Therapeutic combinations for dyskinesia

Abstract

Therapeutic combinations, pharmaceutical compositions and pharmaceutical kits comprising bioactive molecules from fungi, plants and algae are provided. In some embodiments, the fungi are from any fungi that produce nummulina velutipes, such as from Psilocybe spp. Fungi. In some embodiments, the plants are from one or both of the genus Cannabis and Diptyx. In some embodiments, the algae may be marine algae, for example, from the Bangicaeae family, including Pyropia and Porphyra genus. Also provided are methods of making the disclosed combinations, compositions, and kits, e.g., using natural, biosynthetic, or synthetic means. Further provided are methods of using the disclosed combinations, compositions and kits in therapy, particularly for dyskinesia, such as Parkinson's disease, and the disclosed combinations have proven to provide significant advantages in their therapy.

Description

[0001] Cross-references

[0002] Priority is claimed under PCT Section 8(1) and Rule 4.10 of U.S. Provisional Application No. 63 / 405,430, filed on September 10, 2022, and is incorporated herein by reference for all purposes as if fully set forth herein. Technical Field

[0003] Provided are therapeutic combinations of bioactive molecules from fungi, plants, and algae, pharmaceutical compositions and kits comprising such molecules, and methods of their use in medicine, particularly in the treatment of movement disorders, such as Parkinson's disease. Background Art

[0004] Nearly 40 million people in the United States suffer from movement disorders (Morishita, 2013). Most movement disorders are incurable, and treatments typically only attempt to relieve symptoms or slow their progression. Once function is lost, treatments typically fail to restore the patient's function and are insufficient to significantly slow the progression of most diseases. Current therapies can also be invasive, such as deep brain stimulation (DBS), which uses a surgically implanted device to send electrical pulses to the brain (Kringelbach et al., 2007). In addition, current therapies are unable to treat most non-motor symptoms of movement disorders, such as those involving thinking, memory, behavior, and mood. Therefore, there is an urgent need for new treatments that can reduce the severity of current symptoms, prevent the development of new symptoms, and widely reverse disease progression.

[0005] Provided herein are therapeutic combinations, pharmaceutical compositions and kits, and methods of using the same for treating movement disorders, that meet these needs and other needs, and possess such advantages and improvements over prior art treatment options, as will be readily appreciated. Summary of the Invention

[0006] The following is a simplified overview of some embodiments of the present invention to provide a basic understanding thereof. This overview is not an extensive overview and is not intended to identify every key or critical element of the present invention or to depict the full scope of the present invention. Its sole purpose is to present some exemplary embodiments in a simplified form as a prelude to the more detailed description below.

[0007] In some aspects, a therapeutic combination useful for preventing or treating movement disorders is disclosed, comprising: a fungal part; a first plant part; an optional second plant part; and an algae part. In some additional aspects, a therapeutic combination is disclosed, comprising: a fungal part; a first plant part; a second plant part; and an algae part.

[0008] In some embodiments, the fungal portion is from a psilocybin-producing species. In some embodiments, the psilocybin-producing species is from any one of the following genera: Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In some embodiments, the psilocybin-producing species is from the genus Psilocybe. In some embodiments, the psilocybin-producing species from the genus Psilocybe is any one 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 the genus Psilocybe; a first plant part; a second plant part; and an algal part.

[0009] In some embodiments, the first plant part is from a Cannabis species. In some embodiments, the Cannabis species is any one of Cannabis sativa, Cannabis indica, and 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.

[0010] In some embodiments, the second plant part is from a Dipteryx species. 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 Dipteryx species; 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 from a Dipteryx species; and an algal part.

[0011] In some embodiments, the algae portion is from a marine algae species. In some embodiments, the marine algae species is from the Bangiaceae family. In some embodiments, the marine algae species is from the genera Pyropia and Porphyra. In some embodiments, the marine algae species is any one of Pyropia yezoensis, Pyropia perforata, and Porphyra umbilicalis. In some embodiments, the therapeutic combination comprises: a fungal portion; a first plant part; a second plant part; and an algae portion from the genus Pyropia or Porphyra. In some embodiments, the therapeutic combination comprises: a fungal portion from a species of the genus Psilocybe; a first plant part from a species of the genus Cannabis; a second plant part from a species of the genus Dipteryx; and an algae portion from the genus Pyropia or Porphyra.

[0012] In some embodiments, the fungal portion comprises a fungal extract from the psilocybin-producing species. In some embodiments, the fungal extract is from P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, 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.

[0013] In some embodiments, the first plant part comprises a Cannabis plant extract from a species of the genus Cannabis. In some embodiments, the Cannabis plant extract is from Cannabis sativa, Cannabis indica, or Cannabis ruderalis. In some embodiments, the Cannabis plant extract is obtained by Soxhlet extraction.

[0014] 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 diafiltration of anhydrous ethanol.

[0015] In some embodiments, the algae portion comprises an algae extract from a marine algae species. In some embodiments, the algae extract is from Pyropia yezoensis, Pyropia perforata, or Porphyraumbilicalis. In some embodiments, the algae extract is obtained by ultrasonic extraction.

[0016] In some embodiments, the therapeutic combination comprises: a fungal extract from a species of the genus Psilocybe; a Cannabis plant extract from a species of the genus Cannabis; a Dipteryx plant extract from a species of the genus Dipteryx; and an algae extract from the genera Pyropia or Porphyra.

[0017] 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 percolation of anhydrous ethanol; and an algae extract obtained by ultrasonic extraction.

[0018] 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 coumarins; and algae extract containing Porphyra polysaccharides.

[0019] In some embodiments, the therapeutic combination comprises: a fungal portion comprising psilocybin and psilocin; a fungal portion comprising Δ 9 - a first plant part containing THC (THC) and cannabidiol (CBD); a second plant part containing coumarins; and an algae part containing porphyra polysaccharides.

[0020] In some embodiments, the fungal portion comprises a bioactive molecule from a fungus. In some embodiments, the bioactive molecule from a fungus is the primary bioactive molecule from a species that produces psilocybin. In some embodiments, the primary bioactive molecule from a species that produces psilocybin is one or more tryptamines or one or more β-carbolines. In some embodiments, the one or more tryptamines are any one of 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 weight ratio of psilocybin to psilocin is about 5:3. In some embodiments, the one or more β-carbolines are any one of harmane, harmine, harmol, pinoline, harmaline, cordysinin C, cordysinin D, norharmane, and perlolyrine. In some embodiments, the bioactive molecule from a fungus is a secondary bioactive molecule from a species that produces psilocybin. In some embodiments, the secondary bioactive molecule from a species that produces psilocybin is any one of a polysaccharide, a peptide, a terpene, a phenolic compound, a mineral, a vitamin, an amino acid, a lipid, choline, and a lactone.

[0021] In some embodiments, the first plant part comprises a bioactive molecule from Cannabis. In some embodiments, the bioactive molecule from Cannabis is the predominant bioactive molecule from the Cannabis species. In some embodiments, the predominant bioactive molecule from the Cannabis species is one or more cannabinoids. In some embodiments, the one or more cannabinoids are Δ 9 -THC-type cannabinoids, Δ 8 - any one 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-type cannabinoids. In some embodiments, the one or more cannabinoids are Δ 9-THC (THC) or cannabidiol (CBD). In some embodiments, the one or more cannabinoids are THC and CBD. In some embodiments, the weight ratio of THC to CBD is about 1:1. In some embodiments, the bioactive molecule from Cannabis is a secondary bioactive molecule from the Cannabis species. In some embodiments, the secondary bioactive molecule from the Cannabis species is any one of a flavonoid 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.

[0022] In some embodiments, the second plant part comprises a bioactive molecule from Dipteryx. In some embodiments, the bioactive molecule from Dipteryx is the major bioactive molecule from Dipteryx odorata. In some embodiments, the major bioactive molecule from Dipteryx odorata is a coumarin. In some embodiments, the bioactive molecule from Dipteryx is a minor bioactive molecule from Dipteryx odorata. In some embodiments, the minor bioactive molecule from Dipteryx odorata is any one of the following: cumaru, a coumarin derivative, an isoflavone, a lupeol derivative, a fatty acid ester, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxyretusin-8-methyl-ether, 5-methoxyanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, betulin, butin, coumaric acid-β-glucoside, dipteryxin, dipteryxic acid, eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyl linolenate, methyl oleate, O-coumaric acid, O-hydroxycoumaric acid, odoratin, P-hydroxy-benzoic acid, retusin, retusin-8-methyl-ether, sulfuretin, salicylic acid, afrormisin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone.

[0023] In some embodiments, the algae portion comprises a bioactive molecule from algae. In some embodiments, the bioactive molecule from algae is a major bioactive molecule from Pyropia or Porphyra. In some embodiments, the major bioactive molecule from Pyropia or Porphyra is any one of laver polysaccharides, laver oligosaccharides, polysaccharides, oligopolysaccharides, monosaccharides, peptides, phycobiliproteins, mycosporin-like amino acids, essential amino acids, non-essential amino acids, carotenes, intermediate carotenoids, glycoproteins, aminosulfonic acid, and taurine. In some embodiments, the major bioactive molecule from Pyropia or Porphyra is laver polysaccharide. In some embodiments, the bioactive molecule from algae is a minor bioactive molecule from Pyropia or Porphyra. In some embodiments, the minor bioactive molecule from Pyropia or Porphyra is any one of minerals, vitamins, lipids, phenolic compounds, and brown algae polyphenols.

[0024] In some embodiments, the therapeutic combination further comprises a flavoring or coloring agent. In some embodiments, the flavoring agent is ginger or laurel.

[0025] In some embodiments, the therapeutic combination further comprises an additional active agent. In some embodiments, the additional active agent is any one of levodopa, carbidopa, carbidopa-levodopa, entacapone, carbidopa-levodopa-entacapone, tolcapone, opicapone, pramipexole, pramipexole, ropinirole, apomorphine, rotigotine, selegiline, rasagiline, safinamide, amantadine, istradefylline, trihexyphenidyl, benztropine, prcyclidine, trihexyphenidyl, orphenadrine, and butanap.

[0026] In some embodiments, at least one of the fungal part, the first plant part, the second plant part, or the algae part further comprises a non-naturally occurring carrier, diluent, or excipient. In 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 algae part further comprise a non-naturally occurring carrier, diluent, or excipient.

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

[0028] In some embodiments, the therapeutic combination comprises: a major bioactive molecule from a species of the genus Psilocybe; a major bioactive molecule from a species of the genus Cannabis; a major bioactive molecule from a species of the genus Dipteryx; and a major bioactive molecule from a species of the genus Pyropia or Porphyra.

[0029] In some embodiments, the therapeutic combination comprises: one or more tryptamines from a species of the genus Psilocybe; one or more cannabinoids from a species of the genus Cannabis; coumarins; and Porphyra polysaccharides.

[0030] In some embodiments, the therapeutic combination comprises: psilocybin and psilocin; THC and CBD; coumarin; and porphyra polysaccharides.

[0031] 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 Porphyra polysaccharide.

[0032] In some embodiments, the therapeutic combination further comprises: a secondary bioactive molecule from a species of the genus Psilocybe; a secondary bioactive molecule from a species of the genus Cannabis; a secondary bioactive molecule from a species of the genus Dipteryx; and a secondary bioactive molecule from a species of the genus Pyropia or Porphyra.

[0033] In some embodiments, one of the biologically active molecules, two of the biologically active molecules, three of the biologically active molecules, four of the biologically active molecules, five of the biologically active molecules, six of the biologically active molecules, at least one of the biologically active molecules, at least two of the biologically active molecules, at least three of the biologically active molecules, at least four of the biologically active molecules, at least five of the biologically active molecules, at least six of the biologically active molecules, all of the biologically active molecules, six or fewer of the biologically active molecules, five or fewer of the biologically active molecules, four or fewer of the biologically active molecules, three or fewer of the biologically active molecules, two or fewer of the biologically active molecules, or none of the biologically active molecules is from or in an extract, is an isolated molecule, is a pure or substantially pure molecule, or is a synthetic molecule.

[0034] In some embodiments, a single dose comprises: 250 μg of psilocybin; 150 μg of psilocin; 1 mg of CBD; 1 mg of THC; 1 mg of coumarin; 8 mg of Pyropia extract; and optionally 8 mg of flavoring or coloring.

[0035] 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.

[0036] In some embodiments, the therapeutic combination further comprises a diluent. In some embodiments, the diluent is water.

[0037] In some embodiments of the therapeutic combination: the fungal portion constitutes about 45% by volume of the total combination; the first plant portion constitutes about 15% by volume of the total combination; the second plant portion constitutes about 2% by volume of the total combination; the algae portion constitutes about 15% by volume of the total combination; the flavoring or coloring agent constitutes about 15% by volume of the total combination; and the diluent constitutes the remainder of the total combination.

[0038] In some embodiments of the therapeutic combination: the fungal portion 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 percolation of anhydrous ethanol; the algae portion comprises an algae extract obtained by ultrasonic extraction; the flavoring or coloring agent comprises ethanol infused with ginger and bay leaves; and the diluent comprises water.

[0039] In some embodiments of the therapeutic combination: the fungal part 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 percolation using anhydrous ethanol; the algae part is an algae extract obtained by ultrasonic extraction; the flavoring or coloring agent is ethanol infused with ginger and bay leaves; and the diluent is water.

[0040] In some embodiments, the diluent comprises water and at least one non-naturally occurring diluent.

[0041] In some aspects, methods of preparing the disclosed therapeutic combinations are disclosed, comprising: obtaining the fungal extract by ultrasonic extraction and / or Soxhlet extraction; obtaining the Cannabis plant extract by Soxhlet extraction; obtaining the Dipteryx plant extract by diafiltration with anhydrous ethanol; obtaining the algae extract by ultrasonic extraction; analyzing the concentration of at least one bioactive molecule in each extract; calculating a mixing percentage to achieve a target dose of each of the at least one bioactive molecule in each extract; mixing an amount of each extract based on the calculated mixing percentage into the mixture; optionally, homogenizing the mixture; optionally, adding a flavoring or coloring agent; and optionally, adding a diluent to obtain a target volume.

[0042] In some embodiments, the target dose of each of the at least one bioactive molecule in each extract includes: 250 μg of psilocybin; 150 μg of psilocin; 1 mg of CBD; 1 mg of THC; and 1 mg of coumarin.

[0043] In some embodiments, the calculated amounts of each extract based on the blend percentages include: 45% by volume of the fungal extract; 15% by volume of the Cannabis plant extract; 2% by volume of the Dipteryx plant extract; 15% by volume of the algae extract; 15% by volume of the flavoring or coloring agent; and 8% by volume of the diluent.

[0044] In some aspects, disclosed are pharmaceutical compositions comprising 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.

[0045] In some embodiments, the pharmaceutical composition is suitable for enteral or parenteral administration. In some embodiments, the pharmaceutical composition is prepared as any of a tincture formulation, an oral spray formulation, an oromucosal spray formulation, a soft mist inhalation formulation, a vaporizer formulation, a tablet formulation, a scoreable double-strength tablet formulation, a capsule formulation, a capsule formulation with an additional active agent, a suspension formulation, an intravenous solution formulation, an injectable solution formulation, a topical formulation for transdermal administration, a cut-matrix sublingual or buccal tablet formulation, a separately formed sublingual or buccal tablet formulation, and an intranasal delivery formulation. In some embodiments, the pharmaceutical composition is prepared as any of a tincture formulation, an oral spray formulation, an oromucosal spray formulation, or a soft mist inhalation formulation.

[0046] In some embodiments, the pharmaceutical composition is a formulation comprising: 45% by volume of the fungal extract of the total combination; 15% by volume of the Cannabis plant extract of the total combination; 2% by volume of the Dipteryx plant extract of the total combination; 15% by volume of the algae extract of the total combination; 15% by volume of the flavoring or coloring agent of the total combination; and 8% by volume of the diluent of the total combination.

[0047] In some embodiments, a single dose comprises: 250 μg of psilocybin; 150 μg of psilocin; 1 mg of CBD; 1 mg of THC; 1 mg of coumarin; 8 mg of Pyropia extract; and optionally 8 mg of flavoring or coloring.

[0048] In some embodiments, a single dose of psilocybin is about 0.5 μg to about 200 mg, about 5 μg to about 5 mg, or about 100 μg to about 600 μg. In some embodiments, a single dose of psilocybin is 250 μg. In some embodiments, a single dose of psilocin is about 0.5 μg to about 200 mg, about 5 μg to about 5 mg, or about 100 μg to about 600 μg. In some embodiments, a single dose of psilocin is 150 μg.

[0049] In some embodiments, a 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. In some embodiments, a single dose of CBD is 1 mg. In some embodiments, a single dose of THC is from about 0.5 g to about 200 mg, from about 0.01 mg to about 75 mg, or from about 0.5 mg to about 15 mg. In some embodiments, a single dose of THC is 1 mg.

[0050] In some embodiments, a single dose of coumarin 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. In some embodiments, a single dose of coumarin is 1 mg.

[0051] In some embodiments, a single dose comprises a Pyropia yezoensis, Pyropia 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. In some embodiments, a single dose comprises a Pyropia whole extract in an amount of 8 mg.

[0052] In some embodiments, a single dose comprises ginger and bay leaf infused ethanol 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. In some embodiments, a single dose comprises ginger and bay leaf infused ethanol in an amount of 8 mg.

[0053] In some aspects, a pharmaceutical kit is disclosed comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein 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 the second pharmaceutical composition comprises the remainder of the therapeutic combination of claim 21 and a pharmaceutically acceptable carrier, diluent, or excipient.

[0054] In some embodiments, the first pharmaceutical composition is prepared as a tincture formulation, an oral spray formulation, an oromucosal spray formulation, or a soft mist inhalation formulation; and the second pharmaceutical composition is prepared as a tincture formulation, an oral spray formulation, an oromucosal spray formulation, or a soft mist inhalation formulation.

[0055] In some aspects, disclosed are methods of preventing or treating movement disorders comprising administering a disclosed therapeutic combination, a disclosed pharmaceutical composition, or a disclosed pharmaceutical kit to a patient in need thereof.

[0056] In some embodiments, the movement disorder is any one or more of ataxia, ataxic disorders, certain specific movement disorders, cervical dystonia, chorea, choreic disorders, dystonia, dystonia, essential tremor, Friedreich's ataxia, functional movement disorders, hemifacial spasm, hereditary spastic paraplegia, Huntington's disease, L-dopa-induced movement disorders, multiple system atrophy (MSA), myoclonus, myoclonic disorders, Parkinson's disease, atypical parkinsonism, parkinsonism, secondary parkinsonism, progressive supranuclear palsy (PSP), restless legs syndrome, Rett syndrome, sleep-related movement disorders, spasticity, tardive dyskinesia (TD), tic syndrome, tic disorders, tremor-related diseases, and Wilson's disease.

[0057] In some embodiments, the pharmaceutical composition is administered 1 to 8 times per day. In some embodiments, the patient experiences an improvement associated with a movement disorder. In some embodiments, the improvement is a decrease in the severity of at least one symptom of the movement disorder.

[0058] In some embodiments, the at least one symptom of the movement disorder is a motor symptom. In some embodiments, the motor symptoms are a hunched posture, masked facial expression, forward leaning of the trunk, bent elbows and wrists, reduced arm swing, bent hips and knees, trembling of the limbs, shuffling gait, short steps, uncoordinated or awkward balance, altered speech, involuntary limb movements, irregular movements, persistent contractions, intermittent contractions of the neck muscles, causing the head to turn in different ways; repetitive, irregular, involuntary movements involving the face, mouth, trunk, and limbs; twisting, repetitive movements; twitching, tremors, stiffness, finger tapping, toe tapping, poor posture, slow, reduced or unbalanced movements of muscles or muscle groups; difficulty walking, random involuntary eye movements, involuntary blinking, involuntary grimacing, unpleasantness, abnormal sensations in the limbs that can be relieved by movement; any of involuntary sounds and rhythmic shaking of parts of the body, usually the hands and / or head. In some embodiments, the motor symptoms are any of the following: problems speaking, excessive saliva production and drooling, problems chewing and swallowing, difficulty eating, difficulty dressing, maintaining proper hygiene, difficulty writing with hands, performing hobbies and other activities, rolling over, getting out of bed, riding in a car or deep chair; difficulty walking and maintaining balance, developing tremors, and freezing in place.

[0059] In some embodiments, at least one symptom of the movement disorder is a non-motor symptom. In some embodiments, the non-motor symptom is any one of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain and other sensations, urinary problems, constipation problems, dizziness on standing, and fatigue. In some embodiments, the non-motor symptom is a mood symptom. In some embodiments, the mood symptom is any one of depression, anxiety, irritability, mood swings, impaired judgment, loss of empathy, aggression, impulsivity, delusions, and paranoia.

[0060] In some embodiments, the reduction in severity of at least one symptom of movement disorder occurs in less than about 75 days from the first administration of the pharmaceutical composition. In some embodiments, the reduction in severity of at least one symptom of movement disorder occurs in less than about 35 days from the first administration of the pharmaceutical composition. In some embodiments, the reduction in severity of at least one symptom of movement disorder persists 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.

[0061] In some embodiments, the improvement is an improvement in motor control. In some embodiments, the improvement in motor control is an improvement in any one of balance, frequency of involuntary movements, amplitude of involuntary movements, strength, endurance, and physical ability. In some embodiments, the improvement in motor control occurs in less than about 75 days from the first administration of the pharmaceutical composition. In some embodiments, the improvement in motor control occurs in less than about 35 days from the first administration of the pharmaceutical composition.

[0062] In some embodiments, the improvement is an improvement in a clinical outcome assessment. In some embodiments, the clinical outcome assessment is any one of the following: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Movement Disorder Society Nonmotor Rating Scale (MDS-NMS), Corticobasal Ganglia Function Scale (SBFS), Gastrointestinal Dysfunction Rating Scale for Parkinson's Disease (GIDS-PD), Wilson's Disease Global Rating Scale (WD's GAS), Global Dystonia Severity Rating Scale (GDS), Modified Bradykinesia Rating Scale (MBRS), Nonmotor Symptom Questionnaire (NMSQ), Nonmotor Symptom Rating Scale for Parkinson's Disease (NMSS), Pantothenate Kinase-Associated Neurodegenerative Disease Rating Scale (PKAN-DRS), Progressive Supranuclear Palsy Clinician Deficit Scale (PSP-CDS), Essential Tremor Quality of Life The questionnaire included the following items: Psychogenic Movement Dysfunction Rating Scale, Rash Movement Dysfunction Rating Scale (RDRS), Rash Video-Based Tic Rating Scale (RVBTRS), SCOPA-AUT, SCOPA-DC, SCOPA-PC, SCOPA-PS, SCOPA-Sleep, SCOPA-S, SCOPA-COG, SPES / SCOPA-MOTOR, NoMoFA, UFMG Sydenham Chorea Rating Scale (USCRS), Unified Movement Disorder Rating Scale (UDysRS), Unified Dystonia Rating Scale (UDRS), Unified Multiple System Atrophy Rating Scale (UMSARS), and 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.

