separately. In some embodiments, the first and / or second bioactive molecules disclosed herein are administered sequentially. In some embodiments, the first and / or second bioactive molecules disclosed herein are administered simultaneously. In some embodiments, the timing of administration of the first and / or second bioactive molecules disclosed herein (including whether multiple administrations of the first and / or second bioactive molecules are required) depends on the particular first and / or second bioactive molecules administered to an individual and the indication being treated.

[0380] a.Medicine kit In some embodiments, particularly when the formulation is prepared in a single unit dosage form, the suggested dosage should be known by reference to the format of the formulation itself. In other embodiments, the suggested dosage can be known by reference to the administration means or by reference to the packaging and label, package insert, marketing materials, training materials, or other information and knowledge available to those skilled in the art or the general public. Accordingly, another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present invention, recommended administration guidelines or prescribing information, and a suitable container. Individual unit dosage forms can be contained in a multi-dose kit or container. The pharmaceutical composition can also be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration. Accordingly, another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present invention, recommended administration guidelines or prescribing information, and a suitable container. Individual unit dosage forms can be contained in a multi-dose kit or container. The pharmaceutical composition can also be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0381] In an exemplary pharmaceutical kit, the capsules, tablets, caplets, or other unit dosage forms are packaged in a blister pack. A "blister pack" refers to any of several types of preformed containers, particularly plastic packaging, containing individual single-dose containers (e.g., cavities or pockets), which are individually sealed and individually openable.

[0382] Blister packs include pharmaceutical packs known to those skilled in the art, such as Aclar® Rx160, Rx20e, SupRx, and UltRx 2000, 3000, 4000, and 6000 (Honeywell). Within the definition of multi-dose container, what are often referred to as blister packs, include blister trays, blister cards, strip packs, push-through packs, and the like. Preferably, information related to dosing and proper administration (if necessary) is printed directly on the multi-dose kit (e.g., on the blister pack or other internal packaging holding the disclosed combination or composition); however, the kits of the present invention can further include package inserts and other printed instructions (e.g., on the external packaging) for administering the disclosed combination or composition and for their proper therapeutic use.

[0383] In some embodiments, patients have the option of using online software, such as a website, or downloadable software, such as a mobile application, to assist with medication adherence or provide data related to their treatment. Such software can be used, for example, to record the last dose taken and the total dose taken, provide reminders and notifications for the next dose, provide feedback to discourage dosing outside of a set schedule, allow for recording of specific subjective effects, or provide a means for unstructured diary entries. Such data collection can be used to assist individual patients in their medication adherence, improve or adjust individual patient care plans, and can be anonymized, aggregated, and analyzed (including by AI or natural language processing means) to enable research into the effectiveness of various treatment modalities.

[0384] I. Treatment method In some aspects, there is a method of preventing or treating a movement disorder comprising administering to a patient a disclosed therapeutic combination or pharmaceutical composition.

[0385] Without being bound by theory, the disclosed combinations, compositions, and methods are useful in some embodiments for treating movement disorders due to their redundant and promiscuous effects on CNS signaling capabilities, including improved neuronal structural integrity and density, neurotransmitter synthesis and regulation, enhanced neuroprotection, and active utilization of plasticity mechanisms (e.g., BDNF, serotonergic muscle control, and glial networks).

[0386] In some embodiments, the disclosed combinations, compositions, and methods are useful for addressing these nervous system disorders and addressing multiple contributing factors to the pathophysiology of movement disorders such as Parkinson's disease. In some embodiments, each component of the disclosed combinations and compositions may affect these neural circuits in multiple ways, e.g., with different pharmacodynamics, supported by privileged access to exogenous inputs from natural sources and a wide range of activities. In one example, the disclosed combinations and compositions affect multiple immunological and mitochondrial interfaces, which, combined with their effects on CNS signaling capabilities, collectively and synergistically create a comprehensive treatment for movement disorders such as Parkinson's disease.

[0387] In some embodiments, the disclosed combinations, compositions, and methods are useful for treating movement disorders, e.g., by reducing cytokines TNF-α and IL-1β via direct and indirect (amplifying) interference with NF-kβ and AP-1 signaling mechanisms, reducing oxidative ROS, NO, and MPO, and by activating the anti-inflammatory networks PPAR-γ and NRf2, thereby negatively regulating the pro-inflammatory cycle in a redundant and promiscuous manner.

[0388] In some aspects, the disclosed combinations, compositions, and methods are useful for treating inflammation and oxidative systems that contribute to the pathophysiology of movement disorders, such as Parkinson's disease. For example, neurodegeneration in movement disorders has been proposed to be characterized by metal homeostasis and oxidative stress (Trist et al., 2018). Oxidative stress has been well documented in Parkinson's disease and has been attributed to the oxidative metabolism of dopamine (Ahlskog, 2005). Oxidative mechanisms have been linked to substantia nigra cell death in Parkinson's disease (Jenner, 1998). In several embodiments, the disclosed combinations interact with inflammation and oxidative systems, for example, by synergistically avoiding receptor depletion, activating autoregulatory compensatory measures, and / or inducing an immunological response. In some embodiments, the disclosed combinations possess antioxidant properties that directly or indirectly treat or prevent movement disorders, for example, by mediating or reducing oxidative stress associated with the disorder.

[0389] In some embodiments, the disclosed combinations are useful for treating the inflammatory and oxidative systems. As one illustrative example, Parkinson's disease typically coincides with a dramatic loss of dopaminergic neurons in the substantia nigra (Meiser et al., 2013). Oxidative stress is involved in the loss of dopaminergic neurons, and dopamine metabolism itself is thought to be strongly linked to oxidative stress, as dopamine degradation generates reactive oxygen species (ROS) and dopamine oxidation leads to endogenous neurotoxicity (ibid.). Thus, without being bound by theory, dopamine metabolism is particularly important for neuronal redox homeostasis and viability. In some embodiments, the disclosed combinations exert antioxidant effects useful for treating or preventing Parkinson's disease or another movement disorder. In some embodiments, the antioxidant effects of the disclosed combinations prevent or reduce dopaminergic neuron loss in individuals with Parkinson's disease or another movement disorder, for example, by reducing oxidative stress. In some embodiments, reducing oxidative stress comprises reducing the concentration of ROS associated with dopamine metabolism. In some embodiments, reducing oxidative stress comprises neutralizing (e.g., chemically reducing) reactive oxygen species associated with dopamine metabolism. In some embodiments, the antioxidant effects of the disclosed combinations reduce the concentration of endogenous neurotoxins associated with dopamine oxidation. In some embodiments, the antioxidant effects of the disclosed combinations promote neuronal redox homeostasis. In some embodiments, the antioxidant effects of the disclosed combinations promote neuronal viability.

[0390] Furthermore, in some embodiments, the antioxidant effects of the disclosed combinations can be measured by changes in biomarkers of movement disorders (e.g., Parkinson's disease), such as changes (e.g., decreases) in iron levels and / or decreases in the concentrations of enzymes and substrates associated with oxidative stress. Several biomarkers of oxidative stress have been associated with Parkinson's disease (Frijhoff, 2015). In some embodiments, the biomarker is substantia nigra cell death, free iron, glutathione (GSH), glutathione disulfide (GSSG), nuclear factor erythroid 2-related factor 2 (NRF2), advanced glycation end products (AGEs), the aldehyde 4-hydroxynonenal (HNE), malonalaldehyde (MDA), F2-isoprostane, isolevulgandin (isoLG), nitrotyrosine (NO2-Tyr), or a combination thereof. In some embodiments, the biomarker is substantia nigra cell death. In some embodiments, the biomarker is free iron. In embodiments, the biomarker is glutathione (GSH). In embodiments, the biomarker is glutathione disulfide (GSSG). In embodiments, the biomarker is nuclear factor erythroid 2-related factor 2 (NRF2). In embodiments, the biomarker is advanced glycation end products (AGEs). In embodiments, the biomarker is the aldehyde 4-hydroxynonenal (HNE). In embodiments, the biomarker is malonalaldehyde (MDA). In embodiments, the biomarker is F2-isoprostane. In embodiments, the biomarker is isolevuglandin (isoLG). In embodiments, the biomarker is nitrotyrosine (NO2-Tyr).

[0391] In some embodiments, the antioxidant effects of the disclosed combinations may result in a decrease in a biomarker of oxidation (e.g., a biomarker of oxidative stress). In embodiments, the concentration of the biomarker is decreased by at least about 99%, 99%, 98%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or less than 1%, including ranges between these values. In embodiments, the concentration of the biomarker is decreased by at least 99%. In embodiments, the concentration of the biomarker is decreased by about 99%. In embodiments, the concentration of the biomarker is decreased by about 98%. In embodiments, the concentration of the biomarker is decreased by about 95%. In embodiments, the concentration of the biomarker is decreased by about 90%. In embodiments, the concentration of the biomarker is decreased by about 85%. In embodiments, the concentration of the biomarker is reduced by about 80%. In embodiments, the concentration of the biomarker is reduced by about 75%. In embodiments, the concentration of the biomarker is reduced by about 70%. In embodiments, the concentration of the biomarker is reduced by about 65%. In embodiments, the concentration of the biomarker is reduced by about 60%. In embodiments, the concentration of the biomarker is reduced by about 55%. In embodiments, the concentration of the biomarker is reduced by about 50%. In embodiments, the concentration of the biomarker is reduced by about 45%. In embodiments, the concentration of the biomarker is reduced by about 40%. In embodiments, the concentration of the biomarker is reduced by about 35%. In embodiments, the concentration of the biomarker is reduced by about 30%. In embodiments, the concentration of the biomarker is reduced by about 25%. In embodiments, the concentration of the biomarker is reduced by about 20%. In embodiments, the concentration of the biomarker is reduced by about 15%. In embodiments, the concentration of the biomarker is reduced by about 10%. In embodiments, the concentration of the biomarker is reduced by about 5%. In some embodiments, the concentration of the biomarker is reduced by about 4%. In some embodiments, the concentration of the biomarker is reduced by about 3%. In some embodiments, the concentration of the biomarker is reduced by about 2%.In some embodiments, the concentration of the biomarker is reduced by about 1%. In some embodiments, the concentration of the biomarker is reduced by less than 1%.

[0392] In some embodiments, the antioxidant properties and antioxidant effects of the disclosed combinations can be measured by a total antioxidant assay such as that disclosed in Apak, 2007. In some embodiments, the total antioxidant assay is a Folin-Ciocalteu assay. In some embodiments, the total antioxidant assay is a 2,2-diphenyl-1-picryl (DPPH) assay. In some embodiments, the total antioxidant assay is a Trolox equivalent antioxidant capacity (TEAC) assay. In some embodiments, the total antioxidant assay is a ferric reducing antioxidant power (FRAP) assay. In some embodiments, the total antioxidant assay is a total antioxidant capacity (TAC) assay. In some embodiments, the total antioxidant assay is a superoxide dismutase (SOD) assay. In some embodiments, the total antioxidant assay is a lipid peroxidation assay. In some embodiments, the total antioxidant assay is a hydroxyl radical scavenging assay. In some embodiments, the total antioxidant assay is a copper ion reducing antioxidant capacity (CUORAC) assay.

[0393] In some embodiments, the antioxidant properties of the disclosed combinations result from a synergistic effect between the fungal, plant, and algal parts, which in embodiments is defined as an antioxidant effect that is greater than the additive antioxidant effect or antioxidant properties of the parts when administered alone, e.g., synergistic effect in antioxidant capacity, efficacy, bioactivity, bioaccessibility, bioavailability, therapeutic effect, or a combination thereof.

[0394] "Treatment" covers any treatment of a disorder in a mammal, particularly a human, and includes: (a) preventing the disorder from occurring in a subject who may be predisposed to the disorder but has not yet been diagnosed with the disorder; (b) inhibiting the disorder, i.e., arresting its onset (e.g., including prevention); (c) alleviating the disorder, i.e., causing regression of the disorder or its clinical symptoms; (d) protecting against or alleviating symptoms or conditions caused by or associated with the disorder; (e) reducing, reducing, suppressing, ameliorating, or preventing the onset, severity, duration, progression, frequency, or probability of one or more symptoms or conditions associated with the disorder; and (f) preventing or inhibiting the worsening or progression of symptoms or conditions associated with the disorder. It will be understood that the therapeutic amount required to effectively treat for purposes of this invention is that amount that provides objective evidence of improvement, for example, in a patient with a clinically diagnosable condition. The effect may be prophylactic, in that it completely or partially prevents the disorder or its symptoms, and / or therapeutic, in that it partially or completely cures the disorder and / or adverse effects resulting from the disorder.

[0395] Whether a patient has a movement disorder can be determined using conventional techniques. Without being bound by theory, movement disorders are generally diagnosed after the onset of motor symptoms. Examples of methods used to diagnose movement disorders include genetic testing to detect known abnormalities that may indicate a movement disorder; blood, urine, and cerebrospinal fluid tests; the use of condition-specific medications useful for alleviating the symptoms of the condition; nuclear imaging, magnetic resonance imaging (MRI), computed tomography (CT), observation of existing symptoms including facial expressions; the presence or absence of tremors in the limbs and gait abnormalities; evaluation of neck stiffness; evaluation of balance (including the time it takes to regain balance); patient history; and additional testing to rule out similar conditions. Because various diseases and conditions have symptoms characteristic of movement disorders, diagnosis may involve a combination of the above methods or may include additional methods known to those skilled in the art.