[0063] In some embodiments, the improvement in MDS-UPDRS is an improvement in nM-EDL. In some embodiments, the improvement in nM-EDL is any one of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain and other sensations, urinary problems, constipation problems, dizziness when standing up, and fatigue.

[0064] In some embodiments, the improvement in the MDS-UPDRS is an improvement in the M-EDL. In some embodiments, the improvement in the M-EDL is an improvement in any of speech, saliva and drooling, chewing and swallowing, feeding tasks, dressing, hygiene, handwriting, performing hobbies and other activities, turning over in bed, tremors, getting out of bed, car, or deep chair; walking and balance, and freezing.

[0065] In some embodiments, the improvement in the MDS-UPDRS is an improvement in a motor exam. In some embodiments, the improvement in the motor exam is an improvement in any one of speech, facial expression, stiffness, finger tapping, hand movement, pronation and supination of the hand, toe tapping, leg agility, caused by a chair, gait, freezing of gait, postural stability, posture, the overall spontaneity of movement (bradykinesia), postural tremor of the hand, kinetic tremor of the hand, rest tremor amplitude, constancy of rest tremor, Hoehn and Yahr stages, the time spent by dyskinesia, the functional impact of dyskinesia, the time spent in the off state, the functional impact of fluctuations, the complexity of movement fluctuations, and painful off-state dystonia.

[0066] In some embodiments, the improvement is a decrease in the score. In some embodiments, the score is decreased by at least 1 point, at least 2 points, at least 3 points, or at least 4 points.

[0067] In some embodiments, the improvement is an improvement in UPDRS.

[0068] In some embodiments, the improvement of UPDRS is an improvement in spirit, behavior and mood. In some embodiments, the improvement in spirit, behavior and mood is any one of intellectual disability, thought disorder, depression and motivation / initiative.

[0069] In some embodiments, the improvement in UPDRS is an improvement in ADL. In some embodiments, the improvement in ADL is any one of speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning over in bed and adjusting bedding, falls, shivering when walking, walking, tremor, and sensory complaints associated with Parkinson's disease.

[0070] In some embodiments, the improvement in UPDRS is an improvement in motor examination. In some embodiments, the improvement in motor examination is an improvement in any of speech, facial expression, tremor at rest, hand movements or postural tremor, rigidity, finger tapping, hand movements, rapid alternating movements of the hands, leg agility, chair, posture, gait, postural stability, and body bradykinesia and hypokinesia.

[0071] In some embodiments, the improvement in UPDRS is an improvement in a treatment complication. In some embodiments, the improvement in a treatment complication is any one of daily duration of dyskinesia, severity of dyskinesia disability, painful dyskinesia, and the proportion of waking days that the patient is averagely "off."

[0072] In some embodiments, the improvement is an improvement in score. In some embodiments, the score improves by at least 1 point, at least 2 points, at least 3 points, or at least 4 points. In some embodiments, the improvement in the UPDRS is a reduction in staging on a modified Hoehn and Yahr staging session. In some embodiments, the reduction is a reduction in at least 1 stage. In some embodiments, the improvement in the UPDRS is a reduction in the percentage of the Schwab and England ADL scale. In some embodiments, the reduction is a reduction of between about 10% and about 100%. In some embodiments, the improvement in the UPDRS is a change in a binary yes and no question.

[0073] 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 persists 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.

[0074] The foregoing has broadly outlined some relevant features of certain exemplary embodiments of the present disclosure so that the detailed description that follows may be better understood and the contribution to the art more fully appreciated. Additional features of the invention will be described hereinafter, which form the subject matter of the claims. It will be understood by those skilled in the art that the specific formulations and methods disclosed can be readily used as a basis for modifying or designing other formulations and methods for achieving the same purposes of the present disclosure. It will also be recognized that such equivalent formulations and methods do not depart from the spirit and scope of the invention as set forth in the claims. Therefore, this overview should be understood as being a brief and general overview of only some aspects and embodiments herein, provided solely for the benefit and convenience of the reader, and is not intended to limit in any way the scope of the claims legally authorized or the scope of equivalents. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] To further illustrate various aspects of the present invention, a more detailed description will be given with reference to certain exemplary embodiments shown in the accompanying drawings. It should be understood that these drawings depict only illustrative embodiments of the present invention and should not be considered as limiting the scope thereof. They are provided merely as illustrative illustrations of certain concepts of some embodiments of the present invention. Therefore, certain aspects of the present invention are further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying drawings, in which:

[0076] Figure 1 Certain observed recurring patterns of therapeutic activity and benefit in individuals utilizing the disclosed combinations are shown by way of summary and overview.

[0077] Figure 2 Shown is improvement in hand motion via software-assisted motion tracking.

[0078] Figure 3 In summary form, certain observed data for the treatment of Parkinson's disease before and after treatment with a composition referred to herein as ABS-108 and defined below, with respect to disease footprint, using the 8-item version of the Unified Parkinson's Disease Rating Scale (UPDRS-8) score (see, e.g., Hauser, Lyons, & Pahwa, 2012), in studies conducted according to some embodiments of the present invention are described.

[0079] Figure 4 Presented in summary form are certain observed data for the treatment of Parkinson's disease by the timing of the ABS-108 motor response relative to disease progression in studies conducted according to some embodiments of the present invention.

[0080] Figure 5Shown are estimated UPDRS-8 scores for each domain of non-motor, motor, and motor complications for patient A2 (described further below) as change from baseline, before and after ABS-108 treatment.

[0081] Figure 6 Shown is the estimated UPDRS-8 score for patient A3.

[0082] Figure 7 Shown is the estimated UPDRS-8 score for patient A4.

[0083] Figure 8 Shown is the estimated UPDRS-8 score for patient A5.

[0084] Figure 9 Shown is the estimated UPDRS-8 score for patient A6.

[0085] Figure 10 Shown is the estimated UPDRS-8 score for patient A9.

[0086] Figure 11 Shown is the estimated UPDRS-8 score for patient A10.

[0087] Figure 12 Shown is the estimated UPDRS-8 score for patient A11.

[0088] Figure 13 Shown is the estimated UPDRS-8 score for patient A12.

[0089] Figure 14 Shown is the estimated UPDRS-8 score for patient A13.

[0090] Figure 15 Shown is the estimated UPDRS-8 score for patient A14.

[0091] Figure 16 Shown is the estimated UPDRS-8 score for patient A16.

[0092] Figure 17 Shown is the estimated UPDRS-8 score for patient A17.

[0093] Figure 18 Shown is the estimated UPDRS-8 score for patient A18.

[0094] Figure 19 is a spider plot with UPDRS-8 scores for each of the eight items before and after treatment with ABS-108 for patient A2 according to the method of Example 16.

[0095] Figure 20is a spider plot with UPDRS-8 scores before and after treatment of patient A3.

[0096] Figure 21 is a spider plot with UPDRS-8 scores before and after treatment of patient A4.

[0097] Figure 22 is a spider plot with pre-treatment and post-treatment UPDRS-8 scores of patient A5.

[0098] Figure 23 is a spider plot with pre-treatment and post-treatment UPDRS-8 scores for patient A6.

[0099] Figure 24 is a spider plot with pre-treatment and post-treatment UPDRS-8 scores for patient A9.

[0100] Figure 25 is a spider plot of UPDRS-8 scores of patient A10 before and after treatment.

[0101] Figure 26 is a spider plot with UPDRS-8 scores of patient A11 before and after treatment.

[0102] Figure 27 is a spider plot with pre-treatment and post-treatment UPDRS-8 scores for patient A12.

[0103] Figure 28 is a spider plot with UPDRS-8 scores of patient A13 before and after treatment.

[0104] Figure 29 is a spider plot with UPDRS-8 scores of patient A14 before and after treatment.

[0105] Figure 30 is a spider plot with UPDRS-8 scores of patient A16 before and after treatment.

[0106] Figure 31 is a spider plot with pre-treatment and post-treatment UPDRS-8 scores for patient A17.

[0107] Figure 32 is a spider plot with pre-treatment and post-treatment UPDRS-8 scores for patient A18.

[0108] Figure 33 The production of exemplary formulations according to methods of certain described embodiments is shown.

[0109] Figure 34Exemplary analysis of formulations by liquid chromatography-mass spectrometry (LC-MS) testing is shown, including chromatograms showing various concentrations of bioactive molecules contained in formulations having the parameters disclosed in Table 6.

[0110] Figure 35 Exemplary NMR spectra of the disclosed compositions having the parameters described in Table 6 are shown.

[0111] Figure 36 An example analysis of a formulation tested via multiple reaction monitoring (MRM) LC-MS is shown, including a chromatogram showing the concentration of the bioactive molecule contained in the formulation having the parameters disclosed in Table 6.

[0112] Figure 37 Shown are the total antioxidant capacity of the Cannabis raw material as measured by the Folin-Ciocalteu assay, where the Gallic Acid Equivalents (GAE) of the Cannabis raw material calculated in milligrams (mg) is plotted per milliliter / liter (mL / L) of a given solution.

[0113] Figure 38 The total antioxidant capacity of Psilocybe raw material using the Folin-Ciocalteu assay is shown, where the calculated GAE of Psilocybe raw material in mg is plotted per mL / L of a given solution.

[0114] Figure 39 The total antioxidant capacity of Pyropia raw material using the Folin-Ciocalteu assay is shown, where the calculated GAE of Pyropia raw material in mg is plotted per mL / L of a given solution.

[0115] Figure 40 The total antioxidant capacity of tonka concentrate using the Folin-Ciocalteu assay is illustrated, where the calculated GAE of tonka concentrate in mg is plotted per mL / L of a given solution.

[0116] Figure 41 The total antioxidant capacity of Cannabis raw material (Ca raw material), Psilocybe raw material (Ps raw material), and a 2-component mixture of Cannabis / Psilocybe (Ca / Ps) obtained using (ie, by) the Folin-Ciocalteu assay is illustrated. Figure 41 The calculated GAE for Ca stock, Ps stock, and Ca / Ps are shown in mg / mL / L of solution used. Figure 41The table below the graphs shown depicts the statistical significance of the Ca raw material versus Ca / Ps versus the Ps raw material versus Ca / Ps, indicated by asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The 2-ingredient mixture of Cannabis and Psilocybe had a higher antioxidant capacity than each ingredient alone, and the data suggest an additive effect, where both ingredients contribute to the capacity of the 2-ingredient mixture.

[0117] Figure 42 The total antioxidant capacity of Cannabis raw material (Ca raw material), Pyropia raw material (Py raw material) and a 2-component mixture of Cannabis / Pyropia (Ca / Py) obtained by Folin-Ciocalteu assay is presented. Figure 42 The calculated GAE for Ca starting material, Py starting material, and Ca / Py are shown in mg / mL / L of solution used. Figure 1 Table below the chart shown. Figure 42 Statistical significance for the Ca raw material versus Ca / Py versus the Py raw material versus Ca / Py is depicted and indicated with asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The 2-ingredient mixture of Cannabis and Pyropia had a higher antioxidant capacity than each ingredient alone, and this data suggests a synergistic effect, as the antioxidant capacity of the 2-ingredient mixture was greater than expected by adding the numbers for the two ingredients together.

[0118] Figure 43 Shown are the total antioxidant capacities of cannabis raw material (Ca raw material), coumarin raw material (To raw material), and a 2-component mixture of cannabis / coumarin (Ca / To) obtained by Folin-Ciocalteu assay. Figure 43 The calculated GAE of Ca starting material, To starting material, and Ca / To are shown in mg / mL / L of solution used. Figure 43 The table below the graphs depicts the statistical significance of the Ca raw material versus the Ca / to raw material, indicated by asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The two-ingredient blend of cannabis and cannabi has similar antioxidant capacity as the cannabis component. Cannabi provides slightly enhanced antioxidant capacity despite its relatively low proportion in the blend.

[0119] Figure 44Shown are the total antioxidant capacity of Psilocybe raw material (Ps raw material), Pyropia raw material (Py raw material), and the two-component mixture of Psilocybe / Pyropia (Ps / Py), obtained by Folin-Ciocalteu assay. Figure 44 The calculated GAEs for Ps starting material, Py starting material, and Ps / Py are shown in mg / mL / L of solution used. Figure 44 The table below the graphs depicts the statistical significance of the Ps raw material versus the Ps / Py raw material versus the Py raw material, indicated by asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The two-component blend of Psilocybe and Pyropia had slightly lower antioxidant capacity than Psilocybe alone. This suggests that the compounds in the Pyropia raw material interact in a manner that reduces antioxidant capacity, i.e., reduces the ability to donate electrons to the chemical reactions in the assay.

[0120] Figure 45 Shown are the total antioxidant capacities of Psilocybe raw material (Ps raw material), coumarin raw material (To raw material), and the 2-component blend of Psilocybe / coumarin (Ps / To) obtained by Folin-Ciocalteu assay. Figure 45 The calculated GAE of Ps stock, To stock, and Ps / To are shown in mg / mL / L of solution used. Figure 45 The table below the graphs depicts the statistical significance of the Ps raw material versus the Ps / to versus the coumarin raw material, indicated by asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The two-ingredient blend of psilocybe and coumarin has lower antioxidant capacity than psilocybe alone. This suggests that compounds in coumarin interact with compounds in psilocybe in a manner that reduces antioxidant capacity, i.e., the ability to donate electrons to the chemical reactions in the assay.

[0121] Figure 46 Shown are the total antioxidant capacities of Pyropia raw material (Pyraw), coumarin raw material (Toraw) and a 2-ingredient blend of Pyropia / coumarin (Py / To) using the Folin-Ciocalteu assay. Figure 46 The calculated GAE of Py starting material, To starting material, and Py / To are shown in mg / mL / L of solution used. Figure 46The table below the graphs shown in Figure 1 depicts the statistical significance of the Py raw material versus Py / to versus the coumarin raw material versus Py / to, indicated by asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The two-ingredient mixture of Pyropia and coumarin had similar antioxidant capacity as Pyropia alone. No effect of coumarin alone was detectable within the dose range tested.

[0122] Figure 47 Shown is the total antioxidant capacity of a blend of Cannabis / Psilocybe / Pyropia / Coumarin (Ca / Ps / Py / To) compared to matched doses of Cannabis raw material (Ca stock), Psilocybe raw material (Ps stock), Pyropia raw material (Py stock), and Coumarin raw material (To stock) obtained by Folin-Ciocalteu assay. Figure 47 The calculated GAEs for Ca / Ps / Py / To, Ca feed, Ps feed, Py feed, and To feed are shown in mg / mL / L of solution used. Figure 47 The table below the graphs shown describes the statistical significance of Ca / Ps / Py / To to Ca raw material vs. Ca / Ps / Py / To to Ps raw material vs. Ca / Ps / Py / To to Py raw material vs. Ca / Ps / Py / To to To raw material and is indicated by asterisks (when P<0.10: (*), P<0.05: * and P<0.01: **).

[0123] Figure 48 Shown is the total antioxidant capacity of a blend of Cannabis / Psilocybe / Pyropia / Coumar (Ca / Ps / Py / To) compared to matched doses of each of the 2-ingredient blends including Cannabis / Psilocybe (Ca / Ps), Cannabis / Pyropia (Ca / Py), Cannabis / Coumar (Ca / To), Psilocybe / Pyropia (Ps / Py), Psilocybe / Coumar (Ps / To), and Pyropia / Coumar (Py / To), obtained by Folin-Ciocalteu assay. Figure 48 The calculated GAEs of Ca / Ps / Py / To, Ca / Ps, Ca / Py, Ca / To, Ps / Py, Ps / To, and Py / To are shown in mg / mL / L of solution used. Figure 48The table below the shown graphs depicts the statistical significance of Ca / Ps / Py / To to Ca / Ps, Ca / Ps / Py / To to Ca / Py, Ca / Ps / Py / To to Ca / To, Ca / Ps / Py / To to Ps / Py, Ca / Ps / Py / To to Ps / To, Ca / Ps / Py / To to Py / To and is indicated by asterisks (when P<0.10: (*), P<0.05: * and P<0.01: **).

[0124] Figure 49 Shown is the total antioxidant capacity of a 4-ingredient blend of Cannabis / Psilocybe / Pyropia / Coumarin (Ca / Ps / Py / To) obtained by Folin-Ciocalteu assay compared to Applicant's "4+" blend (i.e., Applicant's final products disclosed herein as ABS-108 and NIM-01, and the formulation as Example 1). Figure 49 The calculated GAEs for Ca / Ps / Py / To and 4+ blends are shown in mg / mL / L of solution used. Figure 49 Data are depicted as the mean ± standard deviation of replicate data points for each dose. Figure 49 The statistical significance of the Ca / Ps / Py / To blend relative to the 4+ blend is depicted and indicated with asterisks (when P < 0.10: (*), P < 0.05: *, and P < 0.01: **). The 4+ blend exhibited higher antioxidant capacity than the 4-ingredient blend of Cannabis / Psilocybe / Pyropia / Coumarin. This suggests that the additional ingredients in the 4+ blend contribute to the antioxidant properties of the final product. DETAILED DESCRIPTION

[0125] While the above summarizes various aspects and features of certain embodiments, the following detailed description further describes certain exemplary embodiments in detail to enable a person of ordinary skill in the art to which the invention pertains ("technicians") to practice the embodiments and to make and use the full scope of the claimed invention.

[0126] Those skilled in the art may make many modifications, substitutions, changes and variations to the examples, embodiments, applications and details of the invention shown herein without departing from the spirit of the invention or the scope of the invention as described in the appended claims, and the general principles defined herein may be applied to a wide range of aspects. Therefore, the present invention is not intended to be limited to the aspects presented, but rather to the widest scope consistent with the principles and features disclosed. The following description is designed to make these embodiments obvious to those skilled in the art, as these embodiments should be both easily recognized and easily created without undue experimentation using only the teachings herein and common sense in the art.

[0127] Aspects of the present invention are therapeutic combinations comprising bioactive molecules from fungi, plants, and / or algae. Other aspects of the present invention are pharmaceutical compositions comprising the therapeutic combinations. Other aspects are methods of using the therapeutic combinations and pharmaceutical compositions to treat movement disorders (e.g., Parkinson's disease).

[0128] A. General Definitions and Terminology

[0129] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an "excipient" includes reference to a combination of one or more excipients, and reference to a "biologically active molecule" includes reference to a combination of one or more biologically active molecules. Similarly, "biologically active molecule" includes reference to the biologically active molecule in another substance (e.g., an extract) unless the biologically active molecule indicates, either explicitly or by context, that it has been purified or isolated therefrom, and even then, includes the other substance as long as the biologically active molecule, for example, is within the indicated purity range.

[0130] The terms "comprising," "including," "such as," and "having" are intended to be inclusive and not exclusive (i.e., additional elements may be present in addition to the listed elements). Thus, as used herein, the term "comprising" means, and is used interchangeably with, the phrase "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, and the specific use of the term "and / or" does not imply that any use of "or" is merely disjunctive; rather, such use simply highlights the possibility that the term "and / or" may be conjunctive in particular embodiments, but otherwise disjunctive, like "or." The term "and" is to be understood as conjunctive.

[0131] Compositions that "consist of" a particular biologically active molecule may include only that biologically active molecule, and those that "consist essentially of" a particular biologically active molecule may include that biologically active molecule, optionally together 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" may be used, its absence (or its replacement by the singular) does not imply singularity; rather, such use simply emphasizes the possibility of multiple agents or components in a particular embodiment.

[0132] Where ranges are given herein, the present invention includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included but the other endpoint is excluded. It should be assumed that, unless otherwise stated, both endpoints are included. It should also be understood that, unless otherwise stated or apparent from the context and understanding of the skilled person, values ​​expressed as ranges may take any specific value or sub-range within the range in different embodiments, to one-tenth of the lower unit of the range, unless the context clearly specifies otherwise. It should also be understood that where a series of numerical values ​​is stated herein, the present invention includes embodiments that similarly relate to any intermediate value or range defined by any two values ​​in the series, and the lowest value may be taken as the minimum value, while the maximum value may be taken as the maximum value. As used herein, numerical values ​​include values ​​expressed as percentages. For any embodiment in which a numerical value begins with "about" or "approximately", the present invention includes embodiments in which the exact value is described. For any embodiment in which a numerical value is not preceded by "about" or "approximately", the present invention includes embodiments in which a numerical value is preceded by "about" or "approximately". Thus, unless otherwise indicated, all numbers expressing amounts of ingredients, properties such as concentrations, reaction conditions, and the like used to describe and claim certain embodiments of the present invention are to be understood as being modified in some instances by the term “about.” “Approximately” or “about” is intended to encompass numbers that fall within ±10% of the number, in some embodiments within ±5% of the number, in some embodiments (including in some preferred embodiments) within ±2% of the number, in some embodiments within ±1% of the number, in some embodiments within ±0.5% of the number, and in some embodiments within ±0.1% of the number, unless otherwise indicated or obvious from the context (unless such a number would impermissibly exceed 100% of the possible value).

[0133] In some embodiments, the numerical parameter of setting forth in the specification and claims is an approximate value, which can be changed (and as those skilled in the art will understand) according to the desired properties sought to be obtained by a particular embodiment. The term "substantially" will be read in the context of the present invention and according to the knowledge of the art when being used to modify the features or restrictions herein, to provide appropriate certainty, for example, by using a standard recognized in the art for measuring the meaning of "substantially" as a term of degree, or by determining the scope as those skilled in the art. In some embodiments, the numerical parameter should be interpreted according to the number of reported significant figures and by applying common rounding techniques. Although the numerical range and the parameters of the broad range of some embodiments of the present invention are approximate values, the numerical value set forth in the specific examples is reported as accurately as possible. The numerical value presented in the embodiments can include certain errors that are inevitably caused by the standard deviation found in their respective test measurements.

[0134] A comprehensive list of abbreviations used by ordinary organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry; the list is usually presented in a table entitled "List of Standard Abbreviations." The current list as of the date of this application is incorporated herein by reference as if fully set forth herein.

[0135] Unless otherwise expressly defined, all technical and scientific terms herein have the meanings commonly understood by those skilled in the art. The following are further definitions that may help the reader understand the disclosed and illustrative embodiments; however, it should be understood that such definitions are not intended to limit the scope of the present invention, which should be appropriately interpreted and understood in light of the language used in the claims, by reference to the entire specification (and any clear meanings known to those skilled in the art). The terms herein are used only for the purpose of describing specific embodiments and are not intended to be limiting.