[0396] In embodiments, measurements of treatment effectiveness include measures of effect within a clinical or medical practice or study that can be used to assess outcome measures (primary or secondary), endpoints, effect measures, and the effects (positive and / or negative) of an intervention or treatment, whether patient-reported (e.g., questionnaires), based on other patient data (e.g., patient monitoring), collected through clinical tests such as blood or urine, through consultation with a physician or other healthcare professional, or through digital means such as using electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps.

[0397] In embodiments, measures of therapeutic efficacy include (a) symptom severity, (b) motor control, (c) MDS-UPDRS, (d) UPDRS, and (e) UPDRS-8.

[0398] In several embodiments, the therapeutic efficacy measurements include (a) DaTscan to measure dysfunction of the dopamine transporter system and (b) αSyn-SAA (α-synuclein seed amplification assay). In DaTscan, technetium-99m (a tropane derivative) is injected into the bloodstream, where it binds to dopamine transporters in the brain. A gamma camera then detects the radiation, creating images detailing the distribution and density of dopamine transporters in the brain. The integrity of dopamine-producing cells in specific brain regions can then be assessed using known methods. αSyn-SAA examines the aggregation and propagation of abnormal α-synuclein protein structures, which may be involved in the progression of neurodegenerative diseases such as Parkinson's disease. αSyn-SAA involves seed formation (e.g., generation or isolation of abnormal α-synuclein), propagation, amplification, and detection (e.g., immunohistochemistry, immunofluorescence, ELISA).

[0399] In some embodiments, movement disorders refer to a group of nervous system (neurological) conditions that cause increased, decreased, slowed, or sluggish abnormal movements, which can be voluntary or involuntary (Mayo Clinic, 2017). In some embodiments, movement disorders include amyotrophic lateral sclerosis (ALS), ataxia, congenital ataxia, hereditary ataxia (e.g., Friedreich's ataxia, ataxia due to cerebrotendinous xanthomatosis, ataxia due to Refsum's disease, ataxia due to abetalipoproteinemia, hereditary episodic ataxia, ataxia due to mitochondrial mutations, and spinocerebellar ataxia), non-hereditary degenerative ataxia (e.g., late-onset cerebellar cortical atrophy), and acquired ataxia (e.g., ataxia due to alcoholic cerebellar degeneration). , cervical dystonia, choreiform disorders (e.g., chorea, benign hereditary chorea, secondary chorea), Huntington's disease, chorea due to Huntington's disease-like disorders, chorea due to dentatorubral-pallidoluysian atrophy, chorea due to Wilson's disease, chorea due to infectious or parainfectious causes, chorea due to systemic lupus erythematosus, drug-induced chorea, rheumatic chorea), dystonia, dystonias including primary dystonia (e.g., benign essential blepharospasm), secondary dystonia (e.g., drug-induced dystonia, dystonia) plus, and dystonia associated with genetic degenerative diseases), paroxysmal dystonia, and functional dystonia or spasms, functional movement disorders, Huntington's disease, multiple system atrophy, myoclonus, Parkinson's disease, including sporadic Parkinson's disease and familial Parkinson's disease, parkinsonism, including atypical parkinsonism (e.g., progressive supranuclear palsy (PSP) and Lewy body disease), secondary parkinsonism (e.g., parkinsonism due to genetic degenerative diseases, infectious or post-infectious parkinsonism, vascular parkinsonism, Parkinsonism, drug-induced parkinsonism, post-traumatic parkinsonism, parkinsonism due to structural lesions, functional parkinsonism, atypical Parkinson's disease, young-onset Parkinson's disease (YOPD), restless legs syndrome, tardive dyskinesia, L-dopa-induced dyskinesia, disorders with tremor (tremor, essential tremor, enhanced physiological tremor, resting tremor, secondary tremor (e.g., tremor due to metabolic disorders, tremor due to chronic or acute substance use, tremor due to drug withdrawal, tremor due to certain central nervous system diseases),and functional tremor, tic disorders (including primary tics or tic disorders (e.g., Tourette's syndrome, chronic motor tic disorder, chronic tonic tic disorder, and transient motor tics), secondary tics (e.g., infectious or post-infectious tics, tics associated with developmental disorders), myoclonus disorders (e.g., essential myoclonus, segmental myoclonus, focal myoclonus such as palatal myoclonus and chronic hiccups), Wilson's disease, hemifacial spasm, specific well-defined movement disorders (e.g., primary tics, segmental myoclonus, focal myoclonus such as palatal myoclonus and chronic hiccups), These conditions include: stereotypies (e.g., sexual stereotypies and secondary stereotypies), Rett syndrome, akathisia, and exaggerated startle reflex, restless legs syndrome, periodic limb movement disorder, sleep-related leg spasms, sleep-related bruxism, benign sleep myoclonus of infancy), sleep-onset myoclonus, sleep-related movement disorder due to medical conditions, sleep-related movement disorder due to drugs or substances, sleep-related rhythmic movement disorders including REM sleep behavior disorder, and hereditary spastic paraplegia, including autosomal recessive hereditary spastic paraplegia and X-linked hereditary spastic paraplegia.

[0400] In some embodiments, the movement disorder is ataxia, ataxic disorders, certain specific movement disorders, cervical dystonia, chorea, choreiform disorders, dystonia, dystonic disorders, essential tremor, Friedreich's ataxia, functional movement disorders, hemifacial spasm, hereditary spa...

Claims

1. 1. A therapeutic combination useful for preventing or treating a movement disorder, comprising: a. Fungal part; b. a first plant part; c. optionally, a second plant part; d. algae part, A therapeutic combination comprising:

2. a. Fungal part; b. a first plant part; c. a second plant part; and d. algae part, 2. The therapeutic combination of claim 1, comprising:

3. 3. The therapeutic combination of claim 2, wherein said fungal portion is derived from a psilocybin-producing species.

4. 4. The therapeutic combination of claim 3, wherein the psilocybin-producing species is from any of the genera Ateria, Conocybe, Copelandia, Fibrahizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Horiochina, Pluteus, and Psilocybe.

5. 5. The therapeutic combination of claim 4, wherein the psilocybin-producing species is from the genus Psilocybe.

6. 6. The therapeutic combination of claim 5, wherein the psilocybin-producing species from the psilocybin genus is any of P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogschagenii, P. stuntsii, P. cyanofibrillosa, and P. liniformans.

7. a. fungal portions from the Psilocybe species; b. a first plant part; c. a second plant part; and d. algae part, 3. The therapeutic combination of claim 2, comprising:

8. 3. The therapeutic combination of claim 2, wherein said first plant part is derived from said Cannabis species.

9. 9. The therapeutic combination of claim 8, wherein the Cannabis species is any of Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

10. a. Fungal part; b. a first plant part from the Cannabis genus; c. a second plant part; and d. algae part, 3. The therapeutic combination of claim 2, comprising:

11. a. fungal portions from the Psilocybe species; b. a first plant part from said Cannabis species; c. a second plant part; and d. algae part, 11. The therapeutic combination of claim 10, comprising:

12. 3. The therapeutic combination of claim 2, wherein said second plant part is from a species of the genus Dipteryx.