[0136] Unless the context dictates otherwise, terms that have specific meanings within the regulatory laws of the jurisdictions to which this application is submitted or in which it may take effect shall generally be given such meanings. For example, "botanical drug substance" may refer to terms defined by FDA implementing rules and regulations, as well as terms as described in the Guidance for Industrial Botanical Drug Products (Docket No. FDA-2000-D-0103), U.S. Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research ("2016FDA Botanical Drug Guidance"), December 2016. Other such terms, including "botanical drug product" and "botanical raw material," should be similarly understood.

[0137] For the avoidance of doubt, even though "botanical" is often used to mean "relating to plants," for the purposes herein, "botanical," as in a "botanical" drug substance or drug product, will be understood to also include compounds, substances, and products (e.g., extracts) obtained or derived from, or present in, fungal material, such as psilocybin-containing or other fungi, such as those defined by the FDA. A "botanical" drug substance or drug product will also be understood to include compounds, substances, and products (e.g., extracts) obtained or derived from, or present in, algal material, where "algal material" broadly refers to any material from the diverse group of photosynthetic eukaryotic organisms known or understood in the art as "algae," and especially those portions that contain biologically active molecules of interest known to those skilled in the art.

[0138] Botanical drug substances and drug products, and compositions containing them, may be available by prescription or over-the-counter (“OTC”), or as nutritional or dietary supplements, or under any other regulatory regime; they may also be unregulated (e.g., “natural products”).

[0139] As used herein, the term "plant material" includes whole plants and parts thereof that contain the bioactive molecules being sought, such as aerial parts of the plant or isolated leaves, stems, flowers, fruits, roots, or any combination thereof. With respect to Cannabis plant material, it will be understood that the primary part used will be the inflorescences ("buds") of the flowering female plants, which generally contain the greatest concentration of bioactive molecules, such as terpenoids and cannabinoids. However, other plant parts will also be useful in the disclosed compositions and methods, as will be understood by those skilled in the art.

[0140] Where fungal material is used (e.g., in an extraction process), it can be from any part of the fungal fruiting body ("mushroom"), from fungal sclerotia ("truffles"), and from mycelium or other fungal material (e.g., bioreactor biomass), unless the context indicates otherwise, and any or all such parts, as well as combinations thereof, may be referred to as "fungal material."

[0141] Generally, the nomenclature used herein and the procedures performed are those known in the field relevant to one aspect of the invention, such as biology, chemistry, natural product extraction, botany, mycology, physiology, pharmacology and medicine, and are those that are well known and commonly used in such fields. Standard techniques and procedures will be those commonly performed according to conventional methods in the art.

[0142] It should be understood that the headings in this document are only used to expedite the reader's review thereof and should not be construed as limiting the present invention in any way.

[0143] B. Primary and Secondary Bioactive Molecules

[0144] In some aspects, provided therapeutic combinations can be used to prevent or treat movement disorders, such as Parkinson's disease (PD). In some embodiments, the therapeutic combination comprises a fungal part, a plant part, and an algae part. In some embodiments, the therapeutic combination comprises a fungal part, a first plant part, an optional second plant part, and an algae part. In embodiments, the therapeutic combination comprises a fungal part, a first plant part, a second plant part, and an algae part.

[0145] In some embodiments, the fungus, plant or algae part comprises an extract (i.e., a fungus, plant or algae extract, respectively). In embodiments, the therapeutic combination comprises a fungus extract, a plant part and an algae part. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, an optional second plant part and an algae part. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, a second plant part and an algae part. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, an optional second plant extract and an algae part. In some embodiments, the therapeutic combination comprises a fungus part, a first plant extract, a second plant extract and an algae part. In some embodiments, the therapeutic combination comprises a fungus part, a first plant part, an optional second plant part and an algae extract. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, a second plant part and an algae extract. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, an optional second plant extract and an algae part. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, an optional second plant extract and an algae part. In some embodiments, the therapeutic combination comprises a fungus extract, a first plant part, an optional second plant extract and an algae part. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant part, a second plant part, and an algae extract. In some embodiments, the therapeutic combination comprises a fungal extract, a plant extract, and an algae extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, an optional second plant extract, and an algae extract. In some embodiments, the therapeutic combination comprises a fungal extract, a first plant extract, a second plant extract, and an algae extract.

[0146] In some embodiments, the therapeutic combination comprises bioactive molecules from fungi, plants and / or algae. In some embodiments, the therapeutic combination comprises bioactive molecules from fungi and bioactive molecules from plants. In some embodiments, the therapeutic combination comprises bioactive molecules from plants and bioactive molecules from algae. In some embodiments, the therapeutic combination comprises bioactive molecules from fungi, bioactive molecules from plants and bioactive molecules from algae. In some embodiments, the therapeutic combination comprises bioactive molecules from fungi, bioactive molecules from plants, bioactive molecules from algae and bioactive molecules from fungi, plants and / or algae. In some embodiments, the therapeutic combination comprises bioactive molecules from fungi, first bioactive molecules from plants, secondary bioactive molecules from plants and bioactive molecules from algae.

[0147] 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 Dypterix odorata. In some embodiments, the disclosed therapeutic combination is a botanical formulation, such as that prepared in the Examples herein, comprising a whole extract of Psilocybe cubensis fungus, Cannabis sativa plant, Pyropia yesoensis algae, and Dypterix odorata bean. As will be further understood, the bioactive molecule can be provided in an extract, such as in the entire extract, in a fraction or subfraction thereof, or can be provided as an isolated compound, a substantially purified compound, or a purified compound, including compounds produced by biosynthesis or synthetic means, and combinations thereof.

[0148] In some embodiments, the bioactive molecule from a fungus is not a bioactive molecule from a plant or a bioactive molecule from algae (i.e., the bioactive molecule from a fungus is present only in fungi). In some embodiments, the bioactive molecule from a plant is not a bioactive molecule from a fungus or a bioactive molecule from algae (i.e., the bioactive molecule from a plant is present only in plants). In some embodiments, the bioactive molecule from an algae is not a bioactive molecule from any fungus or a bioactive molecule from any plant (i.e., the bioactive molecule from an algae is present only in algae).

[0149] In some embodiments, a bioactive molecule from a fungus is also a bioactive molecule from a plant, or a bioactive molecule from an algae (i.e., it is also present in either a plant or an algae, but not both). In some embodiments, a bioactive molecule from a plant is also a bioactive molecule from any fungus, or a bioactive molecule from an algae (i.e., it is also present in either a fungus or an algae, but not both). In some embodiments, a bioactive molecule from an algae is also a bioactive molecule from any fungus, or a bioactive molecule from a plant (i.e., it is also present in either a fungus or a plant, but not both).

[0150] In some embodiments, a bioactive molecule from a fungus is also a bioactive molecule from a plant, or a bioactive molecule from an algae (i.e., it is also present in a plant or algae). In some embodiments, a bioactive molecule from a plant is also a bioactive molecule from a fungus, or a bioactive molecule from an algae (i.e., it is also present in a fungus or algae). In some embodiments, a bioactive molecule from an algae is also a bioactive molecule from a fungus, or a bioactive molecule from a plant (i.e., it is also present in a fungus or a plant).

[0151] In some embodiments, a bioactive molecule from a fungus is also a bioactive molecule from a plant, as well as a bioactive molecule from algae (i.e., it is also present in plants and algae). In some embodiments, a bioactive molecule from a plant is also a bioactive molecule from a fungus, as well as a bioactive molecule from algae (i.e., it is also present in fungi and algae). In some embodiments, a bioactive molecule from an alga is also a bioactive molecule from a fungus, as well as a bioactive molecule from a plant (i.e., it is also present in fungi and plants).

[0152] The term "secondary" as in "secondary biological activity" is used herein to mean, and may be used interchangeably with, the term "second" or "additional," and is not intended to necessarily indicate any particular degree of priority when compared to the term "primary" as in "primary biological activity," and thus should not necessarily imply a lesser degree of importance or significance, such as in any particular composition, or for any particular disclosed use.

[0153] a. Fungi

[0154] Fungi are organisms that are distinct from plants, do not contain chlorophyll, and are saprophytic (they feed on dead plant and animal material), parasitic (they feed on living hosts), or symbiotic (they share a mutually beneficial relationship with another organism). Fungi reproduce sexually and asexually by means of spores that develop in various ways. Exemplary fungi include the classes Phycomycetes, Ascomycetes, and Basidiomycetes. Fungi can include substances commonly referred to as yeasts, rusts, stains, mildews, molds, and mushrooms. As used herein, "fungi" should be understood to include both filamentous and non-filamentous fungal species, and the term should be understood to include all forms of the word, including "fungal" and "fungi."

[0155] In some exemplary embodiments, the fungus is a psilocybin-producing fungus. A "psilocybin-producing" fungus (or a psilocybin-producing fungus) is any fungus that produces or is capable of producing psilocybin. More than 100 species in the genus Psilocybe of fungi produce psilocybin. Species that produce psilocybin can also be found in many other genera, including Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, and Pluteus. In some embodiments, the psilocybin-producing species is from any of these genera. In embodiments, the psilocybin-producing species is from any of the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In embodiments, it is from Psilocybe. Different species of psilocybin mushrooms and their different strains will be readily known or identifiable to those skilled in the art.

[0156] In the case of a chemical strain, Psilocybe spp Specifications of the following species: P. acutipilea, P. allenii, P. alutacea, P. angulospora, P. antioquiensis, P. araucariicola, P. atlantis, and P. aquamarin a、P.armandii(Mexicana)、P.aucklandiae、P.aztecorum、P.azurescens、P.baeocystis、P.banderillensis、P.bispora、P.brasiliensis、P .brownneocystidiata、P.caeruleoannulata、P.caerulescens、P.caerulipes、P.callosa、P.carbonaria、P.caribaea、P.chuxiongensis、P .collybioides、P.columbiana、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. furtadoana, P. galindoi, P. gallaeciae, P. graveolens, P. guatapensi s, P. heimii, P. herrerae, P. hispanica, P. hoogshagenii, P. inconspicua, P. indica, P. isabelae, P. jacobsii, P. jaliscana, P. kumaenorum P. laurae , P. lazoi , P. liniformans , P. mexicana , P. mairei , P. makarorae , P. mammillata , P. medullosa , P. meridensis , P. meridionalis , P. meridionalis .mescaleroensis、P.moseri、P.muliercula、P.naematoliformis、P.natalensis、P.natarajanii、P.neorhombispora、P.neoxalapensis、P.ovoideocystidiata, P.papuana, P.paulensis, P.pelliculosa, P.pintonii, P.pleurocystidiosa, P.plutonia, P.portoricensis, P.pseudoaztecorum, P.puberula, P.quebecensis, P.rickii, P.rostrate, P.rzedowskii, P.samuiensis, P.schultesii, P.semilanceata, P.septentrionalis, P.serbica, P.sierrae, P.sylvatica, P.singer, P.strictipes, P.stuntzii, P.subacutipilea, P.subaeruginasc ens, P. subaeruginosa, P. subcaerulipes, P. subcubensis, P. subpsilocybioides, P. subtropicalis, P. tampanensis, P. thaicordispora, P. thaiaerugineomaculans, P. thaiduplicatocystidiata, P. uruguayensis, P. uxpanapensis, P. venenata, P. villarrealiae, P. weilii, P. weldenii, P. wera roa, P. wrightii, P. yungensis, P. zapotecoantillarum, P. zapotecocaribaea or P. zapotecorum species, including strains thereof.

[0157] In some embodiments, the psilocybin-producing fungus is not a Psilocybe spp. Other psilocybin-producing fungi that are not of the genus Psilocybe will be readily known to those skilled in the art. Non-limiting examples include: Conocybe siligineoides, Conocybe velutipes, Copelandia tropica, Inocybeaeruginascens, Inocybe caerulata, Inocybe coelestium, Inocybe corydalina, Inocybehaemacta, Inocybe tricolor, Galerina steglichii, Gymnopilus aeruginosus, Gymnopilus braendlei, Gymnopilus cyanopalmicola, Gymnopilus dilepis, Gymnopilusdunensis, Gymnopilus intermedius, Gymnopilus lateritius, Gymnopilus luteofolius, Gymnopilus luteoviridis, Gymnopilus luteus, Gymnopilus palmicola, Gymnopiluspurpuratus, Gymnopilus subpurpuratus, Gymnopilus subspectabilis, Gymnopilusvalidipes, Gymnopilus viridans, Panaeolus venezolanus, Panaeolus tropicalis, Panaeolus tirunelveliensis, Panaeolus rubricaulis, Panaeolus olivaceus, Panaeolus moellerianus, Panaeolus microsporus, Panaeolus lentisporus,Panaeolusfimicola,Panaeolus cyanescens,Panaeolus cinctulus,Panaeolus chlorocystis,Panaeolus cambodginiensis,Panaeolus bisporus,Panaeolus axfordii,Panaeolusafricanus,Panaeolus affinis,Pholiotinacyanopus, Pholiotina smithii, Pluteusalbostipitatus, Pluteus americanus, Pluteus cyanopus, Pluteus glaucus, Pluteusglaucotinctus, Pluteus nigroviridis, Pluteus phaeocyanopus, Pluteus salicinus, Pluteus saupei, Pluteus velutinornatus and Pluteus villosus.

[0158] In some aspects, the disclosed combinations, compositions, and methods comprising a fungal part, a fungal extract, or a bioactive molecule from a fungus affect CNS signaling capacity. In some embodiments, the disclosed combinations, compositions, and methods comprising a fungal part, a fungal extract, or a bioactive molecule from a fungus (e.g., psilocybin and / or psilocin) increase extracellular dopamine and serotonin in animals or rodents. In some embodiments, the disclosed combinations, compositions, and methods comprising a fungal part, a fungal extract, or a bioactive molecule from a fungus (e.g., psilocybin and / or psilocin) increase synaptic density, as measured by, for example, synaptic vesicle glycoprotein 2A (SV2A), for example 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 bioactive molecules from fungi (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 (e.g., Ly et al., 2018).

[0159] In some aspects, disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or bioactive molecules from fungi, regulate pro-inflammatory cycles. In some embodiments, disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or bioactive molecules from fungi (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 inhibit the concentration of LPS-induced pro-inflammatory cytokines (e.g., TNF-α, IL-1β) in a dose-dependent manner. In some embodiments, disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or bioactive molecules from fungi (e.g., psilocybin and / or psilocin), reduce the concentration of IL-6 and / or COX-2, and in some embodiments do not reduce the concentration of anti-inflammatory IL-10, for example, as described in Nkadmeng, Steinmann, and Eloff, 2021. In some embodiments, the disclosed combinations, compositions, and methods comprising fungi, fungal parts, fungal extracts, or bioactive molecules from fungi (e.g., psilocybin and / or psilocin) show reductions in TNF-α, IL-1β, and ROS, e.g., as described in Nkadmeng, Steinmann, & Eloff, 2020.

[0160] ii. Primary and secondary bioactive molecules from fungi

[0161] In some embodiments, the therapeutic combination comprises a fungal part. In some embodiments, the fungal part comprises a fungal extract. In some embodiments, the fungal part comprises a bioactive molecule from a fungus. In some embodiments, the fungal extract comprises a bioactive molecule from a fungus. For example, in embodiments, the fungal part comprises a primary bioactive molecule and / or a secondary bioactive molecule from a fungus. In embodiments, the fungal extract comprises a primary bioactive molecule and / or a secondary bioactive molecule from a fungus. Thus, in embodiments, the disclosed therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule from a fungus.

[0162] In some embodiments (equivalently, and simply as shorthand herein, "in embodiments"), the fungal portion is from a psilocybin-producing fungus. The fungus can be any psilocybin-producing fungus known or identified by one skilled in the art, including, as non-limiting examples, certain species from the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe. Various species of psilocybin-producing fungi and various strains thereof are described herein and are readily known or readily identified by one skilled in the art.

[0163] In embodiments where a fungal portion is described as being "from" a fungus, it is understood that the fungal portion comprises material derived from a fungus, including, as non-limiting examples, fungal material such as raw (i.e., unprocessed) fungal biomass, a fungal extract (e.g., an extract described herein, e.g., an aqueous and / or ethanolic extract), or a molecule naturally occurring in a fungus (e.g., a major or minor bioactive molecule described in the embodiments herein), whether or not the molecule is actually obtained by isolating the molecule from the fungus or by another means (e.g., by chemical synthesis).

[0164] In some embodiments, the fungal portion of the therapeutic combination is from a species that produces psilocybin. In some embodiments, the fungal portion of the therapeutic combination is from a species of the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a fungal extract from a species that produces psilocybin. In some embodiments, the fungal portion comprises a fungal extract from a species of the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a bioactive molecule from a species that produces psilocybin. In some embodiments, the fungal portion comprises a bioactive molecule from a species of the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a species of the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In some embodiments, the fungal portion comprises a fungal extract from a species of the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe. In embodiments, the fungal portion comprises a bioactive molecule from a species of the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe.

[0165] In some embodiments, the fungus is a Psilocybe spp. fungus. In some embodiments, the fungal portion is from a Psilocybe spp. fungus. In some embodiments, the fungal portion is from a species of P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and / or P. liniformans. In some embodiments, the fungal portion comprises a fungal extract from a Psilocybe spp. fungus. In some embodiments, the fungal portion comprises a fungal extract from the following species: P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and / or P. liniformans. In some embodiments, the fungal portion comprises a fungal extract from a Psilocybe spp. fungus. In embodiments, the fungal portion comprises a bioactive molecule from the following species: P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and / or P. liniformans.

[0166] In embodiments, the fungal portion comprises any one of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aeruginascin. In embodiments, the fungal portion comprises a fungal extract comprising any one of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aeruginascin. In embodiments, the fungal portion comprises a major bioactive molecule from a fungus selected from the group consisting of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aeruginascin. 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 norpsilocin. In embodiments, the fungal portion comprises aeruginascin. 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 norpsilocin. In embodiments, the fungal portion comprises a fungal extract comprising aeruginascin. In embodiments, the fungal portion comprises the primary bioactive molecule from a fungus, wherein the molecule is psilocin. In embodiments, the fungal portion comprises the primary bioactive molecule from a fungus, wherein the molecule is psilocin. In embodiments, the fungal portion comprises the primary bioactive molecule from a fungus, wherein the molecule is baeocystin. In embodiments, the fungal portion comprises the primary bioactive molecule from a fungus, wherein the molecule is norbaeocystin. In embodiments, the fungal portion comprises the primary bioactive molecule from a fungus, wherein the molecule is norpsilocin. In embodiments, the fungal portion comprises the primary bioactive molecule from a fungus, wherein the molecule is aeruginascin.

[0167] In some embodiments, the fungal portion comprises both psilocybin and psilocin. In some embodiments, the fungal portion comprises a fungal extract comprising both psilocybin and psilocin. In some embodiments, the fungal portion comprises both psilocybin and psilocin as the primary bioactive molecules from the fungus. In some embodiments, the fungal portion comprises both psilocybin and psilocin in a w / w or molar ratio of 100:1 to 1:100, 50:1 to 1:50, 10:1 to 1:10, 5:1 to 1:5, 2:1 to 1:2, 202 3-09-11, 5:3 to 3:5, or 3:2 to 2:3, all ranges inclusive. In some embodiments, the fungal portion comprises both psilocybin and psilocin in a w / w 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 comprises both psilocybin and psilocin in a w / w 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 comprises both psilocybin and psilocin in a w / w 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 comprising both psilocybin and psilocin, including any of the aforementioned w / w or molar ratios. In some embodiments, the fungal portion comprises both psilocybin and psilocin as the primary bioactive molecules from the fungus, including any of the aforementioned w / w or molar ratios.

[0168] In some embodiments, the ratio of psilocybin to psilocin is about 5:3, about 3:2, or about 1: 1. In embodiments, the ratio of psilocybin to psilocin is about 5:3 or a ratio of 5:3.

[0169] In some embodiments, the fungal portion comprises a β-carboline (β-carboline). In some embodiments, the fungal portion comprises a fungal extract comprising a β-carboline. In some embodiments, the fungal portion comprises a major bioactive molecule from a fungus, wherein the major bioactive molecule is a β-carboline. In embodiments, the β-carboline is hamane, hamaneamine, hamanephenol, hamaneol, hamanebase, tetrahydrohamaneamine, pinophane, cordycepin C, cordycepin D, norhamane, perlolyrine, β-carboline (9H-pyrido[3,4-b]indole), or another L-tryptophan-derived β-carboline. Although "β-carboline" can thus refer to both individual compounds and classes of related compounds, unless the context requires otherwise, the use of the term herein should be understood to refer to the class of compounds (including but not limited to when listed as "β-carboline")

[0170] In embodiments, the secondary bioactive molecule from the fungus is a polysaccharide (including α- and β-glucans and polysaccharide-protein complexes), a peptide (including proteins such as lectins), a terpene or terpenoid (including monoterpene and sesquiterpene oils, diterpenes, triterpenoids and sterols, and carotenoid pigments), a phenolic compound (including phenolic acids, hydroxycinnamic acids, hydroxybenzoic acids, ligands, tannins, flavonoids, stilbenes, and oxidized polyphenols), a mineral (including potassium, phosphorus, sodium, calcium, magnesium, copper, selenium, iron, and zinc), a vitamin (including ascorbic acid, vitamin D, riboflavin, folic acid, thiamine, pantothenic acid, and niacin), an amino acid (including essential amino acids, and including histidine, isoleucine, leucine, lysine, methionine, phenylalanine, taurine, threonine, tryptophan, and valine), a lipid (including saturated, monounsaturated, and polyunsaturated fatty acids, such as oleic acid, linoleic acid, and linolenic acid), choline, or a lactone.

[0171] In an embodiment, the bioactive molecule from a fungus is any one of: Venturella, 2021; Anusiya et al., 2021; Thu et al., 2020; Muszynska, 2018; and Mishraki-Berkowitz et al., 2020.

[0172] b. Plants

[0173] 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 bioactive molecule from a plant. In some embodiments, a fungal extract comprises a bioactive molecule from a plant. For example, in embodiments, the plant part comprises a primary bioactive molecule and / or a secondary bioactive molecule from a plant. In embodiments, the plant extract comprises a primary bioactive molecule and / or a secondary bioactive molecule from a plant. Thus, in some embodiments, the disclosed therapeutic combination comprises a primary bioactive molecule and / or a secondary bioactive molecule from a plant.

[0174] In embodiments where a plant part is described as being "from" a plant, it is understood that the plant part includes material derived from the plant, including, 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 molecules naturally occurring in the plant (e.g., a major or minor bioactive molecule described in the embodiments herein), whether or not the molecule is actually obtained by isolating the molecule from the plant or by other means (e.g., by chemical synthesis).