13. 13. The therapeutic combination of claim 12, wherein said Dipteryx species is Dipteryx odorata.

14. a. Fungal part; b. a first plant part; c. a second plant part from said Dipteryx species; and d. algae part, 3. The therapeutic combination of claim 2, comprising:

15. a. fungal portions from the Psilocybe species; b. a first plant part from said Cannabis species; c. a second plant part from said Dipteryx species; and d. algae part, 15. The therapeutic combination of claim 14, comprising:

16. 3. The therapeutic combination of claim 2, wherein said algal portion is derived from a species of marine algae.

17. 17. The therapeutic combination of claim 16, wherein said species of marine algae is from the family Bangiaceae.

18. 18. The therapeutic combination of claim 17, wherein said species of marine algae are from the genera Pyropia and Porphyra.

19. 19. The therapeutic combination of claim 18, wherein said species of seaweed is any of Pyropia aezoensis, Pyropia perforata, and Porphyra umbilicalis.

20. a. Fungal part; b. a first plant part; c. a second plant part; and d. algal parts from the Pyropia or Porphyra species; 3. The therapeutic combination of claim 2, comprising:

21. a. fungal portions from the Psilocybe species; b. a first plant part from said Cannabis species; c. a second plant part from said Dipteryx species; and d. algal parts from the Pyropia or Porphyra species; 21. The therapeutic combination of claim 20, comprising:

22. 4. The therapeutic combination of claim 3, wherein said fungal portion comprises a fungal extract from said psilocybin-producing species.

23. 23. The therapeutic combination of claim 22, wherein the fungal extract is derived from P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogschagenii, P. stuntii, P. cyanofibrillosa, or P. liniformans.

24. 24. The therapeutic combination of claim 23, wherein the fungal extract is obtained by ultrasonic extraction or Soxhlet extraction.

25. 25. The therapeutic combination of claim 24, wherein the fungal extract comprises a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction.

26. 9. The therapeutic combination of claim 8, wherein said first plant part comprises a cannabis plant extract derived from said Cannabis species.

27. 27. The therapeutic combination of claim 26, wherein the cannabis plant extract is derived from cannabis sativa, cannabis indica, or cannabis ruderalis.

28. 28. The therapeutic combination of claim 27, wherein the cannabis plant extract is obtained by Soxhlet extraction.

29. 13. The therapeutic combination of claim 12, wherein said second plant part comprises a Dipteryx plant extract from a species of the genus Dipteryx.

30. 30. The therapeutic combination of claim 29, wherein said Dipteryx plant extract is derived from Dipteryx odorata.

31. 31. The therapeutic combination of claim 30, wherein the Dipteryx plant extract is obtained by absolute ethanol extraction.

32. 17. The therapeutic combination of claim 16, wherein the algae portion comprises an algae extract derived from a species of marine algae.

33. 33. The therapeutic combination of claim 32, wherein the algae extract is derived from Pyropia aezoensis, Pyropia perforata, or Porphyra umbilicalis.

34. 34. The therapeutic combination of claim 33, wherein the algal extract is obtained by ultrasonic extraction.

35. a. a fungal extract from the Psilocybe species; b. a cannabis plant extract derived from said Cannabis species; c. a Dipteryx plant extract from the Dipteryx species; and d. an algae extract from the Pyropia or Porphyra species; 3. The therapeutic combination of claim 2, comprising:

36. a. A 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction; b. Cannabis plant extract obtained by Soxhlet extraction; c. Dipteryx plant extract obtained by absolute ethanol extraction; and d. Algae extract obtained by ultrasonic extraction; 36. The therapeutic combination of claim 35, comprising:

37. a. a fungal extract containing psilocybin and psilocin; b. Δ ９ - cannabis plant extracts containing THC (THC) and cannabidiol (CBD); c. Dipteryx plant extract containing coumarin; and d. an algae extract containing porphyran; 37. The therapeutic combination of claim 35 or 36, comprising:

38. a. fungal parts containing psilocybin and psilocin; b. Δ ９ - a first plant part containing THC (THC) and cannabidiol (CBD); c. a second plant part containing coumarin; and d. Porphyran-containing algal parts; 22. The therapeutic combination of claim 21, comprising:

39. 37. The therapeutic combination of any preceding claim, wherein the fungal portion comprises a bioactive molecule derived from a fungus.

40. 40. The therapeutic combination of claim 39, wherein said bioactive molecule derived from a fungus is a primary bioactive molecule derived from a psilocybin-producing species.

41. 41. The therapeutic combination of claim 40, wherein the primary bioactive molecule from the psilocybin-producing species is one or more tryptamines or one or more β-carbolines.

42. 42. The therapeutic combination of claim 41, wherein said one or more tryptamines is any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aerogenasin.

43. 43. The therapeutic combination of claim 42, wherein said one or more tryptamines is psilocybin or psilocin.

44. 43. The therapeutic combination of claim 42, wherein said one or more tryptamines are psilocybin and psilocin.

45. 45. The therapeutic combination of claim 44, wherein the psilocybin and psilocin are in a weight ratio of about 5:

3.

46. 42. The therapeutic combination of claim 41, wherein the one or more β-carbolines are any of harmane, harmine, harmol, pinoline, harmaline, cordysinin C, cordysinin D, norharman, and perloline.

47. 40. The therapeutic combination of claim 39, wherein said bioactive molecule derived from a fungus is a secondary bioactive molecule derived from a psilocybin-producing species.

48. 48. The therapeutic combination of claim 47, wherein the secondary bioactive molecule derived from a psilocybin-producing species is any of a polysaccharide, a peptide, a terpene, a phenolic compound, a mineral, a vitamin, an amino acid, a lipid, choline, and a lactone.

49. 37. The therapeutic combination of any preceding claim, wherein said first plant part comprises a bioactive molecule derived from Cannabis.

50. 50. The therapeutic combination of claim 49, wherein said bioactive molecule derived from Cannabis is a primary bioactive molecule derived from a Cannabis species.

51. 51. The therapeutic combination of claim 50, wherein the primary bioactive molecule derived from a Cannabis species is one or more cannabinoids.

52. The one or more cannabinoids may be Δ ９ -THC-type cannabinoids, Δ ８ 52. The therapeutic combination of claim 51, which is any of THC-type cannabinoids, CBG-type cannabinoids, CBD-type cannabinoids, CBND-type cannabinoids, CBE-type cannabinoids, CBL-type cannabinoids, CBC-type cannabinoids, CBN-type cannabinoids, CBT-type cannabinoids, and mixed cannabinoids.

53. The one or more cannabinoids may be Δ ９ 53. The therapeutic combination of claim 52, wherein the active ingredient is THC (THC) or cannabidiol (CBD).

54. 53. The therapeutic combination of claim 52, wherein said one or more cannabinoids are THC and CBD.

55. 55. The therapeutic combination of claim 54, wherein the THC and CBD are in a weight ratio of about 1:

1.