[0175] Plants are photosynthetic eukaryotic organisms of the kingdom Plantae. In some embodiments, the therapeutic combination comprises a plant extract. In some embodiments, the therapeutic combination comprises a major bioactive molecule and / or a minor bioactive molecule 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 major bioactive molecule and / or a minor bioactive molecule from a plant of the genus Cannabis and / or Dipteryx. In some embodiments, the therapeutic combination comprises a major bioactive molecule and / or a minor bioactive molecule from a plant of the genus Cannabis.

[0176] ii. Cannabis

[0177] Cannabis is a genus of flowering plants in the family Cannabaceae. There is controversy over the number of species in the genus, and three separate species are recognized: Cannabis sativa, Cannabis indica, and Cannabis ruderalis; some include C. ruderalis within C. sativa; some include C. sativa, C. indica, and C. ruderalis as subspecies of a single species, C. sativa; and some consider C. sativa L to be a single, undivided species. As used herein, "cannabis" is meant to include all such encompassed species, subspecies, cultivars, varieties, variants, strains, chemovarions, etc., of the genus Cannabis, independent of any such term. For simplicity of abbreviating herein, and without regard to the aforementioned controversial position, the term "Cannabis" will refer to C. sativa, C. indica, and C. ruderalis, and will further include any genetic crosses, self-pollinations, and hybrids thereof.

[0178] In some embodiments, the plant part of the therapeutic combination is derived from Cannabis. In embodiments where the plant part is described as "derived from" Cannabis, it is understood that the plant part comprises substances derived from Cannabis, including, as non-limiting examples, Cannabis materials such as raw (i.e., unprocessed) Cannabis biomass, Cannabis extracts (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or molecules naturally occurring in Cannabis (e.g., the major or minor bioactive molecules described in the embodiments herein), whether or not the molecules were actually obtained by isolating the molecules from Cannabis or in another manner (e.g., by chemical synthesis).

[0179] In some embodiments, the therapeutic combination comprises a Cannabis extract. In some embodiments, the therapeutic combination comprises a major bioactive molecule from Cannabis. In some embodiments, the combination comprises a minor bioactive molecule from Cannabis.

[0180] a. Primary and secondary bioactive molecules from Cannabis

[0181] In some embodiments, the therapeutic combination comprises a primary and / or secondary bioactive molecule from Cannabis.

[0182] ii. Major bioactive molecules from Cannabis

[0183] In some embodiments, the primary bioactive molecules from Cannabis are cannabinoids. Cannabinoids are a different class of small molecules because they are able to act on cannabinoid receptors. Cannabinoid receptors are found in the brain and throughout the central and peripheral nervous systems of humans and other mammals. There are two main types of cannabinoid receptors, called 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. Signaling mediated by CB1 receptors plays a key role in the neural circuits that mediate mood, motivation, and emotional behavior. CB2 receptors are primarily found in the immune system and hematopoietic stem and progenitor cells, and can also be found in neurons.

[0184] Cannabinoids have been shown to increase the activity and expression of tyrosine hydroxylase (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 proposed that CB1 receptor activation inhibits GABAergic neurotransmission in the VTA through a presynaptic mechanism. Inhibition of GABAergic inhibition of dopaminergic neurons would increase their firing rate in vivo, leading to an increase in dopamine in the NAc. Furthermore, cannabinoids modulate the release and uptake of various neurotransmitters, including acetylcholine, glutamate, norepinephrine, and GABA, through N- and P / Q-type calcium currents and potassium A currents (Gifford et al., 2000).

[0185] Cannabinoids have also been shown to modulate pro-inflammatory cycles. In LPS-stimulated neuroinflammatory assays, THC and CBD reduced IL-1β and IL-6, while CBD inhibited IL-1β secretion and suppressed NF-κB signaling (Kozela et al., 2010; Dos-Santos Pereira et al., 2020). CBD was found to increase NRF2 expression, leading to a decrease in ROS, which in turn may partially inhibit NLRP3 inflammasome activation by reducing NF-κB levels ( and Skrzydlewska, 2019). In one study, CBD increased the expression of NRF2 while actively inhibiting NF-kB through the promoters p65 and p52 ( and Skrzydlewska, 2019). CBD also activates the PPAR-y network and directly inhibits NF-kB transduction via CB1 and CB2 receptors (Nichols and Kaplan, 2020).

[0186] Cannabinoids will be known to those skilled in the art, and some are also described and illustrated by Radwan et al. in Cannabinoids, Phenolics, Terpenes and Alkaloids of Cannabis, Molecules, 26(9), 2774 (2021), which is incorporated herein by reference as if fully set forth herein. Without being limited by theory, cannabinoids classified according to Radwan 2021 include compounds having a characteristic C21 terpene phenol skeleton, which are part of one of 11 cannabinoid subclasses, namely: cannabichromene (CBC) type, cannabidiol (CBD) type, cannabinoid (CBE) type, cannabigerol (CBG) type, cannabicyclol (CBL) type, cannabinol (CBN) type, cannabidiol (CBND) type, cannabitriol (CBT) type, (-)-Δ 8 -trans-tetrahydrocannabinol (Δ 8 -THC) type, (-)-Δ 9 -trans-tetrahydrocannabinol (Δ 9 -THC)-type and mixed-type cannabinoids. Non-limiting examples of such cannabinoids are known by reference to Radwan 2021 and the disclosures below, all of which will be understood to be useful in the practice of the present invention. In embodiments, the primary bioactive molecule from Cannabis is any such cannabinoid.

[0187] In embodiments, the primary bioactive molecule from Cannabis is 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, CBN-type cannabinoids, CBC-type cannabinoids, CBT-type cannabinoids or mixed cannabinoids.

[0188] 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-phenyl (-) -Δ9-trans-tetrahydrocannabinol ester, α-phenyl (-) -Δ9-trans-tetrahydrocannabinol ester, epibornyl (-) -Δ9-trans-tetrahydrocannabinol ester, bornyl (-) -Δ9-trans-tetrahydrocannabinol ester, α-terpenyl (-) -Δ9-trans-tetrahydrocannabinol ester, γ-cineole (-) -Δ9-trans-tetrahydrocannabinol ester, 8α-hydroxy-(-)-Δ9-trans-tetrahydrocannabinol, 8β-hydroxy-(-)-Δ9-trans-tetrahydrocannabinol, 11-acetoxy-(-)-Δ9-trans-tetrahydrocannabinol A, 8-oxo-(-)-Δ9-trans-tetrahydrocannabinol, cannabinol, (-)-Δ9-trans-tetrahydrocannabinol and (-)-Δ9-trans-tetrahydrocannabinol.

[0189] Δ 8 Examples of THC-type cannabinoids include Δ 8 -THC, Δ 8 -THCA, 10α-OH-Δ 8 -THC, 10β-OH-Δ 8 -THC and 10a-α-hydroxy-10-oxo-Δ8-THC.

[0190] In an embodiment, CBG-type cannabinoids include (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-epoxycannabigerolic acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epxoycannabigerol, camagerol, and sesquicannabigerol.

[0191] 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, CBeA-C5, CBEAB-C5, CBE-C3, and CBEAB-C3. Examples of CBL-type cannabinoids include CBL, CBLA, and CBLV. 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, CBNA-C5, CBN-C4, CBN-C3, CBN-C2, CBN-C1, CBNM-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-homologs, (-)-trans-CBT-OEt-C5, (-)-trans-CBT-OEt-C3, 8,9-di-OH-CBT-C5, CBDA-C5, and 9-OH-CBT-C5 ester.

[0192] Examples of mixed-type cannabinoids include DCBF-C5, CBF-C5, OH-iso-HHCV-C3OTHC, cannabicitran, 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)-cannabicoumarononic acid, 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-hexylhydroxy-hydrocannabinol, 7-oxo-9α-hexylhydroxy-hydrocannabinol, 10α-hexylhydroxy-hydrocannabinol, 10αR-hydroxyhexahydrocannabinol and 9α-hydroxy-10-oxo-Δ 6a,10a -THC.

[0193] In embodiments, the primary bioactive molecule from Cannabis 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-fenyl (-) -Δ9-trans-tetrahydrocannabinol ester, α-fenyl (-) -Δ9-trans-tetrahydrocannabinol ester, epibornyl (-) -Δ9-trans-tetrahydrocannabinol ester, bornyl (-) -Δ9-trans-tetrahydrocannabinol ester, α-terpenyl (-) -Δ9-trans-tetrahydrocannabinol ester, 4-terpenyl (-) -Δ9-trans-tetrahydrocannabinol ester, α-terpenyl (-) -Δ9-trans-tetrahydrocannabinol ester, γ-cineole (-) -Δ 9-trans-tetrahydrocannabinol ester, 8α-hydroxy-(-)-Δ9-trans-tetrahydrocannabinol, 8β-hydroxy-(-)-Δ9-trans-tetrahydrocannabinol, 11-acetoxy-(-)-Δ9-trans-tetrahydrocannabinolic acid A, 8-oxo-(-)-Δ9-trans-tetrahydrocannabinol, cannabisol, (-)-Δ9-trans-tetrahydrocannabinol, (-)-Δ9-trans-tetrahydrocannabihexol, Δ 8 -THC, Δ 8 -THCA, 10α-OH-Δ 8 -THC, 10β-OH-Δ 8-THC, 10a-α-hydroxy-10-oxo-Δ8-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 acid, (±)-6,7-cis-epoxycannabigerol, (±)-6,7-trans-epxoycannabigerol, 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-Δ4″-cannabichromene, (–)- 7-Hydroxy-cannabichromane, 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, and 9-OH-CBT-C5 esters, DCBF-C5, CBF-C5, OH-iso-HHCV-C3 OTHC, cannabicitran, 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)-cannabicoumarononic acid, 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-hydroxyhexa-hydrocannabinol or 9α-hydroxy-10-oxo-Δ 6a,10a -THC. In embodiments, "cannabinoid" includes any of the cannabinoid carboxylic acids and carboxylate salts thereof (see US Pat. No. 9,376,367).

[0194] Each cannabinoid is also understood to include its isomers, such as structural isomers 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, in embodiments, "THC" will be understood to include THC-A and THC-B. References to cannabinoids will include various alkyl chain lengths associated therewith, such as C nAs shown in Figure 2, 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 will also include all possible isomers, such as, but not limited to, its -A and -B isomers, as well as all possible combinations of alkyl chain lengths, including chains composed of 1, 2, 3, 4, 5, 6, or 7 carbon atoms. Thus, herein, reference to "THC" will include THC-C1A, THC-C1B, THC-C2A, THC-C2B, THC-C3A, THC-C3B, THC-C4A, THC-C4B, THC-C5A, THC-C5B, THC-C6A, THC-C6B, THC-C7A, and THC-C7B, and as will be apparent to one skilled in the art, 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, cannabinoids 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, cannabinoids include "synthetic cannabinoids."

[0195] In some embodiments, the plant part comprises both THC and CBD. In some embodiments, the plant part comprises a plant extract containing both THC and CBD. In some embodiments, the plant part comprises both THC and CBD as the main bioactive molecules from plants (e.g., Cannabis). In some embodiments, the plant part comprises both THC and CBD in a w / w or molar ratio of 100: 1 to 1: 100, 50: 1 to 1: 50, 10: 1 to 1: 10, 5: 1 to 1: 5, 2: 1 to 1: 2, 5: 3 to 3: 5, or 3: 2 to 2: 3, with all ranges included. In some embodiments, the plant part comprises both THC and CBD in a w / w 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 part comprises THC and CBD in a w / w or molar ratio of about 1:100, 1:50, 1:10, 1:5, 1:2, 3:5, 2:3, or 1:1. In embodiments, the plant part comprises both THC and CBD in a w / w or molar ratio of about 1:1. In embodiments, the plant part comprises a plant extract (e.g., a Cannabis extract) comprising both THC and CBD, including any of the aforementioned w / w or molar ratios. In embodiments, the plant part comprises both THC and CBD as the primary bioactive molecules from the plant, including any of the aforementioned w / w or molar ratios.

[0196] ii. Secondary bioactive molecules from Cannabis

[0197] In some embodiments, the therapeutic combination comprises a secondary bioactive molecule from Cannabis.

[0198] In some embodiments, the secondary bioactive molecule from Cannabis is a flavonoid 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.

[0199] Flavonoids are a broad class of water-soluble polyphenolic molecules (i.e., containing a phenyl group (-C6H5) bonded to a hydroxyl group (-OH), of which approximately 20 are widely found in Cannabis. The primary function of flavonoids is to provide colorful pigmentation to plants, particularly flowers. In Cannabis, the coloration of deep purple strains is attributed to flavonoids, anthocyanidins, and anthocyanidins. In addition to providing color, flavonoids have been shown to provide health benefits by modulating cell signaling pathways and through various anti-inflammatory, antioxidant, antifungal, anticancer, and other effects. For example, the Cannabis flavonoid apigenin has potent anxiolytic, anti-inflammatory, and anticancer properties; butin has been shown to alleviate oxidative stress-related cellular dysfunction. Other bioactive flavonoids found in cannabis include cannabinoids, kaempferol, orientin, luteolin, quercetin, silymarin, and vitexin.

[0200] In embodiments, flavonoids include those broadly described in Radwan 2021, including orientin, vitexin, isovitexin, apigenin, luteolin, kaempferol, and quercetin flavonoids; which, in embodiments, may be methylated, glycosylated, prenylated, or geranylated.

[0201] In an embodiment, the flavonoid is orientin, orientin-O-glucoside, orientin-7-O-glucoside, orientin-7-O-rhamnosyl glucoside, vitexin, vitexin-O-glucoside, vitexin-7-O-glucoside, vitexin-7-O-rhamnosyl glucoside, cytidine, cytidine-glucoside, isovitexin, isovitexin-O-glucoside, isovitexin-7-O-rhamnosyl glucoside, apigenin-7-O-glucuronic acid, apigenin-7-Op-coumaroyl glucoside, 6-isopentenylrutin, quercetin, naringenin, or naringin.

[0202] Terpenes are a large class of organic hydrocarbon compounds that contain one or more repeating units of a five-carbon structural unit called an isoprene unit (i.e., 2-methyl-1,3-butadiene, having the molecular formula C5H8). As isoprene polymers, terpenes as a group are also often referred to as "isoprenoids." The isoprene units can be linked end-to-end to form a straight chain, or they can be arranged to form a ring (thus having the molecular formula (C5H8)n, where n is the number of linked isoprene units). Depending on the number of isoprene units that make up the terpene, terpenes are classified as hemiterpenes (one unit), monoterpenes (two), sesquiterpenes (three), diterpenes (four), sesquiterpenes (five), triterpenes (six), sesquiterpenes (seven), tetraterpenes (eight), and polyterpenes (nine or more).

[0203] When terpenes have undergone oxidation and have additional oxygen-containing functional groups (for example, after cannabis has been cured and dried), or when terpenes have been modified in other ways by adding or removing functional groups (for example, methyl groups (-CH3)), the terpenes may be referred to as "terpenoids." The presence and specific combinations of terpenes give different plants (and different Cannabis varieties) their unique smells and flavors. In Cannabis, terpenes are the largest group of phytochemicals, with at least 120 identified molecules. Terpenes typically make up 10-20% of the total oil content produced by Cannabis resin glands. Terpenes also make up the majority of the chemicals in the smoke of heated or vaporized Cannabis flower, typically making up over 50%, with cannabinoids typically making up 10-20%.

[0204] While cannabinoids are more commonly understood as responsible for the psychoactive and physical effects of cannabis, terpenes also exhibit a wide range of these effects (see, for example, Russo, 2011). For example, the terpene β-myrcene has been shown to have sedative effects and is believed to be responsible for a significant "body high." β-myrcene has also demonstrated the ability to reduce inflammation and block the development of liver cancer, acting as an analgesic and muscle relaxant. The terpenes linalool, nerolidol, and pulegone also exhibit sedative effects. In contrast, others, such as limonene and terpinolene, exhibit stimulating effects. Still other terpenes exhibit varying effects. For example, α-humulene acts as an appetite suppressant. Limonene exhibits anticancer, anxiolytic, and immunostimulatory properties, and nerolidol also has anticancer properties. β-caryophyllene has anti-inflammatory and gastrocytoprotective effects. Pentacyclic triterpenes, such as β-amyrin and cycloartenol, exhibit antibacterial, antifungal, anti-inflammatory, and anticancer properties.

[0205] When consumed, terpenes may cause effects due to modulation of neurotransmitter systems in the brain, as terpenes readily cross the blood-brain barrier (BBB). For example, linalool has been shown to modulate glutamatergic and gabaminergic neurotransmitter systems, which may explain its analgesic, anxiolytic, anti-inflammatory, and anticonvulsant properties. α-Pinene is an acetylcholinesterase inhibitor and may therefore aid memory. And phytol, a diterpenoid, increases gabaminergic expression. Other terpenes have been shown to affect serotonergic and dopaminergic neurotransmitter systems.

[0206] 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 effects. Terpenes have also been shown to alter the permeability of cell membranes, thereby modulating the effects of THC and other cannabinoids. Because terpenes are lipophilic, they interact with lipid membranes, ion channels, a variety of different receptors (including G-protein-coupled odorant and neurotransmitter receptors), and enzymes. Through these and other mechanisms, terpenes in cannabis not only elicit effects individually and in combination with other terpenes, but can also modulate the effects of the different cannabinoids present.

[0207] In embodiments, the secondary bioactive molecule from Cannabis can be any of a hemiterpenoid, monoterpene, sesquiterpene, diterpene, diterpene, triterpene, sesquiterpene, tetraterpene, polyterpene, carbohydrate, fatty acid and its esters, amide, amine, phytosterol, or phenolic compound.

[0208] Examples of monoterpenes include myrcene, cis-β-ocimene, trans-β-ocimene, p-cymene, α-terpinene, β-phellandrene, γ-terpinene, α-terpinene, α-phellandrene, 3-phenyl-2-methyl-prop-1-ene, α-pinene, β-pinene, camphene, Δ3-perylene, Δ4-perylene, sabinene, α-thujacene, linalool, citral B, nerol, geraniol, ipsienol , citronellol, 2-methyl-2-hepten-6-one, geranylacetone, m-menthol-1,8-(9)-dien-5-ol, carvacrol, carvone, α-terpine cis-rosene hydrate, rosene hydrate, 8-cineole, 1,4-cineole, piperitone oxide, piperidone oxide, anise alcohol, aniseone, borneol, bornyl acetate, camphor, camphene hydrate, α-pinene oxide, pinanol and pinanone.

[0209] Examples of sesquiterpenes include α-caryophyllene, β-caryophyllene, caryophyllene oxide, curcumene, α-trans-bergamotene, α-selinene, β-farnesene, longifolene, epoxyhumulene I, epoxyhumulene II, caryophyllenol, β-bisabolene, allo-aromardendrene, calamenene, α-copalene, nerolidol, α-gujunene, isocaryophyllene, Examples of the present invention include selina-3,7(11)-diene, selina-4(14),7(11)-diene, α-bisabolol, α-cedrene, α-cubo-β-elemene, β-eudesmol, epi-α-bisabolol, γ-cis-bisabolene, γ-curcumene, γ-muurolene, γ-trans-bisabolene, viridiflorene, germacrene-B, and neocoronadiol. Examples of diterpenes include phytol and neophytadiene. Examples of triterpenes include foetidol and epifoetidol. Examples of heteroterpenes include vomifoliol, dihydrovomifoliol, β-ionone, and dihydroactinol.

[0210] Examples of phenolic compounds include, in addition to those disclosed as part of, for example, terpenes and flavonoids, lignans, spiroindanes, dihydrostilbenes, dihydrophenanthrene derivatives, stilbenes, cannabichromene, denbinobine, catechins, chlorogenic acid, caffeic acid, epicatechin, luteolin-7-O-glucoside, p-coumaric acid, caffeoyl, tyramine, ferulic acid, quercetin-3-glucoside, kaempferol, apigenin-7-glucoside, luteolin, cannabinoids, and apigenin.

[0211] In embodiments, the secondary bioactive molecule from Cannabis can be any of the following: flavonoids including orientin, orientin-O-glucoside, orientin-7-O-glucoside, orientin-7-O-rhamnosyl glucoside, vitexin, vitexin-O-glucoside, vitexin-7-O-glucoside, vitexin-7-O-rhamnosyl glucoside, isovitexin, isovitexin-O-glucoside, isovitexin-7-O-glucoside , apigenin-7-O-glucuronic acid, apigenin-7-Op-coumaryl glucoside, kaempferol-3-O-sophoroside, quercetin-3-O-sophoroside, rutin, quercetin, naringenin and naringin; terpenes including myrcene, cis-β-ocimene, trans-β-ocimene, p-cymene, α-terpinene, β-phellandrene, γ-terpinene, α-terpinene, α-phellandrene, 3-phenyl-2-methyl-prop-1-ene, α-pinene, β-pinene, camphene, Δ 3 -pinene, Δ 4-Pinene, smilaxene, α-thujene, linalool, citral B, nerol, geraniol, isopropyl alcohol, citronellol, 2-methyl-2-hepten-6-one, geranylacetone, m-menth-1,8-(9)-dien-5-ol, carvacrol, carvone, α-terpineol, terpinene-4-ol, eucalyptol hydrate, 8-cineole, 1,4-cineole, piperitone oxide, piperidone oxide, anise alcohol, anise ketone , borneol, bornyl acetate, camphor, camphene hydrate, α-pinene oxide, pinanol, pinanone, α-caryophyllene, β-caryophyllene, caryophyllene oxide, curcumin, α-trans-bergamotene, α-selinene, β-farnesene, longifolene, epoxyhumulene I, epoxyhumulene II, caryophyllene alcohol (caryophyllene alcohol), β-bisabolene, allo-armodendrene, cal amenene, α-copalene, nerol, α-gujuene, iso-caryophyllene, (Z)-β-farnesene, farnesyl acetone, α-erucylene, α-cis-bergamotene, α-cineole, α-guaiacene, α-longipinene, α-kilanthene, β-elemene, β-cineole, epi-α-bisabolol, γ-cis-bisabolol, γ-curcumene, γ-muurolene, γ-trans-bisabolol, viridiflorene, germacrene-B, dichlorodiol, phytol, neophytadiene, fulvene, epifulvene, vomifoliol, dihydrovomifoliol, β-ionone, dihydroactinol, carbohydrates, fatty acids and their esters, amides, amines, phytosterols and phenolic compounds, including lignans, spiroluteolin, cannabinoids and apigenin.

[0212] In embodiments, bioactive molecules from Cannabis further include 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.