56. 50. The therapeutic combination of claim 49, wherein said bioactive molecule derived from Cannabis is a secondary bioactive molecule derived from a Cannabis species.

57. 57. The therapeutic combination of claim 56, wherein the secondary bioactive molecule derived from a Cannabis species is any of a flavone or flavonoid, a terpene or terpenoid, a carbohydrate, a fatty acid or fatty acid ester, an amide, an amine, a phytosterol, and a phenolic compound.

58. 37. The therapeutic combination of any preceding claim, wherein said second plant part comprises a bioactive molecule from Dipteryx.

59. 59. The therapeutic combination of claim 58, wherein said bioactive molecule from Dipteryx is a primary bioactive molecule from Dipteryx odorata.

60. 60. The therapeutic combination of claim 59, wherein the primary bioactive molecule from Dipteryx odorata is coumarin.

61. 59. The therapeutic combination of claim 58, wherein said bioactive molecule from Dipteryx is a secondary bioactive molecule from Dipteryx odorata.

62. The secondary bioactive molecules derived from Dipteryx odorata include coumaric acid, coumarin derivatives, isoflavones, lupeol derivatives, fatty acid esters, (±)-balanofonin, (-)-lariciresinol, 3'-hydroxyretsin-8-methyl-ether, 5-methoxyxanthocercin A, 6,4'-dihydroxy-3'-methoxyuron, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, betulin, butine, coumaric acid-β-glucoside, dipteryxin, dipteryxic acid, eriodictyol.

62. The therapeutic combination of claim 61, wherein the hydroxybenzoic acid is any one of benzoyl, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyl-linolenic acid, methyl-oleic acid, O-coumaric acid, O-hydroxycoumaric acid, odoratin, p-hydroxybenzoic acid, lettucin, lettucin-8-methyl-ether, sulfuretin, salicylic acid, afromycin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone.

63. 37. The therapeutic combination of any of claims 1 to 36, wherein the algae portion comprises an algae-derived bioactive molecule.

64. 64. The therapeutic combination of claim 63, wherein said bioactive molecule derived from algae is a primary bioactive molecule derived from Pyropia or Porphyra.

65. 65. The therapeutic combination of claim 64, wherein the primary bioactive molecule derived from Pyropia or Porphyra is any of a porphyran, oligoporphyran, polysaccharide, oligopolysaccharide, monosaccharide, peptide, phycobiliprotein, mycosporine-like amino acid, essential amino acid, non-essential amino acid, carotene, intermediate carotenoid, glycoprotein, aminosulfonic acid, and taurine.

66. 66. The therapeutic combination of claim 65, wherein the primary bioactive molecule derived from Pyropia or Porphyra is a porphyran.

67. 64. The therapeutic combination of claim 63, wherein said bioactive molecule derived from algae is a secondary bioactive molecule derived from Pyropia or Porphyra.

68. 68. The therapeutic combination of claim 67, wherein the secondary bioactive molecule derived from Pyropia or Porphyra is any of a mineral, a vitamin, a lipid, a phenolic compound, and a phlorotannin.

69. 37. The therapeutic combination of any one of claims 1 to 36, further comprising a flavoring or coloring agent.

70. 70. The therapeutic combination of claim 69, wherein the flavoring agent is ginger or bay leaf.

71. 37. The therapeutic combination of any one of claims 1 to 36, further comprising an additional active agent.

72. 72. The therapeutic combination of claim 71, wherein the additional active agent is any of levodopa, carbidopa, carbidopa-levodopa, entacapone, carbidopa-levodopa-entacapone, tolcapone, opicapone, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, procyclidine, trihexyphenidyl, orphenadrine, and buntanetap.

73. 37. The therapeutic combination of any one of claims 1-36, wherein at least one of the fungal part, the first plant part, the second plant part, or the algal part further comprises a non-naturally occurring carrier, diluent, or excipient.

74. 74. The therapeutic combination of claim 73, wherein at least two, at least three, or all four of said fungal part, said first plant part, said second plant part, and said algal part further comprise a non-naturally occurring carrier, diluent, or excipient.

75. a. a bioactive molecule from the species of the genus Psilocybe; b. a bioactive molecule derived from said Cannabis species; c. a bioactive molecule from said Dipteryx species; and d. a bioactive molecule derived from the Pyropia or Porphyra species; 22. The therapeutic combination of claim 21, comprising:

76. a. a primary bioactive molecule from said Psilocybe species; b. a primary bioactive molecule from said Cannabis species; c. a primary bioactive molecule from said Dipteryx species; and d. a primary bioactive molecule from said Pyropia or Porphyra species; 76. The therapeutic combination of claim 75, comprising:

77. a. one or more tryptamines from said Psilocybe species; b. one or more cannabinoids from said Cannabis species; c. Coumarin; and d. porphyran, 77. The therapeutic combination of claim 76, comprising:

78. a. psilocybin and psilocin; b. THC and CBD; c. Coumarin; and d. porphyran, 78. The therapeutic combination of claim 77, comprising:

79. a. psilocybin and psilocin in a 5:3 weight ratio; b. THC and CBD in a 1:1 weight ratio; c. Coumarin; and d. porphyran, 79. The therapeutic combination of claim 78, comprising:

80. a. a secondary bioactive molecule from said Psilocybe species; b. a second bioactive molecule from said Cannabis species; c. a second bioactive molecule from said Dipteryx species; and d. a secondary bioactive molecule from said Pyropia or Porphyra species; 80. The therapeutic combination of any one of claims 75 to 79, further comprising:

81. 80. The therapeutic combination of any one of claims 75-79, wherein one said bioactive molecule, two said bioactive molecules, three said bioactive molecules, four said bioactive molecules, five said bioactive molecules, six said bioactive molecules, at least one said bioactive molecule, at least two said bioactive molecules, at least three said bioactive molecules, at least four said bioactive molecules, at least five said bioactive molecules, at least six said bioactive molecules, all said bioactive molecules, no more than six said bioactive molecules, no more than five said bioactive molecules, no more than four said bioactive molecules, no more than three said bioactive molecules, no more than two said bioactive molecules are derived from or contained in the extract, or wherein none of said bioactive molecules are derived from or contained in the extract.

82. 80. The therapeutic combination of any one of claims 75-79, wherein one said biologically active molecule, two said biologically active molecules, three said biologically active molecules, four said biologically active molecules, five said biologically active molecules, six said biologically active molecules, at least one said biologically active molecule, at least two said biologically active molecules, at least three said biologically active molecules, at least four said biologically active molecules, at least five said biologically active molecules, at least six said biologically active molecules, all said biologically active molecules, no more than six said biologically active molecules, no more than five said biologically active molecules, no more than four said biologically active molecules, no more than three said biologically active molecules, no more than two said biologically active molecules are isolated molecules, or none of said biologically active molecules are isolated molecules.

83. 80. The therapeutic combination of any one of claims 75-79, wherein one said biologically active molecule, two said biologically active molecules, three said biologically active molecules, four said biologically active molecules, five said biologically active molecules, six said biologically active molecules, at least one said biologically active molecule, at least two said biologically active molecules, at least three said biologically active molecules, at least four said biologically active molecules, at least five said biologically active molecules, at least six said biologically active molecules, all said biologically active molecules, no more than six said biologically active molecules, no more than five said biologically active molecules, no more than four said biologically active molecules, no more than three said biologically active molecules, no more than two said biologically active molecules are pure or substantially pure molecules, or wherein none of said biologically active molecules are pure or substantially pure molecules.

84. 80. The therapeutic combination of any one of claims 75-79, wherein one said biologically active molecule, two said biologically active molecules, three said biologically active molecules, four said biologically active molecules, five said biologically active molecules, six said biologically active molecules, at least one said biologically active molecule, at least two said biologically active molecules, at least three said biologically active molecules, at least four said biologically active molecules, at least five said biologically active molecules, at least six said biologically active molecules, all said biologically active molecules, no more than six said biologically active molecules, no more than five said biologically active molecules, no more than four said biologically active molecules, no more than three said biologically active molecules, no more than two said biologically active molecules are synthetic molecules, or none of said biologically active molecules are synthetic molecules.

85. 80. The therapeutic combination of claim 79, wherein a single dose comprises: a. 250 μg psilocybin; b. 150 μg psilocin; c. 1 mg CBD; d. 1 mg THC; e. 1 mg coumarin; f. 8 mg of Pyropia extract: g. Optionally, 8 mg of flavoring or coloring agent.

86. 86. The therapeutic combination of claim 85, wherein said flavoring or coloring agent comprises ginger or bay leaf.

87. 86. The therapeutic combination of claim 85, wherein said flavoring or coloring agents include ginger and bay leaf.

88. 86. The therapeutic combination of claim 85, further comprising a diluent.

89. 89. The therapeutic combination of claim 88, wherein the diluent is water.

90. a. the fungal portion comprises about 45% by volume of the total combination; b. the first plant part comprises about 15% by volume of the total combination; c. the second plant part comprises about 2% by volume of the total combination; d. the algae portion comprises about 15% by volume of the total combination; e. the flavor or color comprises about 15% by volume of the total combination; and f) The therapeutic combination of Claim 21, wherein the diluent comprises the remainder of the total combination.

91. a. the fungal fraction comprises a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction; b. the first plant part comprises a cannabis plant extract obtained by Soxhlet extraction; c. the second plant part comprises a Dipteryx plant extract obtained by absolute ethanol extraction; d. the algae portion comprises an algae extract obtained by ultrasonic extraction; e. the flavoring or coloring agent comprises an ethanolic infusion of ginger and bay leaves; and f) The therapeutic combination of Claim 21 or 90, wherein said diluent comprises water.

92. a. the fungal fraction is a 2:1 mixture of a fungal extract obtained by ultrasonic extraction and a fungal extract obtained by Soxhlet extraction; b. the first plant part is a cannabis plant extract obtained by Soxhlet extraction; c. the second plant part is a Dipteryx plant extract obtained by absolute ethanol extraction; d) the algae portion is an algae extract obtained by ultrasonic extraction; e. the flavoring or coloring agent is an infusion of ginger and bay leaves in ethanol; and f) The therapeutic combination of Claim 91, wherein said diluent is water.

93. 92. The therapeutic combination of claim 91, wherein said diluent comprises water and at least one non-naturally occurring diluent.

94. a. Obtaining the fungal extract by ultrasonic extraction and / or Soxhlet extraction; b. Obtaining the cannabis plant extract by Soxhlet extraction; c. Obtaining the Dipteryx plant extract by absolute ethanol extraction; d. Obtaining the algae extract by ultrasonic extraction; e. analyzing the concentration of at least one bioactive molecule in each extract; f. calculating a formulation ratio for each of the at least one bioactive molecule contained in each extract to achieve a target dose; g. Blending the calculated amount of each extract into the mixture based on the blending ratio; h. optionally homogenizing the mixture; i. adding flavoring or coloring agents, if desired; j) A method for preparing the therapeutic combination of claim 35, including the step of adding a diluent, if necessary, to obtain a target volume.

95. 95. The method of preparing a therapeutic combination of claim 94, wherein the target dose of each of the at least one biologically active molecule in each extract comprises: a. 250 μg psilocybin; b. 150 μg psilocin; c. 1 mg CBD; d. 1 mg THC; and e. 1 mg of coumarin.

96. 95. The method of preparing a therapeutic combination of claim 94, wherein the calculated amount of each extract based on the blending ratio comprises: a. 45% by volume of the fungal extract of the total combination; b. 15% by volume of the total combination of said cannabis plant extract; c. 2% by volume of the Dipteryx plant extract of the total combination; d. 15% by volume of the algae extract of the total combination; e. 15% by volume of the total combination of said flavor or color; and f) 8% by volume of said diluent of said total combination.

97. 86. A pharmaceutical composition comprising a therapeutic combination according to any of claims 1 to 36 or 85 and a pharmaceutically acceptable carrier, diluent or excipient.

98. 98. The pharmaceutical composition of claim 97, wherein the pharmaceutically acceptable carrier, diluent or excipient is non-naturally occurring.

99. 98. The pharmaceutical composition of claim 97, suitable for enteral or parenteral administration.

100. 98. The pharmaceutical composition of claim 97, formulated as a tincture, oral spray, oral mucosal spray, soft mist inhaler, vapor, tablet, divisible multiple-action tablet, capsule, capsule with added active agent, suspension, intravenous solution, injectable solution, topical formulation for transdermal administration, cut matrix sublingual or buccal tablet, individually molded sublingual or buccal lozenge, or intranasal formulation.

101. 101. The pharmaceutical composition of claim 100, formulated as either a tincture, an oral spray, an oral mucosal spray, or a soft mist inhalation formulation.

102. 102. The pharmaceutical composition of claim 101, wherein the formulation comprises: a. 45% by volume of the fungal extract of the total combination; b. 15% by volume of the total combination of said cannabis plant extract; c. 2% by volume of the Dipteryx plant extract of the total combination; d. 15% by volume of the algae extract of the total combination; e. 15% by volume of the total combination of said flavor or color; and f) 8% by volume of said diluent of said total combination.

103. 102. The pharmaceutical composition of claim 101, wherein a single dose comprises: a. 250 μg psilocybin; b. 150 μg psilocin; c. 1 mg CBD; d. 1 mg THC; e. 1 mg coumarin; f. 8 mg of Pyropia extract; g. Optionally, 8 mg of flavoring or coloring agent.

104. 98. The pharmaceutical composition of claim 97, wherein the single dose of psilocybin is between about 0.5 μg and about 200 mg, about 5 μg and about 5 mg, or about 100 μg and about 600 μg.