[0213] ii.Dipteryx

[0214] 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 is understood that the plant part comprises material derived from Dipteryx, including, as non-limiting examples, Dipteryx material such as crude (i.e., unprocessed) Dipteryx biomass, Dipteryx extracts (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or molecules naturally occurring in Dipteryx (e.g., the major or minor bioactive molecules described in the embodiments herein), regardless of whether the molecule was actually obtained by isolating the molecule from Dipteryx or otherwise (e.g., by chemical synthesis).

[0215] In some embodiments, the therapeutic combination comprises a Dipteryx extract. In some embodiments, the therapeutic combination comprises a major bioactive molecule and / or a minor bioactive molecule from a species of the genus Dipteryx.

[0216] While in some preferred embodiments, the primary bioactive molecule and / or the secondary bioactive molecule is from Dipteryx, in other embodiments, the primary bioactive molecule and / or the secondary bioactive molecule is from another genus from the order Dipteryx, further including the genera Monopteryx, Pterodon, and Taralea.

[0217] In embodiments, the primary and / or secondary bioactive molecules are derived from Dipteryx, including from D. odorata, also referred to herein as the "Cumaru tree" or "Cumaru"

[0218] While in some preferred embodiments, the bioactive molecules, such as coumarins, are derived from plants of the genus Dipteryx, such as Dipteryx odorata (Cumaru), in other embodiments, the bioactive molecules, such as coumarins, are derived from plants of another genus, including any genus within the Amburaneae family, 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 thereof will be considered equivalent to similar extracts and bioactive molecules from Dipteryx.

[0219] Dipteryx is a genus of large trees belonging to the Fabaceae family, native to South and Central America and the Caribbean, formerly known as the genus Coumarouna.

[0220] In some embodiments, the therapeutic combination comprises a primary and / or secondary bioactive molecule from the species Dipteryx odorata.

[0221] Dipteryx odorata is known by many names, including Coumarouna odorata, Cumaru tree (Brazil), TONKA bean tree, Brazilian teak, Tonquin bean, rumara, Kumaru (Guyana), cumaruzeiro (Portugal), charapilla (Peru), charapilla del murciélago (Peru), shihuahuaco (Peru), and sarapia (Venezuela, Colombia), all of which may be used interchangeably or considered equivalent in light of the disclosure herein. Dipteryx odorata is a large rainforest canopy tree that grows up to 30 meters tall 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 native Amazonian peoples. The seeds are fermented in rum and used for snake bites, cuts, bruises, coughs, rheumatism, and as a shampoo. The seed oil is used to prevent earaches and ear infections, and the bark is used to create baths for fever sufferers.

[0222] The seeds (also known as beans) produced by the Cumaru tree ("tonka bean") contain the bioactive molecule coumarin, which has a pleasant vanilla-like aroma and has been used as a flavoring in perfumes, soaps, and food and tobacco products. To prepare them, the beans are typically fermented in local rum and then air-dried. This causes the formation of coumarin crystals that dust the outside of the seeds, giving them a frosted appearance.

[0223] In some embodiments, the disclosed combinations comprising bioactive molecules of interest from Dipteryx, such as coumarins, can exhibit antispasmodic, emmenagogue, cardiotonic, and antiasthmatic effects.

[0224] In some aspects, the disclosed combinations comprising bioactive molecules of interest from Dipteryx, such as coumarins, modulate serotonin, dopamine (including upregulation of their synthesis and release), and / or adrenergic receptors and can exhibit neuroprotective effects, e.g., as disclosed in Ostrowska, 2020 and Abdelhafez et al., 2011. In some embodiments, the disclosed combinations comprising bioactive molecules from Dipteryx, such as coumarins, inhibit MAO-B, thereby allowing dopamine to remain active, e.g., as disclosed in Huang et al., 2015.

[0225] In some aspects, the disclosed combinations comprising bioactive molecules from Dipteryx, such as coumarins, reduce the production of nitric oxide (NO), tumor necrosis factor alpha (TNFα), and / or interleukin-1 beta (IL-1β) in a dose-dependent manner. In some aspects, the disclosed combinations comprising bioactive molecules from Dipteryx, such as coumarins, inhibit LPS-induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and mRNA expression levels in RAW264.7 cells. In some aspects, the disclosed combinations comprising bioactive molecules from Dipteryx, such as coumarins, activate PPAR-γ, which negatively regulates inflammatory activity in a tissue-specific manner; and the transcription factor NRf2, which further regulates NF-kB activity and exerts a useful cytoprotective mechanism, for example, as described in Hassanein et al., 2020; and Distasi, 2021.

[0226] ii. Primary and secondary bioactive molecules from Dipteryx

[0227] In embodiments, the therapeutic combination comprises a primary and / or secondary biologically active molecule from Dipteryx.

[0228] In embodiments, the primary bioactive molecule from Dipteryx is coumarin (2H-chroman-2-one; 2H-1-benzopyran-2-one), a colorless crystalline solid that gives coumarin its characteristic vanilla-like aroma and flavor, and which may also serve as a chemical defense against predators.

[0229] Coumarin can be obtained from Dipteryx and countless other plant species, including: vanilla grass (Anthoxanthum odoratum), sweet woodruff (Galium odoratum), sweet grass (Hierochloe odorata), sweet-clover (genus Melilotus), cinnamon, including Ceylon cinnamon or "true cinnamon" (Cinnamomum verum), Chinese cinnamon or Chinese cinnamon (C. cassia), Indonesian cinnamon or Padangcassia (C. burmannii), Saigon cinnamon or Vietnamese cinnamon (C. loureiroi), deertongue (Carphephorus odoratissimus), Tilo (Justicia pectoralis), Mullein (genus Verbascum), many species of cherry trees in the genus Prunus, and trace amounts in strawberries, black currants, apricots, and cherries (Ananthakrishnan et al., 2018; Wang et al., 2013; Khan and Ehab, 2010; Ieri, Pinelli, and Romani, 2012; and National Center for Biotechnology Information, 2022). In some embodiments, the coumarin is extracted, isolated, or otherwise obtained from any of the above or other such species, rather than from Dipteryx.

[0230] In some embodiments, the biologically active molecule is a compound derived from coumarins (e.g., phenylpropionic acid, coumarin, or coumarins), and can be used in the disclosed combinations, compositions, and methods; such compounds include, for example, the biologically active molecules umbelliferone, esculetin, hernialin, psoralen, dicoumarol, imperatorin, bromodifenacum, bromadiolone, difenacum, auraptene, enanthate, phenprocoumon, PSB-SB-487, PSB-SB-1202, scopoletin, and warfarin (see, e.g., Laposata, Van Cott, and Lev, 2007; Syah et al., 2009).

[0231] In embodiments, the secondary bioactive molecule from Dipteryx is any of the following: cumaru, a coumarin derivative, an isoflavone, a lupeol derivative, a fatty acid ester, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxyflavone-8-methyl-ether, 5-methoxyflavone A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxy-isoflavone, betulin, butin, coumaric acid-β-glucoside, dipteryxin, dipteryxic acid, eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyl linolenate, methyl oleate, O-coumaric acid, O-hydroxycoumaric acid, odoratin, P-hydroxy-benzoic acid, retusin, retusin-8-methyl-ether, sulfuretin, salicylic acid, afrormisin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone.

[0232] In embodiments, the biologically active molecule from Dipteryx further includes Trincone, 2019; Jofre et al., 2020; or Gomez-Zavaglia et al., 2019.

[0233] c. Algae

[0234] In some embodiments, the therapeutic combination comprises an algae portion. In some embodiments, the algae portion comprises an algae extract. In some embodiments, the algae portion comprises a bioactive molecule from algae. In some embodiments, the algae extract comprises a bioactive molecule from algae. For example, in some embodiments, the algae portion comprises a primary bioactive molecule and / or a secondary bioactive molecule from algae. In some embodiments, the algae extract comprises a primary bioactive molecule and / or a secondary bioactive molecule from algae. Thus, in some embodiments, the disclosed therapeutic combinations comprise a primary bioactive molecule and / or a secondary bioactive molecule from algae.

[0235] In embodiments where an algal portion is described as being "from" algae, it is understood that the algal portion comprises material derived from algae, including, as non-limiting examples, algal material such as raw (i.e., unprocessed) algal biomass, algal extracts (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or molecules naturally occurring in algae (e.g., the major or minor bioactive molecules described in the embodiments herein), whether or not the molecule is actually obtained by isolating the molecule from the algae or by other means (e.g., by chemical synthesis).

[0236] Algae broadly refers to a large, multi-organism group of photosynthetic eukaryotic organisms. Generally speaking, there is no single universally accepted definition of algae; however, one means of describing the various clades that comprise "algae" is that they have chlorophyll as their primary photosynthetic pigment and lack a sterile covering of cells surrounding their reproductive cells (Lee, 2008). Algae include species that can live in freshwater and / or saltwater, and generally include the 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).

[0237] In embodiments, the algae useful in the therapeutic combinations of the present invention are marine algae. In embodiments, the marine algae can be any of the brown algae (Phaeophyta), green algae (Chlorophyta), and red algae (Rhodophyta). In embodiments, the marine algae are marine red algae. In embodiments, the marine red algae are from the family Bangiacea. In embodiments, the marine red algae are from the genus Pyropia or Porphyra.

[0238] Culturally, Porphyra has been cultivated in East Asia and used to make "nori" and other forms of edible seaweed, such as in sushi, to bind and secure rice to other proteins such as fish. Some Porphyra species are also harvested in Western Europe to produce laverbread, a traditional food eaten primarily in Wales as part of the local cuisine (Harford, n.d.).

[0239] In an embodiment, the red algae is Porphyra umbilicalis. Broadly speaking, umbilicalis is a membranous, monolayer algae with an irregularly lobed olive to brown frond (up to 200 mm long) attached to a central holdfast that splits from a central holdfast and typically has a lettuce-like appearance. Textured, umbilicalis is typically smooth and gelatinous, lacking rigidity (Harford, n.d.). Like other Porphyra species, umbilicalis may grow on rocks in the mid-tidal to splash zone, sometimes on mussels, and is abundant in spring and summer. In an embodiment, the red algae is Pyropia perforata. Perforata is generally purple / green in color, with lobed leaves that can be up to 30 cm wide and long. Perforata may grow on rocks or as epiphytes on other algae species. In an embodiment, the red algae is Pyropia yezoensis. Yezoensis has a disc-shaped holdfast with a short stalk, and folded leaves that are membranous and monostromal, and are red, brown, and dark green.

[0240] a. Primary and secondary bioactive molecules from algae

[0241] In embodiments, the therapeutic combination comprises primary and / or secondary bioactive molecules from algae.

[0242] In embodiments, the predominant bioactive molecule from algae is a predominant bioactive molecule from a genus of the family Bangiaceae. In embodiments, the predominant bioactive molecule from algae is a predominant bioactive molecule from a species of the genus Pyropia or Porphyra. In embodiments, the predominant bioactive molecule from algae is a predominant bioactive molecule from Porphyraumbilicalis. In embodiments, the predominant bioactive molecule from algae is a predominant bioactive molecule from Pyropia yezoensis. In embodiments, the predominant bioactive molecule from algae is a predominant bioactive molecule from Pyropia perforata.

[0243] In an embodiment, the major bioactive molecules from Pyropia or Porphyra are any of Porphyra polysaccharides and / or oligosaccharides, polysaccharides, oligopolysaccharides and / or monosaccharides; peptides, phycobiliproteins, mycosporin-like amino acids, essential amino acids, non-essential amino acids, carotenes, intermediate carotenoids, glycoproteins and aminosulfonic acids such as taurine.

[0244] In some embodiments, the disclosed combinations, compositions, and methods comprising bioactive molecules from algae, such as oligosaccharides from Pyropia, will be shown to increase dopamine synthesis by inhibiting the loss of tyrosine hydroxylase, as according to the methods disclosed in Liu et al., 2019. In some embodiments, the disclosed combinations, compositions, and methods comprising bioactive molecules from algae, such as Porphyra polysaccharides, will be shown to provide neuroprotection. In some embodiments, the disclosed combinations, compositions, and methods comprising bioactive molecules from algae, such as taurine, will be shown to protect dopaminergic neurons and elevate dopamine, as shown in the methods disclosed in Liu et al., 2018; Che et al., 2018; and Ericson et al., 2006.

[0245] In some embodiments, the disclosed combinations, compositions, and methods comprising bioactive molecules from algae, such as taurine, will demonstrate reduced neuropathy through downregulation of NF-κB and activation of the Nrf2 signaling cascade. In some embodiments, taurine will demonstrate reduced serum levels of IL-6 in TBI patients, for example, according to the methods disclosed in Agca et al., 2014; and Vahdat et al., 2021. In embodiments, taurine will demonstrate biostabilization of membranes, promotion of redox homeostasis, and scavenging of oxidative factors, for example, according to the methods disclosed in Yildirim et al., 2007; and Thirupathi et al., 2020.

[0246] In an embodiment, phycobiliproteins include phycoerythrin, phycoerythrobilin, phycocyanin, and allophycocyanin. In an embodiment, mycosporin-like amino acids include porphyrin-334 and shinorine. In an embodiment, amino acids include isoleucine, leucine, threonine, methionine, phenylalanine, lysine, histidine, valine, arginine, and cysteine. In an embodiment, non-essential amino acids include aspartic acid, glutamic acid, glycine, tyrosine, serine, alanine, and proline. In an embodiment, peptides include monopeptides, dipeptides, tripeptides, and proteins. In an embodiment, carotenes include lutein, zeoxanthin, α-carotene, β-carotene, and astaxanthin. In an embodiment, intermediate carotenoids include α-cryptoxanthin, zeaxanthin, and β-cryptoxanthin.

[0247] In an embodiment, the major bioactive molecule from Pyropia or Porphyra is any of the following: porphyra polysaccharides and / or oligoporphyra polysaccharides, polysaccharides, peptides, including monopeptides, dipeptides, tripeptides, and proteins; phycobiliproteins, including phycoerythrin, phycoerythrobilin, phycocyanin, and allophycocyanin; mycosporin amino acids, including porphyran-334 and shinorine; essential amino acids, including isoleucine, leucine, threonine, methionine, phenylalanine, lysine, histidine, valine, arginine, and cysteine; non-essential amino acids, including aspartic acid, glutamic acid, glycine, tyrosine, serine, alanine, and proline; carotenes, including lutein, zeoxanthin, α-carotene, β-carotene, and astaxanthin; intermediate carotenoids, including α-cryptoxanthin, zeaxanthin, and β-cryptoxanthin; and taurine.

[0248] In embodiments, the therapeutic combination comprises a bioactive molecule from algae, wherein the bioactive molecule is, in embodiments, a secondary bioactive molecule from algae. In embodiments, the secondary bioactive molecule from algae is a secondary bioactive molecule from a genus of the family Bangiaceae. In embodiments, the secondary bioactive molecule from algae is a secondary bioactive molecule from a species of the genus Pyropia or Porphyra. In embodiments, the secondary bioactive molecule from algae is a secondary bioactive molecule from Porphyra umbilicalis. In embodiments, the secondary bioactive molecule from algae is a secondary bioactive molecule from Pyropia Yezoensis.

[0249] In an embodiment, the secondary bioactive molecule from Pyropia or Porphyra is any one of a mineral, a vitamin, a lipid, a phenolic compound, and a brown algae polyphenol.

[0250] In embodiments, minerals include potassium, phosphorus, magnesium, sodium, calcium, manganese, iron, copper, and zinc. In embodiments, vitamins include vitamin K, ascorbic acid, folate, and cobalamin. In embodiments, lipids include fatty acids such as eicosapentaenoic acid and palmitic acid. In embodiments, brown algae polyphenols include brown algae polyphenol A.

[0251] In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is any of the following: minerals, including potassium, phosphorus, magnesium, sodium, calcium, manganese, iron, copper, and zinc; vitamins, including vitamin K, ascorbic acid, folate, and cobalamin; lipids, including fatty acids such as eicosapentaenoic acid and palmitic acid; phenolic compounds and fucoidans, including fucoidan A.

[0252] C. Obtaining bioactive molecules

[0253] In embodiments, the major and minor bioactive molecules disclosed herein can be obtained by any of the methods of extraction, synthesis, biosynthesis as non-limiting examples, as whole plants, such as Cannabis flowers or Cannabis biomass, fruiting fungal bodies, fungal mycelial masses, bioreactor-produced fungal biomass, truffles (fungal sclerotia), cumaru seeds, or whole Porphyra or Pyropia algae, isolated and / or collected as fractions.

[0254] In some embodiments, the biologically active molecules of the therapeutic combination will be commercially available and will be of commercial origin (eg, Cayman Chemical Company, Ann Arbor, MI; Sigma-Aldrich, Burlington, MA).

[0255] While such methods are known to those skilled in the art, exemplary means of obtaining primary and secondary biologically active molecules are disclosed herein.

[0256] a. Extraction

[0257] In some embodiments, extracts (e.g., fungal extracts, plant extracts, or algal extracts) used in the disclosed therapeutic combinations are obtained using extraction techniques known to those skilled in the art. In some embodiments, the disclosed major and minor bioactive molecules are provided in the form of extracts produced according to extraction techniques known to those skilled in the art.

[0258] Broadly speaking, but not being bound by theory, an extraction system is described by introducing a material, such as a fungal material, a plant material, and / or an algal material (e.g., containing a desired major and / or minor bioactive molecule), into contact with a solvent capable of separating the desired major and / or minor bioactive molecule from the material to form a solution (extract) containing the solvent and the major and / or minor bioactive molecule.

[0259] The extract can be used directly in the disclosed combinations, compositions, or methods, or can first be further processed, for example, by further extraction, filtration, distillation, fractionation, refractionation, separation and / or purification, and other such methods known in the art, including combinations thereof.

[0260] There are various types of extraction systems, utilizing different methods and having different parameters (e.g., temperature, pressure, solvents) that can be tailored to the desired end product, such as the desired primary and / or secondary bioactive molecules. These properties are known to those skilled in the art. For example, without being bound by theory, extraction systems generally follow the rule of "like dissolves like." Thus, when extracting polar bioactive molecules, a polar solvent can be used; when extracting non-polar bioactive molecules, a non-polar solvent can be used (Lowery and Richardson, 1987).

[0261] Methods for extracting major and / or minor bioactive molecules, producing plant and fungal extracts thereof, and generally obtaining purified products containing the desired compounds free of undesirable plant or fungal matter, chemicals, and other impurities are known in the art, see, for example, U.S. Patent Nos. 6,403,126; 8,846,409; 8,895,078; 10,059,684; 10,239,808; 10,224,431; 10,300,494; 10,307,447; 10,406,453; 10,413,845; and 10,414,709; and U.S. Application Nos. 2003 / 0017216A1 and 2016 / 0038437A1, and the references cited therein, all of which are incorporated herein by reference.

[0262] The exemplary extraction methods and systems disclosed in such references and otherwise herein should not be construed as limiting, and those skilled in the art will appreciate numerous variations. Although exemplary extraction methods, including those described herein, are disclosed as a series of steps, other extraction methods useful in practicing the present invention and thereby obtaining biologically active molecules may deviate from these steps, including by modifying, removing, adding, or rearranging any of these steps, as will be understood by those skilled in the art in light of this disclosure and general knowledge in the art.

[0263] As used herein, an "extract" may refer to, for example, a plant extract prepared from a plant source (e.g., a fungus, plant, Cannabis, Dipteryx, algae, or other extract containing the major and / or minor bioactive molecules disclosed herein) (as defined herein as a "plant extract"). In some embodiments, the extract undergoes further extraction, filtration, fractionation, subfractionation, partial purification, substantial purification, or complete purification, or other processing to obtain a specific bioactive molecule separated from other components, wherein such bioactive molecule is present in a filtrate, fraction, subfraction, partially purified product, substantially purified product, fully purified product, isolate, or the like, and in some cases can be obtained as a single component or as a single component separated from all other components. In some embodiments, the extract does not undergo fractionation, subfractionation, partial purification, substantial purification, or complete purification, or other processing to obtain a specific bioactive molecule separated from other components, and is obtained as a whole plant, whole fungus, or whole algae extract, which may be referred to herein as a "whole extract." In alternative embodiments to any of the exemplary disclosed embodiments herein, the intact extract is replaced with a fraction, subfraction, partially purified product, substantially purified product, completely purified product, isolate, etc., as well as by a single biologically active molecule or one or more molecules from (included in) the extract, or by a synthetically produced molecule, e.g., by partial or complete chemical synthesis, or by biological synthesis.

[0264] Extract can therefore comprise the extract of purification. As understood by those skilled in the art, " extract of purification " can refer to the plant extract that has undergone further processing after preparation. In some exemplary embodiments, the extract of purification can be for example following product: preparation is soaked or heated in water and / or alcohol (for example, depending on whether the bioactive molecule sought is water-soluble and to what extent water-soluble), stir, cool down the gained liquid, filter, filter, and remove unwanted product (if necessary, repeat), then evaporate enough liquid solvents to obtain desired concentration (or evaporate completely, to obtain crystalline precipitate), or use spray dryer to produce the dry powder of purification. Other purification techniques will be well known to those skilled in the art, and usually, the extraction and purification techniques for obtaining high-purity bioactive compounds will be known in the art.

[0265] Starch or other carriers may be added to the purified extract to maintain the purified dry powder as a free-flowing powder that is easy to use during formulation, for example if the dry powder is to be added to capsules; however, when referring to the weight of the "purified extract", any such carriers, diluents or excipients are not included in the total amount.

[0266] In embodiments, the extract can be "standardized," which refers to an extract that includes a specific concentration of a major and / or minor bioactive molecule. Methods of producing standardized extracts, such as by quantifying the concentration of the extract and then adding a carrier, diluent, or excipient to dilute the extract to the standardized concentration, or further concentrating the extract to increase its concentration, will be known to those skilled in the art.

[0267] "Natural" can refer to substances that are isolated, extracted, or otherwise obtained from natural sources such as fungi, plants, or algae. Thus, natural primary or secondary bioactive molecules, such as natural cannabinoids, can be isolated or extracted from the Cannabis plant. Thus, in various disclosed embodiments, the compositions will be derived from botanical sources including fungi, plants, and algae in the form of extracts or by other means, and will contain a botanical drug substance or a Cannabis-derived drug substance. In embodiments, such compositions will contain a botanical drug product or a Cannabis-derived drug product. In other embodiments, such compositions will contain a botanical drug product or a Cannabis-derived drug product that is substantially free of impurities.