105. 105. The pharmaceutical composition of claim 104, wherein a single dose of psilocybin is 250 μg.

106. 98. The pharmaceutical composition of claim 97, wherein a single dose of psilocin is from about 0.5 μg to about 200 mg, from about 5 μg to about 5 mg, or from about 100 μg to about 600 μg.

107. 107. The pharmaceutical composition of claim 106, wherein a single dose of psilocin is 150 μg.

108. 98. The pharmaceutical composition of claim 97, wherein the single dose of CBD is from about 0.5 μg to about 200 mg, from about 0.01 mg to about 75 mg, or from about 0.5 mg to about 15 mg.

109. 109. The pharmaceutical composition of claim 108, wherein the single dose of CBD is 1 mg.

110. 98. The pharmaceutical composition of claim 97, wherein a single dose of THC is between about 0.5 μg to about 200 mg, about 0.01 mg to about 75 mg, or about 0.5 mg to about 15 mg.

111. 111. The pharmaceutical composition of claim 110, wherein a single dose of THC is 1 mg.

112. 98. The pharmaceutical composition of claim 97, wherein a single dose of coumarin is between about 0.5 μg to about 200 mg, about 0.01 mg to about 75 mg, or about 0.5 mg to about 15 mg.

113. 113. The pharmaceutical composition of claim 112, wherein the single dose of coumarin is 1 mg.

114. 98. The pharmaceutical composition of claim 97, wherein a single dose comprises the Piropia aezoensis, Piropia perforata, or Porphyra umbilicalis whole extract in an amount of about 0.5 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 20 mg.

115. 115. The pharmaceutical composition of claim 114, wherein a single dose contains an amount of 8 mg of Pilopia whole extract.

116. 98. The pharmaceutical composition of claim 97, wherein a single dose comprises an ethanolic decoction of ginger and bay leaves in an amount of about 0.5 mg to about 100 mg, about 1 mg to about 50 mg, or about 5 mg to about 20 mg.

117. 117. The pharmaceutical composition of claim 116, wherein a single dose comprises ethanolic decoction of ginger and bay leaves in an amount of 8 mg.

118. A pharmaceutical kit comprising a first pharmaceutical composition and a second pharmaceutical composition, a. the first pharmaceutical composition comprises at least a portion of the therapeutic combination of claim 21 and a pharmaceutically acceptable carrier, diluent, or excipient; and b) A pharmaceutical kit, wherein the second pharmaceutical composition comprises the remainder of the therapeutic combination of claim 21 and a pharmaceutically acceptable carrier, diluent, or excipient.

119. a. the first pharmaceutical composition is formulated as a tincture, oral spray, oral mucosal spray, or soft mist inhalation formulation; and b) The pharmaceutical kit of claim 118, wherein the second pharmaceutical composition is formulated as a tincture, an oral spray, an oral mucosal spray, or a soft mist inhalation formulation.

120. 100. A method for preventing or treating movement disorders, comprising administering to a patient in need thereof a therapeutic combination according to any of claims 1 to 36 or 85.

121. 104. A method for preventing or treating a movement disorder, comprising administering the pharmaceutical composition of claim 103 to a patient in need thereof.

122. 122. The method of claim 121, wherein the movement disorder is any one or more of ataxia, ataxic disorders, certain defined movement disorders, cervical dystonia, chorea, choreiform disorders, dystonia, dystonic disorders, essential tremor, Friedreich's ataxia, functional movement disorders, hemifacial spasm, hereditary spastic paraplegia, Huntington's disease, L-dopa-induced dyskinesia, multiple system atrophy (MSA), myoclonus, myoclonic disorders, Parkinson's disease, atypical Parkinson's disease, parkinsonism, secondary parkinsonism, progressive supranuclear palsy (PSP), restless legs syndrome, Rett syndrome, sleep-related movement disorder, spasticity, tardive dyskinesia (TD), Tourette's syndrome, tic disorders, disorders associated with tremor, and Wilson's disease.

123. 122. The method of claim 121, wherein the pharmaceutical composition is administered 1 to 8 times per day.

124. 122. The method of claim 121, wherein the patient experiences improvement associated with the movement disorder.

125. 125. The method of claim 124, wherein the improvement is a decrease in the severity of at least one symptom of the movement disorder.

126. 126. The method of claim 125, wherein the at least one symptom of the movement disorder is a motor symptom.

127. The motor symptoms include stooped posture, masked facial expression, forward trunk lean, elbow and wrist flexion, decreased arm swing, hip and knee flexion, trembling of the limbs, shuffling gait, short stride walking, uncoordinated or awkward balance, strange speech, involuntary limb movements, irregular movements, prolonged contractions, intermittent contractions of the neck muscles, turning the head in different ways, repetitive, irregular, involuntary movements of the face, mouth, trunk, and limbs; twisting, reflexes.

127. The method of claim 126, wherein the symptoms are any of: reflex movements; spasms of muscles or muscle groups, tremors, stiffness, finger tapping, toe tapping, poor posture, slowness, decline, or imbalance of movements; difficulty walking, irregular involuntary eye movements, involuntary blinking, involuntary grimacing, unpleasant or abnormal sensations in the limbs (which may be relieved by movement), involuntary vocalizations, or rhythmic trembling of a part of the body (generally the hands and / or head).

128. 127. The method of claim 126, wherein the motor symptoms are any of the following: problems speaking; excessive saliva and drooling; problems chewing and swallowing; difficulty eating, dressing, maintaining proper hygiene, handwriting, hobbies and other activities; difficulty rolling over, getting out of bed, a car, or a deep chair; difficulty walking and maintaining balance; experiencing tremors; and freezing in place.

129. 126. The method of claim 125, wherein at least one symptom of the movement disorder is a non-motor symptom.

130. 130. The method of claim 129, wherein the non-motor symptoms are any of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, lethargy, features of dopamine dysregulation syndrome, sleep disturbances, daytime sleepiness, pain and other sensations, urinary disturbances, constipation disturbances, orthostatic dizziness, and fatigue.

131. 130. The method of claim 129, wherein the non-motor symptom is a mood symptom.

132. 132. The method of claim 131, wherein the mood symptoms are any of feelings of depression, anxiety, irritability, mood swings, poor judgment, loss of empathy, aggression, impulsivity, delusions, and paranoia.

133. 126. The method of claim 125, wherein the reduction in severity of at least one symptom of the movement disorder occurs in less than about 75 days from initial administration of the pharmaceutical composition.

134. 126. The method of claim 125, wherein the reduction in severity of at least one symptom of the movement disorder occurs in less than about 35 days from initial administration of the pharmaceutical composition.

135. 126. The method of claim 125, wherein the reduction in severity of at least one symptom of the movement disorder lasts for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

136. 125. The method of claim 124, wherein the improvement is improved motor control.

137. 137. The method of claim 136, wherein the improvement in motor control is an improvement in any of balance, frequency of involuntary movements, amplitude of involuntary movements, muscle strength, endurance, and physical performance.

138. 137. The method of claim 136, wherein the improvement in motor control occurs in less than about 75 days from the first administration of the pharmaceutical composition.

139. 137. The method of claim 136, wherein the improvement in motor control occurs in less than about 35 days from initial administration of the pharmaceutical composition.

140. 125. The method of claim 124, wherein the improvement is with respect to a clinical outcome assessment.

141. The clinical outcome assessments included the Movement Disorder Society-Uniform Parkinson's Disease Rating Scale (MDS-UPDRS), Movement Disorder Society Non-Motor Rating Scale (MDS-NMS), Corticobasal Ganglia Function Scale (SBFS), Gastrointestinal Dysfunction Scale for Parkinson's Disease (GIDS-PD), Wilson's Disease Assessment Scale (GAS for WD), General Dystonia Severity Scale (GDS), Bradyneurosis Rating Scale-Revised (MBRS), Non-Motor Symptom Questionnaire (NMSQ), Parkinson's Disease Non-Motor Scale (NMSS), Pantothenate Kinase-Related Neurodegenerative Disease Rating Scale (PKAN-DRS), Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-DS). Scale) (PSP-CDS), Essential Tremor Quality of Life Questionnaire, Psychogenic Movement Disorders Scale, Rush Dyskinesia Rating Scale (RDRS), Rush Video-Based Tic Rating Scale (RVBTRS), Parkinson's Disease Outcome Assessment Scale - Autonomic Dysfunction (SCOPA-AUT), Parkinson's Disease Outcome Assessment Scale - Diary Cards (SCOPA-DC), Parkinson's Disease Outcome Assessment Scale - Psychiatric Comorbidities (SCOPA-PC), Parkinson's Disease Outcome Assessment Scale - Psychosocial Functioning (SCOPA-PS), Parkinson's Disease Outcome Assessment Scale - Sleep (SCOPA- SCOPA-S), Parkinson's Disease Outcome Scale-Cognitive (SCOPA-COG), Brief Parkinson's Disease Rating Scale (SPES) / Parkinson's Disease Outcome Scale-Motor Function (SPES / SCOPA-Motor), Non-Motor Fluctuation Assessment (NoMoFA) questionnaire, UFMG Sydenham Chorea Rating Scale (USCRS), Unified Dyskinesia Rating Scale (UDysRS), Unified Dystonia Rating Scale (UDRS), Unified Multiple System Atrophy Rating Scale (UMSARS), and 8-item Unified Parkinson's Disease Rating Scale-8 (UPDRS-8).

142. 142. The method of claim 141, wherein the clinical outcome assessment is MDS-UPDRS, UPDRS, or UPDRS-8.

143. 143. The method of claim 142, wherein the clinical outcome assessment is MDS-UPDRS.

144. The method of claim 143, wherein the improvement in MDS-UPDRS is an improvement in nM-EDL.

145. The method of claim 144, wherein the improvement in nM-EDL is in any of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, lethargy, features of dopamine dysregulation syndrome, sleep disturbances, daytime sleepiness, pain and other sensations, urinary disturbances, constipation disturbances, orthostatic dizziness, and fatigue.

146. 144. The method of claim 143, wherein the improvement in the MDS-UPDRS is an improvement in the M-EDL.

147. 147. The method of claim 146, wherein the improvement in the M-EDL is in any of speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, hobbies and other activities, rolling over, tremor, rising from a bed, car, or deep chair, walking and balance, and freezing.

148. 144. The method of claim 143, wherein the improvement in the MDS-UPDRS is an improvement in a motor test.

149. 149. The method of claim 148, wherein the improvement in motor tests is for any of speech, facial expression, rigidity, finger tapping, hand movements, hand pronation-supination, toe tapping, leg agility, chair rising, gait, gait rigidity, postural stability, posture, overall movement spontaneity (bradykinesia), postural tremor of the hand, kinetic tremor of the hand, resting tremor amplitude, resting tremor constancy, Hoehn and Yahr stage, time spent with dyskinesias, functional impact of dyskinesias, time spent in off-states, functional impact of fluctuations, complexity of motor fluctuations, and painful off-state dystonia.

150. 150. The method of any one of claims 143 to 149, wherein the improvement is a decrease in score.

151. 151. The method of claim 150, wherein the decrease in score is at least 1 point, at least 2 points, at least 3 points, or at least 4 points.

152. 125. The method of claim 124, wherein the improvement is an improvement in the UPDRS.

153. 153. The method of claim 152, wherein the improvement in UPDRS is improvement in mental, behavioral, and mood.

154. 154. The method of claim 153, wherein said improvement in mental, behavioral, and mood is any of intellectual disability, thought disorder, depression, and motivation / initiative.

155. 153. The method of claim 152, wherein the improvement in UPDRS is an improvement in ADL.

156. 156. The method of claim 155, wherein the improvement in ADL is for any of the following complaints: speech, salivation, swallowing, handwriting, cutting food and using utensils, dressing, hygiene, turning and adjusting bedding, falls, stiffness when walking, gait, tremor, and sensory impairments associated with Parkinsonism.

157. 153. The method of claim 152, wherein the improvement in UPDRS is an improvement in motor testing.

158. 158. The method of claim 157, wherein the improvement in motor tests is for any of speech, facial expression, resting tremor, hand kinetic or postural tremor, rigidity, finger tapping, hand movements, rapid alternating hand movements, lower limb dexterity, chair rising, posture, gait, postural stability, bradykinesia, and decreased motor function.

159. The method of claim 152, wherein the improvement in UPDRS is an improvement in complications of treatment.

160. The method of claim 159, wherein the improvement in a therapeutic complication is with respect to any of the following: daily duration of dyskinesia, severity of dyskinetic disability, painful dyskinesia, and percentage of waking days that the patient is, on average, "off."

161. 161. The method of any one of claims 152 to 160, wherein the improvement is an improvement in score.

162. 162. The method of claim 161, wherein the improvement in score is at least 1 point, at least 2 points, at least 3 points, or at least 4 points.

163. 153. The method of claim 152, wherein the improvement in the UPDRS is a reduction in the stage of the modified Hoehn and Yahr staging session.

164. 164. The method of claim 163, wherein the reduction is a decrease in disease stage by at least one.

165. 153. The method of claim 152, wherein the improvement in the UPDRS is a percentage reduction in the Schwab and England ADL scale.

166. 166. The method of claim 165, wherein the reduction is between about 10% and about 100%.

167. 153. The method of claim 152, wherein the improvement in the UPDRS is a change in binary "yes" and "no" questions.

168. 150. The method of any one of claims 140-149, wherein the improvement occurs in less than about 75 days from initial administration of the pharmaceutical composition.

169. 150. The method of any one of claims 140-149, wherein the improvement occurs in less than about 35 days from initial administration of the pharmaceutical composition.

170. 150. The method of any one of claims 140-149, wherein the improvement lasts for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, at least 48 months, or at least 60 months.

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