[0268] In some embodiments, when the disclosed combination or composition comprises a plurality of extracts (e.g., fungal extracts, plant extracts, algae extracts), the concentration of the bioactive molecules contained therein is quantified (e.g., according to methods disclosed herein and methods otherwise known to those skilled in the art). The concentration of the bioactive molecules in the extract can vary according to the concentration of the bioactive molecules in the corresponding source material (e.g., original fungal, plant or algae biomass). Thus, based on the variability between batches of extracts, the concentration of the bioactive molecules in the disclosed composition can vary between batches. In compliance with FDA regulations (2016, USHHS, FDA, CDER, Industrial Botanical Development Guide), bioactive molecules (e.g., major and / or minor bioactive molecules as disclosed herein) can be added to the extracts disclosed herein (e.g., fungal, plant or algae extracts); or relate to the disclosed combination or composition comprising the extracts. This can be done, for example, to standardize the disclosed combination or composition and ensure a fixed concentration of the bioactive molecules between batches, even when the bioactive molecule concentration of the source material or its extract may vary.

[0269] i. Exemplary extraction of molecules from fungi

[0270] In embodiments, the therapeutic combination comprises a primary and / or secondary bioactive molecule from a fungus.In embodiments, the primary and / or secondary bioactive molecule may be obtained via extraction of fungal material.

[0271] Without being bound by theory, the fungal extraction process can be generally described as follows. First, a fungal material containing the desired primary and / or secondary bioactive molecules is obtained, optionally dried (using, for example, an apparatus such as a low temperature oven, a food dehydrator, and / or a commercial dryer), and optionally ground, pulverized, macerated, and / or milled to form a substantially fine powder, which is then optionally sieved, for example, for consistency.

[0272] The fungal material is then combined with a solvent (e.g., methanol, ethanol, water, or a mixture thereof) capable of extracting the required primary and / or secondary bioactive molecules to form a slurry, and the slurry is stirred to promote the duration of extraction specified, e.g., about 24 hours. The solvent is then filtered and collected. In embodiments, the filter may comprise cheesecloth, filter paper, and / or a filtration system. Optionally, any one of environmental evaporation, rotary evaporation, vacuum evaporation, and an evaporation method in which heat is applied may be used to evaporate the extract to produce a more concentrated extract, such as those utilizing a baking oven. In embodiments, the fungal material can be resaturated with the same or different solvent after initial filtration to complete a second, third, or further extraction. Conventional techniques may be used to select extraction methods and variants thereof.

[0273] In embodiments, heat extraction is utilized. In embodiments, heat extraction follows the process generally described above, except, for example, that the solvent is heated, stirring is performed in a heated environment, or extraction is otherwise performed at an elevated temperature relative to ambient temperature. In embodiments, extraction is performed at a temperature at which psilocybin is substantially dephosphorylated to psilocin. In embodiments, heat extraction is performed at a temperature exceeding about 70° C. In embodiments, extraction occurs at a temperature below which substantial dephosphorylation of psilocybin occurs.

[0274] In an embodiment, ultrasonic extraction is utilized. In some embodiments, mushrooms or other fungal materials are dried and cut and / or crushed prior to ultrasonic extraction. In an embodiment, an ultrasonic extractor is used to expose the fungal material to ultrasonic vibrations via an ultrasonic probe. In an embodiment, the ultrasonic probe vibrates at a frequency of 20 kHz or higher. Without being bound by theory, when ultrasonic waves pass through a liquid, they produce alternating high-pressure (compression) and low-pressure (rarefaction or expansion) cycles (Hielscher, 2022). During the low-pressure vacuum cycle, tiny vacuum bubbles or cavities appear in the liquid, which grow over several pressure cycles. During the compression phase of the liquid and bubbles, the pressure is positive, while the rarefaction phase produces a vacuum (negative pressure) (Hielscher, 2022). During the compression-expansion cycle, the cavities in the liquid grow until they reach a size that can no longer absorb any more energy, at which point they implode. The implosion of these cavities leads to various high-energy sonomechanical effects, termed acoustic / ultrasonic cavitation (Hielscher, 2022), during which 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.

[0275] In some embodiments, Soxhlet extractor is utilized to extract. In some embodiments, ethanol and water solvent (for example, 80% ethanol and 20% water) are used to carry out Soxhlet extraction. In some embodiments, solvent is heated to reflux, and solvent vapor is advanced into the distillation arm and pours into the chamber of the sleeve that holds fungal material. The condenser at the top of the device ensures that any solvent vapor cools down, and drips back downwards into the chamber that holds fungal material. As a result, the chamber containing fungal material is slowly filled with hot solvent. When the Soxhlet chamber is almost full, the chamber is emptied by siphon, and the solvent is returned to the distillation flask. In some embodiments, using standard equipment well known to those skilled in the art, Soxhlet extraction is carried out for about 6 to 10 hours, including about 6 hours, about 7 hours, about 8 hours, about 9 hours or about 10 hours. In embodiments, Soxhlet extraction is carried out for about 7 hours.

[0276] Extracts of fungal materials (comprising major and / or minor bioactive molecules) produced according to the various methods described herein or other methods known to those skilled in the art can be combined to provide various advantages. For example, fungal extracts produced according to different techniques can contain major and / or minor bioactive molecules at different concentrations, and combining such extracts in the disclosed therapeutic combinations can confer advantageous properties.

[0277] 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 extract and a Soxhlet extract, and the ultrasonic: Soxhlet ratio (e.g., the volume ratio (v / v) or weight ratio (w / w) of the extract solution, or a molar ratio, such as the molar ratio of the constituent bioactive molecules in the extract) is between about 0.5:1 and 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 extract and a Soxhlet extract at a volume 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 a mixture of an ultrasonic extract and a Soxhlet extract at a ratio of about 2:1 (v / v).

[0278] Advantages of combining different fungal extracts in the disclosed combinations can include, for example, improved solution stability. For example, certain compositions disclosed herein comprise psilocin and / or psilocin as components of the fungal portion. The solution instability of psilocin, and particularly psilocin, has long been recognized, but the decomposition mechanism and the exact chemical nature of the products remain ongoing research questions. Studies of Psilocybe mushrooms that have been damaged to expose their alkaloids to ambient oxygen revealed that psilocin is dephosphorylated to psilocin, the hydroxyl group of which is subsequently oxidized to produce a 4-oxo degradation product (Lenz et al., 2020). Studies of possible solution decomposition mechanisms suggest that oxidative dimerization may also contribute to the solution instability of psilocin (Lenz et al., 2021). In some embodiments, combining fungal extracts (e.g., a combination as disclosed, wherein the fungal portion comprises both an ultrasonic extract and a Soxhlet extract) protects the resulting combination from oxidative decomposition. Without being bound by theory, different levels of major and / or minor bioactive molecules in different fungal extracts, which may include naturally occurring stabilizers and antioxidants, can combine to produce additive or synergistic effects that stabilize the resulting formulations against decomposition pathways, such as oxidative dimerization. In some embodiments, oxidative decomposition 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 other methods known to those skilled in the art) or qualitatively (e.g., by visually monitoring the characteristic "blueing" reaction of psilocybin- and / or psilocin-containing extracts and materials).

[0279] In some embodiments, the disclosed combinations in which the fungal portion comprises a plurality of 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). For example, certain compositions disclosed herein comprise a component with high water solubility (e.g., a fungal extract comprising psilocin and / or psilocin, or a fungal extract comprising these compounds) and a component with low water solubility (e.g., a plant portion comprising a cannabinoid or Cannabis extract). During the 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 produce an additive or synergistic effect that stabilizes the resulting formulation against precipitation.

[0280] In some embodiments, the disclosed combinations wherein the fungal portion comprises a plurality of different fungal extracts have improved stability (e.g., anti-oxidation and / or precipitation) such that additional stabilizing excipients (e.g., antioxidants, stabilizers) are unnecessary for the combination to have sufficient stability under ambient conditions. Since these ingredients may interfere with the absorption of the primary and / or secondary bioactive molecules, reducing or eliminating the need for such additional stabilizing excipients can result in further advantages, such as improved bioavailability.

[0281] a. Determine the concentration of primary and / or secondary bioactive molecules

[0282] It will be appreciated that determining the concentration of primary and / or secondary bioactive molecules within an extract or within a fungal, plant and / or algal material is within the capabilities of one skilled in the art. Several such devices are disclosed below and may be used in embodiments.

[0283] As a non-limiting example of such an approach, concentrations of major bioactive molecules from various Psilocybe species are presented in Table 1 below (obtained from Mahmood, 2013, and organized by psilocybin content; see also Stamets, 1996), showing the w / w % of psilocybin, psilocin, and baeocystin in dried mushrooms (containing negligible water weight, or sometimes referred to as "dry crackers"), as further discussed herein:

[0284] Table 1: % Psilocybin, Psilocin, and Baeocystin Content of Exemplary Psilocybe Species

[0285] Psilocybe species Psilocybin % Psilocin% Baeocystin % P. azurescens 1.70 0.38 0.35 P. bohemica 1.34 0.11 0.02 P.semilanceata 0.98 0.02 0.36 P. baeocystis 0.85 0.59 0.10 P.cyanescens 0.85 0.36 0.03 P. tampanensis 0.68 0.32 n / a P.cubensis 0.63 0.60 0.025 P. weilii 0.61 0.27 0.05 P.hoogshagenii 0.60 0.10 n / a P. stuntzii 0.36 0.12 0.02 P.cyanofibrillosa 0.21 0.04 n / a P.liniformans 0.16 n / a 0.005

[0286] Thus, 100 mg of an extract of P. cubensis may, in some embodiments, contain about 0.63 mg of psilocybin. In some embodiments, 275 mg of an extract of P. azurenscens may contain about 4.895 mg.

[0287] 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. The concentration of bioactive molecules can also vary depending on the part of the organism from which they are obtained (e.g., cap versus stipe or mycelium, flower versus leaf or stem, etc.), as well as other variables known to those skilled in the art. However, one will understand how to select such growth conditions, part of the organism, etc., and understand how to determine the concentration of bioactive molecules using the disclosed methods or methods generally known in the art.

[0288] In embodiments, the concentration of primary and / or secondary bioactive molecules in fungi, plants, and / or algae is determined using liquid chromatography, such as high performance liquid chromatography (HPLC). Broadly speaking, 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. Because each individual component in the sample interacts differently with the adsorbent material, different components flow at different rates, resulting in the separation of the components as they exit the column (Freshminds, 2021).

[0289] In 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 by Samuelsson et al., which is incorporated herein by reference. Broadly speaking, reversed-phase HPLC is generally performed in the same manner as the exemplary HPLC method disclosed above, but with a hydrophobic rather than hydrophilic stationary phase. That is, hydrophobic molecules will adsorb to the column packing, while hydrophilic molecules will be eluted and detected first (Mehta, 2012; Molnár and Horváth, 1976).

[0290] In 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 described in Oetjen et al., 2020, which is incorporated herein by reference.

[0291] 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), which is described in Jiang et al., 2020 and incorporated by reference. Broadly speaking, HILIC is a normal phase HPLC technique that utilizes a reversed-phase eluent. Thus, the column has a hydrophilic stationary phase, and the eluent comprises water, a buffer, and a high concentration of a water-miscible organic solvent ("Hydrophilic Interaction Liquid Chromatography," 2022).

[0292] In embodiments, the concentration of a primary and / or secondary bioactive molecule in a fungus, plant, and / or algae is determined using a rapid, personal quantitative assay that can be used to determine concentration, an example of which is the pSilor-QTest (Miraculix; Jena, Germany), which can be used to determine the concentration of psilocybin. The pSilor-QTest uses a chemical colorimetric reaction to detect concentration, with the intensity of the color proportional to the concentration of the bioactive molecule (Mandrake, 2021). In some embodiments, characterization of the fungus, plant, and / or algae portion of the disclosed combination (e.g., characterization of the primary and / or secondary bioactive molecules) includes characterization of 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 fungus, plant, and / or algae portion.

[0293] ii. Exemplary Extraction of Molecules from Cannabis

[0294] In embodiments, the therapeutic combination comprises a primary and / or secondary bioactive molecule from a Cannabis species. In embodiments, the primary and / or secondary bioactive molecule can be obtained via extraction of Cannabis plant material.

[0295] In embodiments, an exemplary extraction system is as follows: First, a Cannabis plant material can be obtained, which in embodiments has been substantially dried. In embodiments, the dried Cannabis plant material can then be ground and optionally pulverized to produce a fine powder, which can optionally be sieved. As elsewhere, grinding and pulverizing can increase the surface area for the solvent to interact with the material, and therefore can increase the yield of the desired primary and / or secondary bioactive molecules within the material. In embodiments, the dried and optionally ground and / or pulverized plant material is then placed into an extraction system, which typically comprises a loop, in which cooled ethanol (maintained between -30°C and -40°C) is circulated. The solvent is removed by evaporation, and then the extract is further concentrated by distillation and filtration to remove impurities.

[0296] In such an exemplary extraction system, high temperature and pressure will produce decarboxylation (occurring at approximately 110°C at standard pressure). For example, if the intoxicating effects of THC are undesirable, an extraction method with temperatures and pressures below the aforementioned thresholds may be selected. Similarly, THC may be removed after extraction using, for example, column chromatography.

[0297] It should be understood that while this extraction system is disclosed as a series of steps, deviations from the steps are within the scope of the invention, as are modifications, removals, and additions to various steps at any point during the extraction process.

[0298] Furthermore, ethanol extraction is only one extraction method that can produce an extract that can be used in therapeutic combinations. In embodiments, other extraction methods and solvents can be utilized, non-limiting examples of which include subcritical and supercritical CO extraction, hydrocarbon extraction such as extraction with butane and / or propane, methanol extraction, isopropyl alcohol extraction, and other such extraction methods known to those skilled in the art. While any such extraction method can be used, it should be understood that certain extraction methods may provide specific benefits, depending on the desired composition of the extract.

[0299] As an example, supercritical extraction, such as supercritical CO2 extraction, can be used for the extraction of cannabinoids and the preservation of terpenoids; warm alcohol extraction is useful for the extraction and decarboxylation of cannabinoids, while also extracting various pigments and impurities; cold alcohol extraction is more successful than warm ethanol extraction in separating terpenes and cannabinoids from impurities, but is less efficient; on the other hand, hydrocarbon extraction, including butane and propane extraction, is effective in reducing impurities and pigments in extracts and may be more effective than cold alcohol extraction.

[0300] Primary and / or secondary bioactive molecules from Cannabis can be obtained via extraction of Cannabis plant material and can be used to prepare Cannabis-derived drug substances and Cannabis-derived drug products.

[0301] "Cannabis-derived drug substance" may refer to a botanical drug substance derived from the Cannabis plant (including plant parts, plant part biomass, and plant exudates), as a non-limiting, purely illustrative example, a primary extract prepared by methods including maceration, percolation, extraction with solvents such as C1-C5 alcohols (e.g., ethanol), hydrocarbons (e.g., propane, butane), and subcritical or supercritical carbon dioxide.

[0302] A "cannabis-derived drug product" may refer to a primary cannabis extract that has been further purified, for example, by distillation or chromatography. It is known to those skilled in the art that when certain solvents are used to prepare a primary extract, the resulting extract may contain nonspecific fat-soluble substances. Those skilled in the art will appreciate that these impurities can be removed by a variety of methods, including winterization (e.g., cooling to -20°C followed by filtration to remove waxy ballast), further extraction, or filtration and distillation.

[0303] iii. Exemplary extraction of molecules from Dipteryx plants

[0304] In embodiments, the therapeutic combination comprises a major and / or minor bioactive molecule from the Dipteryx plant. In embodiments, the major and / or minor bioactive molecule is obtainable by extraction of cumaru (coumarum) beans.

[0305] As mentioned, the primary bioactive molecule in Dipteryx is coumarin. In embodiments, coumarin can be extracted from cumaru beans by extraction with polar solvents such as, but not limited to, water, alcohols, including ethanol and methanol, and various ethers. Below, an exemplary extraction system utilizing ethanol is described.

[0306] In embodiments, ethanol extraction can be used to extract coumarins from cumaru beans. In embodiments, the ethanol extraction can be ethanol percolation, in embodiments, using anhydrous ethanol. In embodiments, the ethanol percolation extraction system works by first crushing the cumaru beans, allowing the ethanol solvent to enter and exit the beans. Preferably, the seeds are thoroughly ground to increase the surface area for extraction, forming a collection of plant material. The seed material is then placed in a filter located on top of a collection device. Ethanol is then poured over the seed material, which then passes through the filter and is collected in the collection device. In embodiments, this is continued until the color of the ethanol indicates that substantially no additional bioactive molecules have been collected.

[0307] Optionally, excess ethanol is then evaporated. This can be accomplished by applying heat to the resulting solution or utilizing ambient evaporation.

[0308] As known to those skilled in the art, other extraction methods may also be used. In addition, while coumarin is mentioned directly, it should be readily understood that, for example, secondary bioactive molecules from cumaru can also be extracted in the same or similar manner and that, when the exemplary ethanol extraction method is used, the secondary bioactive molecules may be present in the extract. Furthermore, the concentrations of primary and / or secondary bioactive molecules can be determined as disclosed herein.

[0309] b. Synthesis

[0310] In embodiments, the major and minor biologically active molecules disclosed herein can be synthetic, where "synthetic" herein can refer to substances made in the laboratory by chemical synthesis (e.g., by a series of chemical processes or reactions using chemical substrates, reagents, and optionally a catalyst) or biosynthesized as discussed herein (e.g., from bioengineered organisms, and thus including those compounds also referred to as "biosynthetic" or involved in "synthetic biology" or "synbio").

[0311] In general, methods for chemical synthesis are well known in the art, including for the bioactive molecules disclosed herein. Thus, methods for synthesizing bioactive molecules and / or starting materials will be readily apparent to one skilled in the art in view of general references known in the art (see, e.g., 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 where they are not otherwise available, e.g., by extraction. Generally, methods for similar 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; Pérez-Silanes et al., 2001; and references therein) are known and understood by those of ordinary skill in the art.

[0312] In embodiments, the disclosed major and minor biologically active molecules can be obtained via biosynthesis. Biosynthesis refers to the production of molecules, such as major and / or minor biologically active molecules used in therapeutic combinations, within a cell or cell-free system. In embodiments, the major and / or minor biologically active molecules useful in therapeutic combinations can be produced via biosynthesis.

[0313] Methods for the biosynthesis of biologically active molecules will be readily apparent to those skilled in the art in view of general references known in the art (see, for example, PCT Publication Nos. WO2021 / 052989, WO2019 / 173797, WO2021 / 086513, and WO2019 / 180309). Non-limiting examples of biosynthetic pathways known in the art include those for cannabinoids, flavonoids, carotenoids, psilocybin, psilocin and other indole alkaloids (e.g., major and minor bioactive molecules found in fungi), amino acids, and peptides (including monopeptides, dipeptides, tripeptides, and proteins).

[0314] In embodiments, the primary bioactive molecule and / or the secondary bioactive molecule from a fungus is produced by biosynthesis. In embodiments, the primary bioactive molecule and / or the secondary bioactive molecule from a plant is produced by biosynthesis. In embodiments, the primary bioactive molecule and / or the secondary bioactive molecule from an algae is produced by biosynthesis.

[0315] c. Separation, fractionation and purification

[0316] In embodiments, the major and / or minor bioactive molecules can be obtained via fractionation, separation and / or purification. Fractionation refers to a separation method in which a quantity of a mixture is divided into many smaller quantities, called fractions, during a phase transition, whose compositions vary according to a gradient.

[0317] In embodiments, fractions containing the target major and / or minor bioactive molecules can be obtained via fractional distillation, column chromatography, fractional crystallization, fractional freezing, and bioassay-guided fractionation.

[0318] In embodiments, separation of the primary and / or secondary bioactive molecules from an extract comprising the primary and / or secondary bioactive molecules can be accomplished. Many methods for isolating compounds from extracts are known to those skilled in the art. However, exemplary methods include thin layer chromatography, column chromatography, flash chromatography, sephadex chromatography, and high performance liquid chromatography (Sasidharan et al., 2011).

[0319] In embodiments, the extract may be further purified to isolate specific major and / or minor bioactive molecules. In embodiments, such purification techniques will be known to those skilled in the art, but may include HPLC and centrifugal partition chromatography (CPC).

[0320] d. Compounds

[0321] In embodiments, the disclosed primary and / or secondary bioactive molecules are pure or substantially pure. As used herein, the term "pure" or "substantially pure" refers to a material that is substantially or substantially free of components that normally accompany the material when the material 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) 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 an HPLC profile 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 any other active compounds that are not intended to be administered to a subject. As used herein, "substantially free" refers to the fact that, other than the primary and / or secondary bioactive molecule intended to be administered to a subject, no active compound(s) are detectable by HPLC or another similar detection method, or are below the desired detection threshold as defined above.

[0322] The disclosed primary and / or secondary biologically active molecules may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present invention encompasses all such possible isomers and mixtures thereof, including racemic and optically pure forms. Optical isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity.

[0323] The present invention also includes primary and / or secondary biologically active molecules having at least one desired isotope substituted with an atom in an amount greater than the natural abundance of the isotope, i.e., isotopically enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but different numbers of neutrons. For example, deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the structure to achieve the desired result. Alternatively or additionally, isotopes of carbon, such as 13C and 14C, can be used. Isotopic substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched in at least 60%, 70%, 80%, 90%, 95% or 99% or more of the isotope at any position of interest. In one embodiment, deuterium is enriched in 90%, 95% or 99% at the desired position.

[0324] The primary and / or secondary biologically active molecules of the therapeutic combination will be understood to also encompass pharmaceutically acceptable salts of such molecules. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, which can be synthesized by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of these agents with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol or acetonitrile) are preferred. For therapeutic use, salts of a compound are those in which the counterion is pharmaceutically acceptable. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-naphthalenesulfonate, 3-hydroxy-2-naphthalenesulfonate, 3-phenylpropionate, 4-acetamidobenzoate, acetylphylline, acetate, acetate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, benzenesulfonate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphorcarbonate, camphorate, camphorsulfonate, camphorsulfonate, carbonate, bile salt, citrate, clavulanate, cyclopentanepropionate, cyclopentane, d-aspartate, d-camphorsulfonate, d-lactate, decanoate, dichloroacetate, digluconate, dodecyl sulfate, edetate, edetate, hippurate, hepamine, Hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isosulfonate, l-aspartate, l-camphorsulfonate, l-lactate, lactate, lactobionate, laurate, laurylsulfonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, methanesulfonate, methanesulfonate, methyl bromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, naphthalene disulfonate, naphthalene disulfonate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate triethyl iodide, undecanoate, undecenoate, valerate, valproate, hydroxynaphthoate, zinc, etc. (See Berge et al., 1977).

[0325] Prodrugs of the primary and / or secondary biologically active molecules are also to be understood as being within the scope of the present invention. The term "prodrug" refers to a precursor of a biologically active agent. The prodrug undergoes a chemical or metabolic transformation to become the biologically active agent, e.g., the conversion of the prodrug psilocybin to its active metabolite, psilocin.

[0326] In the case of solid compositions, it will be understood that the disclosed primary and / or secondary bioactive molecules can exist in different forms. For example, the primary and / or secondary bioactive molecules can exist in stable and metastable crystalline forms, isotropic and amorphous forms, ground forms, and nanoparticle forms, all of which are intended to be within the scope of the present invention. In addition, the primary and / or secondary bioactive molecules include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of the bioactive molecule. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can lead to a single crystalline form dominating.

[0327] For any disclosed major and / or minor biologically active molecule, the substitution of the major and / or minor biologically active molecule by its ion, free base, salt form, polymorph, hydrate or solvate form, co-crystal, or isomerically or enantiomerically enriched mixture is to be understood as merely providing alternative embodiments that are still within the scope of the present invention (with modifications to formulation and dosage, if necessary or desired, based on the teachings herein and those of ordinary skill). Furthermore, the compositions within the scope of the present invention are to be understood as open ended and may include additional major and / or minor biologically active molecules, active or inactive agents, and ingredients.

[0328] In some embodiments, the disclosed major and / or minor biologically active molecules, or pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof, are produced and tested in accordance with Good Laboratory Practice (GLP) or Good Manufacturing Practice (GMP) requirements and / or their equivalents and any relevant practices, e.g., in Canada, the Good Manufacturing Practices (GPP) of Cannabis regulations when referring to the Cannabis plant.

[0329] D. Treatment Combinations

[0330] In some aspects are therapeutic combinations comprising primary and / or secondary bioactive molecules from fungi, plants and / or algae.

[0331] In embodiments, therapeutic combinations comprising a major and / or minor bioactive molecule from a fungus and a major and / or minor bioactive molecule from a plant will be synergistic or have a synergistic effect. In embodiments, therapeutic combinations comprising a major and / or minor bioactive molecule from a fungus and a major and / or minor bioactive molecule from a plant will be synergistic or have a synergistic effect. In embodiments, therapeutic combinations comprising a major and / or minor bioactive molecule from a fungus and a major and / or minor bioactive molecule from a plant will be synergistic or have a synergistic effect. In embodiments, therapeutic combinations comprising a major and / or minor bioactive molecule from a fungus and a major and / or minor bioactive molecule from a algae will be synergistic or have a synergistic effect. In embodiments, therapeutic combinations comprising a major and / or minor bioactive molecule from a plant and a major and / or minor bioactive molecule from a algae will be synergistic or have a synergistic effect.

[0332] E. Synergy and synergistic effects

[0333] In embodiments, "synergy" can refer to a combination that is more effective than the additive effect of any two or more single major and / or minor bioactive molecules. For example, a synergistic effect allows the use of individual therapies with lower amounts (dosages) to effectively treat a disease. This includes a lower dose of the first major and / or minor bioactive molecule or the second major and / or minor bioactive molecule ("apparent unidirectional synergy"), or a lower dose of both major and / or minor bioactive molecules ("bidirectional synergy") than is typically required when using major and / or minor bioactive molecules alone. In fact, lower doses result in lower toxicity without reducing efficacy. Compared to any monotherapy, a synergistic effect can additionally result in improved efficacy, including improved disease avoidance or reduction. A "synergistic effect" will also be understood to include an increase in effectiveness, biological activity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects), greater than the additive contribution of the components acting alone, and / or greater than the contribution of the isolated major and / or minor bioactive molecules themselves.

[0334] Many methods known to those skilled in the art can determine whether a particular effect exists in synergy, that is, whether the effect, when two or more components are mixed together, is greater than the sum of the effects of the components applied separately, resulting in "1+1>2". Suitable methods include contour plot (or contour) analysis (Huang et al., 2019) or the Loewe summation equation (Loewe & Muischnek, 1926). Synergistic effects can also be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981) and the median effect equation (Chou & Talalay, 1984). The corresponding graphs associated with the above equations are the concentration-effect curve and the combination index curve, respectively. Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs to help evaluate the effects of drug combinations.

[0335] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus and a major and / or minor bioactive molecule from Cannabis. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0336] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus and a major and / or minor bioactive molecule from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0337] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus and a major and / or minor bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0338] In embodiments, the combination comprises 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.

[0339] In embodiments, the combination comprises a primary and / or secondary bioactive molecule from Cannabis and a primary and / or secondary bioactive molecule from Pyropia or Porphyra. In embodiments, the combination will be synergistic or have a synergistic effect.

[0340] In embodiments, the combination comprises a major and / or minor bioactive molecule from Dipteryx and a major and / or minor bioactive molecule from Phyllostachys or Porphyra. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0341] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus, a major and / or minor bioactive molecule from Cannabis, and a major and / or minor bioactive molecule from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0342] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus, a major and / or minor bioactive molecule from Cannabis, and a major and / or minor bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0343] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus, a major and / or minor bioactive molecule from Dipteryx, and a major and / or minor bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0344] In embodiments, the combination comprises a major and / or minor bioactive molecule from Cannabis, a major and / or minor bioactive molecule from Pyropia or Porphyra, and a major and / or minor bioactive molecule from Dipteryx. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0345] In embodiments, the combination comprises a major and / or minor bioactive molecule from a psilocybin-producing fungus, a major and / or minor bioactive molecule from Cannabis, a major and / or minor bioactive molecule from the order Dipteryx, and a major and / or minor bioactive molecule from Pyropia or Porphyra. In some embodiments, the combination will be synergistic or have a synergistic effect.

[0346] In some embodiments, the disclosed therapeutic combinations are botanicals comprising minimal or low doses of whole extracts of C. sativa plants, P. cubensis fungi, P. yesoensis algae, and D. odorata beans relative to those otherwise understood or anticipated in the art, and synergy is the ability to provide an effect at a given dose. Because the disclosed combinations, compositions, and methods synergistically allow for the effective use of surprisingly low doses of one or more biologically active molecules, in some embodiments, these low doses will avoid receptor depletion, avoid activation of autoregulatory compensatory measures, or avoid induced compensatory neural responses.

[0347] F. Additional Active Agents

[0348] Therapeutic combinations can also be used with additional active agents that can, for example, contribute to or provide an additional therapeutic effect, or contribute to or provide a synergistic effect.

[0349] In an embodiment, the additional active agent is an agent useful for treating Parkinson's disease, including carbidopa-levodopa, carbidopa-levodopa (controlled release), carbidopa-levodopa (orally disintegrating tablets), carbidopa-levodopa (extended release capsules), carbidopa-levodopa (oral suspension), carbidopa-levodopa-entacapone (enteral suspension), levodopa, levodopa (inhalation powder), whole extract botanical forms of levodopa, for example. , velvet bean or broad bean, entacapone, tolcapone, opicapone, pramipexole, pramipexole (extended release), ropinirole, ropinirole (extended release), apomorphine (injection), apomorphine sublingual film, rotigotine (transdermal patch), selegiline, selegiline (orally disintegrating tablet), rasagiline, safinamide, amantadine, amantadine (extended release), istradefylline, trihexyphenidyl, benztropine, prcyclidine, trihexyphenidyl (trihexyphenidyl), orphenadrine and butantepol (posiphen, ANVS-401). In embodiments, the additional active agent can be administered in a separate dosage form or as a single dosage form comprising the primary and / or secondary biologically active molecule according to the present invention in combination with the additional active agent.

[0350] In embodiments, additional active agents are serotonergic agents. In embodiments, "serotonergic agent" refers to any compound that binds to, blocks or otherwise affects (e.g., by allosteric reaction) serotonin receptor activity, including any serotonin receptor subtype. In embodiments, serotonergic agents bind to serotonin receptors. In embodiments, 5-hydroxytryptamine energy agents indirectly affect serotonin receptors, such as by affecting the interaction of other molecules with the responsiveness of serotonin receptors. In embodiments, 5-hydroxytryptamine energy agents are agonists, such as compounds that activate serotonin receptors. In embodiments, serotonergic agents are antagonists, such as compounds that bind to but do not activate serotonin receptors, such as blocking receptors. In embodiments, serotonergic agents are effector molecules, such as compounds that are bound to enzymes for allosteric regulation. In embodiments, serotonergic agents (directly or indirectly) act on more than one type of receptor, including receptors other than serotonin energy or other monoamine receptors. In embodiments, serotonergic agents block the serotonin transporter (SERT) and result in an increase in the synaptic concentration of serotonin and an increase in neurotransmission. In embodiments, serotonergic agents are serotonin uptake or reuptake inhibitors. In embodiments, serotonergic agents act as reuptake modulators and inhibit the reuptake of serotonin mediated by plasma membrane transporters from synapses to presynaptic neurons, resulting in an increase in the extracellular concentration of serotonin and an increase in neurotransmission. In embodiments, serotonergic agents inhibit the activity of one or two monoamine oxidases, resulting in an increase in serotonin concentration and an increase in neurotransmission. In embodiments, serotonergic agents are antidepressants or antianxiety drugs, such as SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or atypical antidepressants. In other embodiments, the serotonergic agent is selected from the group consisting of: (1) a serotonin transport inhibitor; (2) a serotonin receptor modulator; (3) a serotonin reuptake inhibitor; (4) a serotonin and norepinephrine reuptake inhibitor; (5) a serotonin dopamine antagonist; (6) a monoamine reuptake inhibitor; (7) a pyridazinone aldose reductase inhibitor; (8) a serotonin receptor agonist; (9) a serotonin synthesis stimulator; (10) a serotonin receptor agonist; (11) a serotonin receptor antagonist; and (12) a serotonin metabolite.

[0351] In embodiments, additional activating agents can be one or more of phenolic compounds, terpenes, polysaccharides, polyphenols, lipids, organic acids, polyunsaturated fatty acids (PUFA) and tocopherols extracted from fungi, algae or plants. In embodiments, additional activating agents can be extracted from the genus comprising any of the following: Cheirolophus, Rhaponticoides, Volutaria, Zingiber, Rosmarinus, Salvia, Thymus, Origanum, Ocimum, Melissa, Mentha, Origanum, Satureja, Hyssopus, Laurus, Bacopa, Bupleurum, Camellia, Berberis and Lathyrus. In embodiments, additional activating agents are from the Zingiber genus, for example, from Zingiberofficinale. In embodiments, additional activating agents are from the Zingiber officinale rhizome. In embodiments, additional activating agents are from the Laurus genus, for example, from Laurus nobilis. In embodiments, additional activating agents are from Laurus nobilis leaves. In embodiments, the disclosed compositions comprise an additional active agent from Zingiber, such as from the rhizome of Zingiber officinale, and an additional active agent from Laurus, such as from the leaf of Laurus nobilis.

[0352] In an embodiment, the additional active agent can be any one or more of an amino acid, an antioxidant, an anti-inflammatory, an analgesic, an antidiabetic and antinociceptive agent, an anti-migraine agent, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD agent, a cannabinoid, an NMDA antagonist, a dissociative, an immunostimulant, an anticancer agent, an antiemetic, an appetite-generating agent, an antiulcer agent, an antihistamine, an antihypertensive, an anticonvulsant, an antiepileptic, a bronchodilator, a neuroprotective agent, a nootropic, a pyrogenic, analgesic and empathogenic agent, a hallucinogen, a monoamine oxidase inhibitor (including RIMA), a tryptamine, a terpene, a phenylethylamine, a sedative, a stimulant. These agents can be in ionic, free base or salt form and can be isomers, prodrugs, derivatives (preferably physiologically functional derivatives) or analogs.

[0353] G. Pharmaceutical Compositions

[0354] In some aspects, pharmaceutical compositions comprising therapeutic combinations are disclosed. A "pharmaceutical composition" (and simply, unless the context indicates otherwise, includes a "composition") comprises an amount (e.g., in unit dosage form) of the therapeutic combination together with a pharmaceutically acceptable carrier, diluent, or excipient. It should be understood that some embodiments do not have a single single carrier, diluent, or excipient, but rather have multiple carriers, diluents, and / or excipients.

[0355] In some embodiments, the disclosed combinations or compositions will include non-naturally occurring carriers, diluents, or excipients, examples of which will be known to those skilled 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 fungi, plants, and / or algae, or does not naturally occur in any of the same fungi, plants, and / or algae from which the extracts and / or bioactive molecules of the combinations or compositions are derived or derivable.

[0356] The compositions can be prepared by standard pharmaceutical formulation techniques, for example, as described 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" for use in conjunction with a drug means that the drug is generally safe, within the scope of sound medical judgment, suitable for use in contact with cells of humans and other animals, without excessive toxicity, irritation, allergic response or complications, and commensurate with a reasonable risk / benefit ratio.

[0357] 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 formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, patches, inhalers, nebulizers, pulsatile release formulations, multiparticulate formulations, immediate release, controlled release, sustained release, extended release and modified release formulations, as well as mixed immediate release and controlled release formulations.

[0358] In an embodiment, the pharmaceutical composition is formulated in unit dosage form. A "unit dosage form" refers to a physically discrete unit suitable for use as a unit dose for a patient to be treated, each unit containing a predetermined amount of a biologically active molecule calculated to produce the desired therapeutic effect, and a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms are typically used for ease of administration and uniformity of dosage. A unit dosage form may contain a single or individual dose or unit, subdose, or an appropriate portion thereof (e.g., half a "full" dose) of the administered pharmaceutical composition. Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampoules, and vials, which may include compositions in a freeze-dried or lyophilized state; for example, a sterile liquid carrier may be added prior to in vivo administration or delivery. Unit dosage forms include ampoules and vials in which a liquid composition is provided. Unit dosage forms include compounds for transdermal administration, such as "patches" that contact the patient's epidermis for a long or short period of time.

[0359] In an embodiment, the pharmaceutical composition is formulated into pharmaceutically acceptable oral dosage forms, including oral solid dosage forms and oral liquid dosage forms.

[0360] In an embodiment, the composition is formulated into a pharmaceutically acceptable oral solid dosage form, including lozenges, troches, tablets, capsules, caplets, powders, pills, multiparticulates, beads, spheres, capsules, pills and / or any combination thereof. Oral solid dosage forms can be formulated into immediate release, controlled release, sustained release, extended release or modified release formulations. In an embodiment, the solid dosage form may comprise a pharmaceutically acceptable excipient such as a filler, a diluent, a lubricant, a surfactant, a glidant, a binder, a dispersant, a suspending agent, a disintegrant, a viscosity increasing agent, a film former, a granulation aid, a flavoring agent, a sweetener, a coating agent, a solubilizing agent and a combination thereof. In an embodiment, the solid dosage form may comprise pharmaceutically acceptable additives, alone or in combination, such as compatible carriers, complexing agents, ion dispersion modifiers, disintegrants, surfactants, lubricants, colorants, wetting agents, plasticizers, stabilizers, wetting agents, defoamers, and supplementary active agents (one or more), including preservatives, antioxidants, antimicrobials including biocides, and biostatics (such as antibacterials, antivirals, and antifungals). Preservatives can be used to inhibit microbial growth or increase the stability of the active ingredient, thereby extending the shelf life of the pharmaceutical composition, and include EDTA, EGTA, benzalkonium chloride, or benzoic acid or benzoate, such as sodium benzoate. Antioxidants include vitamin A, vitamin C (ascorbic acid), vitamin E, tocopherols, other vitamins or provitamins, and compounds such as lipoic acid (ALA).

[0361] In an embodiment, the composition is formulated into a pharmaceutically acceptable oral liquid dosage form. Non-limiting examples of oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions and solutions, etc. In an embodiment, the oral liquid dosage form can be formulated with any pharmaceutically acceptable excipients and solvents, diluents, carriers, excipients, etc. for preparing liquid dosage forms known to those skilled in the art, and the solvents, diluents, carriers, excipients, etc. are appropriately selected according to 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, glycerol, monosyrups, alcohols, medium chain triglycerides (MCT) and combinations thereof.

[0362] In an embodiment, the oral liquid dosage form can be single-phase 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 a common solvent. In an embodiment, over time, the solid particles (i.e., bioactive molecules) in the oral liquid dosage form can form a precipitate at the bottom of the container - requiring vigorous shaking to redisperse the bioactive molecules. Examples of non-limiting single-phase liquid forms include syrups, clinical medicines, spirits / essences, elixirs, and fluid extracts. Non-limiting examples of biphasic liquid forms include oral suspensions, oral emulsions, and mixtures.

[0363] 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, alcohols, pharmaceutically suitable surfactants, suspending agents, and emulsifiers. In embodiments, liquid formulations can also be prepared as single-dose or multi-dose beverages. In embodiments, suspensions can include oils. 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) oils. In embodiments, suspension formulations can also include esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. In embodiments, suspension formulations can include alcohols, such as ethanol, isopropyl alcohol, hexadecanol; glycerol and propylene glycol. In embodiments, ethers, such as polyethylene glycol; petroleum hydrocarbons, such as mineral oil and vaseline; and water can also be used in suspension formulations. In embodiments, suspensions can therefore include aqueous or non-aqueous liquids, oil-in-water liquid emulsions, or water-in-oil emulsions.

[0364] In addition to the primary and / or secondary bioactive molecules, the liquid dosage form may include additives such as (a) disintegrants, (b) dispersants, (c) wetting agents, (d) preservatives, (e) viscosity enhancers, (f) sweeteners, and / or (g) flavorings. In addition to the additives listed above, in embodiments, the liquid formulations of the present invention may also include inert diluents commonly used in the art, such as water or other solvents, solubilizers, emulsifiers, flavorings, and / or sweeteners. In embodiments, cosolvents and adjuvants may also be added to the formulation.

[0365] In embodiments of modified release formulations, the plasma half-life is greater than that of the immediate release formulation by 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 values ​​therebetween. In embodiments of modified release formulations, the formulations are designed to produce comparable area under the curve or AUC0-24 and similar safety and efficacy profiles, but with a delayed 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 values ​​therebetween. In embodiments, the formulations are designed to have a specific time course based on the 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 greater than 4 hours, including time periods therebetween.

[0366] In embodiments, the formulation is selected based on its absorption area. In embodiments, a tincture may be selected based on pre-digestive absorption in epithelial tissue, such as the tinctures described in the formulation examples below.

[0367] In some embodiments, multiple formulations are combined, and the therapeutic combination comprises two or more pharmaceutical compositions together, which can be provided as a single pharmaceutical kit. In some embodiments, one or more parts of the therapeutic combination are provided as an inhalable formulation, such as for a soft mist inhaler, and the remainder of the combination is provided as a tincture. In embodiments, one or more parts of the therapeutic combination are provided as an inhalable formulation, and the remainder of the combination is provided as an orally disintegrating strip. In embodiments, one or more parts of the therapeutic combination are provided as a tincture, and the remainder of the combination is provided as an orally disintegrating strip. In embodiments, one or more parts of the therapeutic combination are provided as an inhalable formulation, and the remainder of the combination is provided as an oral spray formulation, such as an oromucosal spray formulation. In embodiments, one or more parts of the therapeutic combination are provided as a tincture, and the remainder of the combination is provided as an oral spray formulation. In embodiments, more than two separate formulations are combined, and the therapeutic combination therefore comprises more than two pharmaceutical compositions together, which can be provided as a single pharmaceutical kit. In an embodiment, more than three, more than four, more than five, or more than six separate formulations are combined, and the therapeutic combination thus together comprises more than two, more than three, more than four, more than five, or more than six pharmaceutical compositions, which can be provided as a single pharmaceutical kit.

[0368] In embodiments, the pharmaceutical composition is formulated into an inhalation formulation. Non-limiting examples of inhalation formulations include soft mist inhalation formulations, dry powder aerosol formulations, and vaporizer formulations. In embodiments, the inhalation formulation is a soft mist inhalation formulation ("soft mist" formulation). The soft mist formulation can be produced by combining a liquid containing a bioactive molecule in a cartridge or syringe. The cartridge or syringe is then placed in a soft mist inhaler device, such as those described in WO 2020 / 167893 and U.S. Patent No. 9,108,011. A solubilizer can also be selected to help homogenize the formulation (e.g., polysorbate 80, also known as Tween-80). In embodiments, the liquid containing the bioactive molecule can be a liquid extract obtained via the method disclosed herein, with or without a solubilizer. In embodiments, the inhalation formulation can be a dry powder aerosol formulation, wherein the bioactive molecule is obtained as a powder and atomized by an inhaler device, such as a metered dose inhaler (MDI).

[0369] In an embodiment, the inhalation formulation is a vaporizer formulation. The vaporizer formulation can be any of vaporizer juice, e-liquid, e-juice, etc. In an embodiment, the vaporizer formulation can be a liquid (comprising, for example, oil) and / or a solid (comprising, for example, wax or dry powder). In an embodiment, a vaporizer formulation can 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 on vape pens, e-cigarettes, e-cigarette pipes, and other such electronic smoking devices). Examples of suitable liquids include propylene glycol (PG), vegetable glycerin (VG), and polyethylene glycol (PEG). In an embodiment, the base liquid can also include a lower viscosity liquid to act as a diluent, including water and / or ethanol (wherein the ethanol can be an alcoholic beverage or spirits, including vodka). In an embodiment, the vaporizer formulation can additionally include flavorings, wherein the flavorings are any flavor concentrates known to those skilled in the art.

[0370] In an embodiment, the pharmaceutical composition is formulated as an effervescent powder.

[0371] In an embodiment, the pharmaceutical composition is formulated in a pharmaceutically acceptable transdermal application capable of being 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.

[0372] In an embodiment, the pharmaceutical composition is formulated for subcutaneous, intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, or intracerebroventricular injection ("injectable formulation"). In an embodiment, the injectable formulation can be prepared by dissolving, suspending, or emulsifying the primary and / or secondary biologically active molecules in an aqueous or non-aqueous solvent, non-limiting examples of which include oils, such as vegetable oils, synthetic fatty acid glycerides, and esters of higher fatty acids or propylene glycol; and may also contain additives such as solubilizers, stabilizers and suspending agents, preservatives, wetting agents, emulsifiers, dispersants, and isotonic agents.

[0373] In some embodiments, the composition is formulated for use in specific tissues or for specific routes of administration other than oral gastrointestinal administration, such as mucosal (e.g., sublingual, buccal, rectal, nasal), intramuscular, subcutaneous, dermal, intranasal, inhalation, etc. Such administration can result in reduced side effects, decreased toxicity, increased efficacy, improved selectivity, enhanced bioavailability, and minimization of drug-drug interactions.

[0374] Injectable formulations can include additives such as preservatives, wetting agents, emulsifiers and dispersants. Various antibacterial and antifungal agents can be used, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, sorbic acid, etc., to ensure that microbial growth is prevented, and isotonic agents can be included, such as sugar, sodium chloride, etc. The extended drug absorption of injectable pharmaceutical forms can be achieved by using reagents such as aluminum monostearate and gelatin that delay absorption. Injectable formulations designed for sustained release by SC or IM injection can avoid first-pass metabolism, and require lower doses of major and / or minor bioactive molecules to maintain required plasma levels. In such preparations, the particle size and size range of major and / or minor bioactive molecules can be used to control the release of major and / or minor bioactive molecules by controlling the dissolution rate in fat or muscle.

[0375] In an embodiment, the composition is formulated in a pharmaceutically acceptable nanostructured formulation, such as a nanoemulsion, nanocapsule, nanoparticle conjugate, or nanoencapsulated oral, sublingual, buccal, or nasal spray. In an embodiment, the nanostructured formulation is prepared by reference to common knowledge in the art (see, e.g., Jaiswal 2015).

[0376] In some preferred embodiments, where the therapeutic combination, pharmaceutical composition, or other formulation comprises a natural compound or a compound found in nature, at least one of the carriers, diluents, and / or excipients used in the disclosed combination, composition, or formulation is non-natural or non-naturally occurring, or the other agent (e.g., an additional active agent) is non-natural or non-naturally occurring, i.e., a natural compound is combined with a non-natural ingredient such that the combination, composition, or formulation comprises at least one non-natural ingredient.

[0377] As non-limiting and merely suggestive examples, the following formulations can be prepared and may also be used in the methods of the present invention.

[0378] In all of the exemplary formulation embodiments disclosed below, the formulation may comprise only bioactive molecules from fungi and bioactive molecules from plants (wherein "comprising only" means that there are no additional disclosed bioactive molecules, although the formulation may further comprise one or more carriers, diluents or excipients, other inactive ingredients and / or in some embodiments, additional active agents as disclosed herein). In embodiments, the formulation may comprise only bioactive molecules from a single genus of fungi and bioactive molecules from a single genus of plants (i.e., wherein the molecules are extracted, isolated, derived or otherwise obtained from a single genus, and not necessarily that they are only present in one genus). In embodiments, the formulation may comprise only bioactive molecules from a single species of fungi and bioactive molecules from a single species of plants (i.e., wherein the molecules are extracted, isolated, derived or otherwise obtained from a single species, and not necessarily that they are only present in one species). In embodiments, the formulation may comprise only one bioactive molecule from a fungus and one bioactive molecule from a plant.

[0379] In some embodiments, the formulation may include only bioactive molecules from species that produce psilocybin, and bioactive molecules from the Cannabis plant. In embodiments, the formulation may include only bioactive molecules from the species Psilocybeazurescens, Psilocybe bohemica, Psilocybe semilanceata, Psilocybe baeocystis, Psilocybe cyanescens, Psilocybe tampanensis, Psilocybe cubensis, Psilocybeweilii, Psilocybe hoogshagenii, Psilocybe stuntzii, Psilocybe cyanofibrillosa, or Psilocybe liniformans, and bioactive molecules from the Cannabis plant. In embodiments, the formulation may include only one bioactive molecule from a species that produces psilocybin, and one bioactive molecule from the Cannabis plant. In embodiments, the formulation may comprise only one bioactive molecule from the species Psilocybeazurescens, Psilocybe bohemica, Psilocybe semilanceata, Psilocybe baeocystis, Psilocybe cyanescens, Psilocybe tampanensis, Psilocybe cubensis, Psilocybeweilii, Psilocybe hoogshagenii, Psilocybe stuntzii, Psilocybe cyanofibrillosa, or Psilocybe liniformans, and one bioactive molecule from a Cannabis plant. In embodiments, the formulation may comprise only a bioactive molecule from a Psilocybe fungus and a bioactive molecule from a Cannabis plant. "Psilocybe fungus" refers to a Psilocybe spp. fungus. In embodiments, the formulation may comprise only one bioactive molecule from a Psilocybe fungus and one bioactive molecule from a Cannabis plant.

[0380] For example, each of the following embodiments can be made with only psilocybin (or psilocin) or both; only CBD (or THC), or both; and for each of coumarin, whole Pyropia extract, and ethanol, and ginger (and any other disclosed active or inactive ingredient), optionally, i.e., in some embodiments, any one or more of coumarin, whole Pyropia extract, and ethanol, and flavorings and / or coloring agents such as ginger (and any other disclosed active or inactive ingredient), can be excluded. Thus, in some embodiments, the exemplary formulations contain only psilocybin and CBD. In embodiments, the exemplary formulations contain only psilocybin and CBD. In embodiments, the exemplary formulations contain only psilocybin, psilocin, and CBD. In embodiments, the exemplary formulations contain only psilocybin, THC, and CBD. In embodiments, the exemplary formulations contain only psilocin, THC, and CBD. In embodiments, the exemplary formulations contain only psilocin, psilocin, and THC. In embodiments, the exemplary formulations contain only psilocybin and THC. In an embodiment, an exemplary formulation comprises only psilocin and THC. As described above, "comprising only" refers to no additional disclosed biologically active molecules, although the formulation may also include one or more carriers, diluents or excipients, other inactive ingredients, and / or, in some embodiments, active agents as disclosed herein or otherwise suitable for the formulation, such as are known in the art.

[0381] In some embodiments, any one or more of psilocybin, psilocin, THC, and CBD can be replaced with another bioactive molecule, such as another bioactive molecule from the same fungus or the same plant. In some embodiments, flavorings and / or coloring agents (equivalently and as abbreviated "flavorings / coloring agents") are optional. Therefore, any of the following embodiments that do not contain flavorings / coloring agents are additional embodiments. In some preferred embodiments, the "flavorings / coloring agents" in the examples are ethanol and ginger. In some embodiments, the formulations contain additional active agents. In the absence of active and / or inactive ingredients from the disclosed exemplary formulations, the formulations will be prepared as described together with those skilled in the art and knowledge, and with such modifications that will be understood by those skilled in the art. When an ingredient can be provided as a solid or as a liquid, the skilled person will understand how to convert between mass amounts and volume amounts, including having alternative or variable concentrations for the ingredient, whether as a solid or liquid.

[0382] Example 1: Tincture preparation

[0383] Prepare a tincture in the following proportions:

[0384]

[0385] Solutions are prepared by combining bioactive molecules from fungi, plants, and algae and / or extracts comprising them ("bioactive molecules and / or extracts comprising them") with flavorings and solvents. In an embodiment, the amount or ratio of an ingredient, for example when expressed as mass or percentage, includes the term "about." In some embodiments, "about" mass or "about" percentage, including the term "about" where the context implies, refers to a range of ±2%. Thus, for example, in an embodiment where psilocybin extract is 45% of the formulation, it will be understood that the amount in the embodiment refers to "about" 45% of the psilocybin extract, and in some such embodiments, an amount of "about" 45% refers to an amount of 45% ± 2%, i.e., between 43% and 47% psilocybin extract, including the end values. In some other embodiments, for example, an amount expressed as mass or percentage will also refer to "about" that amount, where "about" has the meaning described elsewhere.

[0386] In embodiments, a fungal extract comprises about 45% of each dose and contains about 400 μg of combined psilocybin and psilocin per dose; a cannabis extract comprises about 15% of each dose and contains about 1 mg of CBD and about 1 mg of THC per dose; a cumaru extract comprises about 2% per dose and contains about 1 mg of coumarin per dose; and an algae extract, which in embodiments is a Pyropia extract, comprises about 15% of each dose; a flavoring and / or coloring agent, which in some preferred embodiments is ethanol infused with ginger and bay leaves, and in some embodiments is another flavoring and / or coloring agent, which may be in ethanol, water, or another diluent, comprises about 15% of each dose; and added water comprises about 8% of each dose. In some embodiments, the tinctures or other liquid formulations herein further comprise a solubilizer, such as cyclodextrin, lecithin, propylene glycol, xanthan gum, or a combination thereof.

[0387] Tinctures can be prepared by exposing the fungal, plant, and / or algal material to a solvent capable of extracting the desired primary and / or secondary bioactive molecules, combining the extracts, and then optionally adding flavoring and / or coloring agents.

[0388] In some embodiments, the solvent is an alcohol. In embodiments, the alcohol can be, for example, 40% to 60% alcohol, or can be 80% to 90% alcohol and then diluted to between 40% and 60% alcohol. In some embodiments, the solvent is water. In some embodiments, the solvent can be an acid, such as acetic acid.

[0389] As an example, food coloring can be added to the tincture to provide a certain appearance to the solution and can include additional compounds sufficient to improve the taste of the tincture. In embodiments, the food coloring can include compounds that improve the bioactivity of the primary and / or secondary bioactive molecules. Examples of suitable food colorings 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.

[0390] In some embodiments, the patient will be administered one dose of a tincture having the ingredients in the amounts formulated above, two doses of a tincture in the amounts formulated above, three such doses per day, four such doses, five such doses, or more than five such doses per day. In some preferred embodiments, the daily dose is four such doses.

[0391] Example 2: Oral spray formulation and oral mucosal spray formulation

[0392] An oral spray formulation can be prepared containing the same ingredients, amounts (units) of ingredients, and total ratios as in Example 1. When the oral spray formulation is formulated for oral mucosal (e.g., sublingual or buccal) administration, it may further contain a penetration enhancer and / or a mucoadhesive polymer.

[0393] Example 3: Soft mist inhalation preparation

[0394] A soft mist inhalation formulation was prepared as follows, comprising the same ingredients, amounts (units) of the ingredients, and overall ratios as in Example 1 above: a solution was prepared by mixing bioactive molecules from fungi, plants, and algae and / or extracts containing them with a flavoring / coloring agent and a solvent.

[0395] The bioactive molecules and / or extracts comprising them are mixed and combined. The combined bioactive molecules and / or extracts comprising them can then be combined with ethanol and / or water, and optionally a preservative, such as benzalkonium chloride, in a volume of, for example, 15 mL. Reference may be made to Anderson, 2006 and Dalby, Eicher, and Zierenberg, 2011, both of which are incorporated herein by reference in their entirety.

[0396] Example 4: Evaporator Formulation

[0397] A vaporizer formulation comprising 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, 16 mg of flavoring / coloring agent, and 10 mL of a 50:50 base liquid (50% PG, 50% VG) is prepared as follows: the bioactive molecules and / or extracts comprising them (in solid form and / or as part of one or more liquid extracts) are mixed and combined with a 50:50 base liquid, the 50:50 base liquid being prepared for use in any liquid vaporization device or appliance, such as an e-liquid vaporizer, e-cigarette, mod, vaporizer pen, etc. Flavoring / coloring agents (e.g., comprising ginger and / or bay laurel) may optionally be added. The formulation can also be prepared for use in any oil, thin oil, e-juice, or e-liquid vaporizer according to conventional techniques.

[0398] Example 5: Tablet and Scorable Dual Strength Tablet Formulations

[0399] 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 Pyropia extract, 170 mg of microcrystalline cellulose, 10 mg of colloidal silicon dioxide, and 7.5 mg of stearic acid are prepared by mixing the bioactive molecules and / or extracts containing them with other ingredients and compressing them into tablets.

[0400] Scored double-strength 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 Pyropia 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% aqueous solution) are prepared as follows: the bioactive molecules and / or extracts comprising them, starch, and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The PVP solution is mixed with the resulting powder, which is then passed through a No. 16 mesh U.S. sieve. The granules thus prepared are dried at 50-60° C. and passed through a No. 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules and, after mixing, compressed into tablets on a tablet press. The tablets are scored to provide the ability to produce an equivalent half-dose.

[0401] Example 6: Capsule preparation

[0402] Capsules, each 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 mixing the bioactive molecules and / or extracts containing them with cellulose and / or starch and magnesium stearate, passing them through a No. 20 mesh U.S. sieve, and filling the blended mixture into hard or soft gelatin capsules.

[0403] Example 7: Alternative capsule formulations, optionally with additional active agents

[0404] Capsules, each 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 biologically active molecules and / or extracts comprising them, the cellulose and / or starch, and the magnesium stearate are mixed, passed through a No. 20 mesh U.S. sieve, and filled into hard or soft gelatin capsules. Optionally, an additional active agent can be added during blending. In some embodiments, the additional active agent is a serotonergic agent, such as an antidepressant or anxiolytic. In some embodiments, the additional active agent is an antiparkinsonian agent, such as levodopa, amantadine, a dopaminergic antiparkinsonian agent (e.g., a dopamine agonist), an anticholinergic antiparkinsonian agent, or another antiparkinsonian agent, such as an adenosine A2A antagonist, a COMT inhibitor, an MAO-B inhibitor, or another such antiparkinsonian agent as described herein or generally known in the art.

[0405] Example 8: Suspension formulation

[0406] A suspension 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 25-50 mg of levodopa is prepared as follows: the bioactive molecules and / or extracts comprising them are mixed with 1.75 g of sucrose and 4 mg of xanthan gum, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared aqueous solution of 50 mg of sodium carboxymethylcellulose (11%) and 50 mg of microcrystalline cellulose (89%). 10 mg of sodium benzoate and optional flavoring / coloring (quod vide) are diluted with some water and added with stirring. Levodopa may be added at 5-10 mg / mL. Sufficient water is then added to produce 5 mL.

[0407] Example 9: Intravenous solution formulation

[0408] An intravenous formulation comprising 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 biologically active molecules and / or extracts comprising them are dissolved in an appropriate 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 general knowledge in the art. It will be understood that the amount of each biologically active molecule and / or extract can be adjusted accordingly to achieve the desired mg / mL.

[0409] Example 10: Injectable solution preparation

[0410] An injectable formulation comprising 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 5 mL of isotonic saline can be prepared as follows: the biologically active molecules and / or extracts comprising them are dissolved in a suitable solvent, such as isotonic saline or another suitable solvent; additional active or inactive ingredients, such as preservatives, may be added, as described above and within the knowledge of the art. It will be understood that the amount of each biologically active molecule and / or extract can be adjusted accordingly to achieve the desired mg / mL.

[0411] Example 11: Topical Formulations for Transdermal Administration

[0412] A topical formulation comprising 400 μg of psilocybin, 250 μg of psilocin, 2 mg of CBD, 2 mg of THC, 2 mg of coumarin, 8 mg of whole Pyropia extract, 30 mg of emulsifying wax, and 20 mg of liquid paraffin, with the amount of white soft paraffin equal to a total of 100 g, 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 molecule and / or extract containing the same and continue stirring until dispersed. The mixture is then cooled until solid.

[0413] Example 12: Cut Matrix Sublingual or Buccal Tablet Formulations

[0414] 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 Pyropia extract, 210.5 mg of glycerin, 143 mg of water, 4.5 mg of sodium citrate, 26.5 mg of polyvinyl alcohol, and 15.5 mg of polyvinyl pyrrolidone (PVP) are prepared as follows: glycerin, water, sodium citrate, polyvinyl alcohol, and PVP are mixed by continuous stirring while maintaining a temperature of about 90°C. When the polymer has dissolved, the solution is cooled to about 50-55°C and the bioactive molecules and / or extracts containing them are slowly mixed in. The homogeneous mixture is poured into a form made of an inert material to produce a drug-containing diffusion matrix with a thickness of about 2-4 mm. The diffusion matrix is ​​then cut to form individual tablets of appropriate size.

[0415] Example 13: Separately formed sublingual or buccal lozenge formulations

[0416] 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 Pyropia extract, 350 mg of silica gel powder, 400 mg of citric acid powder, 600 mg of gum arabic powder, 1 g of polyethylene glycol (PEG), and optionally 100 mg of flavoring / coloring agent are prepared as follows: silica gel powder, citric acid powder, gum arabic powder, optional flavoring / coloring agent, and PEG are mixed by continuous stirring at a temperature of about 90° C. When the PEG has melted and the other ingredients have entered the solution, the solution is cooled to about 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. Reference may also be made to U.S. Patent No. 10,034,832 and its examples.

[0417] Example 14: Intranasal Delivery Formulation

[0418] A nasal spray formulation for intranasal delivery, comprising 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, 5 mL of MCT, in saline (1% cremaphor) to a total formulation of 10 mL, can be prepared as follows: a solution of approximately 1 mg / mL of the bioactive molecule and / or extract comprising them in 49.5% MCT, 49.5% saline, 0.5% DMSO, and 0.5% cremaphor is prepared 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 molecule and / or extract comprising them with lactose and mixing for use with a dry powder inhaler, or as described in U.S. Publication No. US2015 / 0367091A1 and references cited therein.

[0419] In some exemplary embodiments, the disclosed therapeutic combinations or pharmaceutical compositions comprise the primary biologically active molecules in the following table, from each listed component of the combination or composition, and such combinations or compositions can be formulated according to any of the examples herein, or in a number of other exemplary formulations according to this disclosure and general knowledge in the art:

[0420]

[0421]

[0422]

[0423]

[0424]

[0425] Note that while certain major and / or minor bioactive molecules and certain extracts containing them are disclosed above, this should not be construed as limiting the invention, nor should it be construed as limiting the formulation of Example 1 to the major and / or minor bioactive molecules disclosed above. Thus, in embodiments, the formulation of Example 1 (or any other example herein) contains more or less major and / or minor bioactive molecules than disclosed; including any major and / or minor bioactive molecules disclosed herein for each of the fungal, cannabis, cumaru, and algae extracts.

[0426] In some alternative embodiments of this embodiment, the formulation comprises at least one bioactive molecule from a fungus, including bioactive molecules from species that produce psilocybin (e.g., Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, and Pluteus), and at least one bioactive molecule from a plant, including bioactive molecules from cannabinoid-producing species (e.g., Cannabis). In some such alternative embodiments, the formulation does not comprise other bioactive molecules from fungi and bioactive molecules from plants other than bioactive molecules from species that contain psilocybin and from species that produce cannabinoids. In some such alternative embodiments, the formulation does not comprise other bioactive molecules from fungi and bioactive molecules from plants other than bioactive molecules from the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, and Pluteus, and from the genus Cannabis. In some such alternative embodiments, the formulation does not contain a bioactive molecule from Dipteryx. In some such alternative embodiments, the formulation does not contain a bioactive molecule from algae, marine algae, the Bangiaceae family, or the genera Pyropia and Porphyra. In some such alternative embodiments, the only bioactive molecules are psilocybin, psilocin, CBD, and THC. In some such alternative embodiments, the only bioactive molecules are psilocybin, CBD, and THC. In some such alternative embodiments, the only bioactive molecules are psilocybin and CBD. In some such alternative embodiments, the only bioactive molecules are psilocybin and THC. In some such alternative embodiments, the only bioactive molecules are psilocin, CBD, and THC. In some such alternative embodiments, the only bioactive molecules are psilocin and CBD. In some such alternative embodiments, the only bioactive molecules are psilocin and THC. In some such alternative embodiments, the only bioactive molecules are psilocin, CBD, and THC. In some such alternative embodiments, the only bioactive molecules are psilocin and CBD. In some such alternative embodiments, the only bioactive molecules are psilocin and THC.

[0427] It will be readily understood that the above formulation examples are illustrative only. Any of the primary and / or secondary biologically active molecules disclosed herein can be used in the above formulation examples, and within the dosage ranges applicable to the primary and / or secondary biologically active molecules. It should be understood that reference to specific primary and / or secondary biologically active molecules is merely exemplary, and that the biologically active molecules may be substituted for other primary and / or secondary biologically active molecules disclosed herein in any instance.

[0428] Furthermore, it will be readily appreciated 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) to a single carrier, diluent and / or excipient, but may also include a combination 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 comprise any of the primary and / or secondary bioactive molecules disclosed above. This means that, in embodiments, the disclosed compositions comprise primary and / or secondary bioactive molecules from fungi, plants and algae, optionally in combination with one or more other bioactive molecules (or derivatives and analogs thereof), in combination with one or more pharmaceutically acceptable carriers, diluents and / or excipients, and additionally in combination with one or more other active agents.

[0429] In embodiments, the disclosed compositions will be prepared to enhance an existing therapeutic effect, provide an additional therapeutic effect, increase adhesion or ease of use, increase a desired property such as stability or shelf life, reduce an unwanted effect or property, alter a property in a desired manner (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide a synergistic effect.

[0430] "Therapeutic effects" that may be increased or augmented in embodiments of the present invention include, but are not limited to, antioxidant, anti-inflammatory, analgesic, antidiabetic, antinociceptive, antimigraine, antianxiety, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulatory, anticancer, antiemetic, appetite, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, nootropic, emotional, psychedelic, sedative or stimulatory effects, as well as such effects known to improve symptoms caused by movement disorders.

[0431] In embodiments, the inclusion of additional active agents is intended to achieve the goal of increasing the effect of an existing treatment, providing an additional therapeutic effect, increasing compliance or ease of use, increasing a desired property such as stability or shelf life, reducing an undesired 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 otherwise inducing a synergistic effect.

[0432] The type of formulation used to administer the disclosed primary and / or secondary biologically active molecules employed in the disclosed methods can generally be determined by the primary and / or secondary biologically active molecules employed, the route of administration, and the type of pharmacokinetic profile desired for the primary and / or secondary biologically active molecules, as well as the patient's condition. It will be readily understood that any of the above-described embodiments and categories of embodiments can be combined to form additional embodiments.

[0433] a. Route of administration

[0434] The disclosed pharmaceutical compositions are suitable for administration by a variety of routes. Non-limiting examples of routes of administration include enteral administration, such as oral, sublingual, buccal, and rectal administration, parenteral administration, including bolus injection or continuous infusion, intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, vaginal, ocular, nasal, dermal, topical, aural, ophthalmic, transdermal, and subcutaneous administration.

[0435] In an embodiment, the pharmaceutical composition is administered in oral solid and oral liquid dosage forms; sublingually or buccally; as an injection, including intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, and intraventricular; rectal, vaginal, ophthalmic, nasal, dermal, topical, otic, transdermal, and subcutaneous.

[0436] In embodiments where administration is enteral, parenteral, or both, an effective amount of the primary and / or secondary bioactive molecule is administered systemically to the subject. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered orally to the subject. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered intravenously to the subject. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered to the subject by inhalation. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered to the subject by nasal administration. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered by injection to the subject. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered topically (transdermally) to the subject. In embodiments, an effective amount of the primary and / or secondary bioactive molecule is administered to the subject by ocular administration. In embodiments, an effective amount of the primary and / or secondary bioactive molecule 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 the subject by other means and are prepared as any acceptable composition known to those skilled in the art. In embodiments, such compositions may be prepared in any manner known in the pharmaceutical art to comprise at least one biologically active molecule (Sheth, 1980).

[0437] In embodiments, the primary and / or secondary biologically active molecules disclosed herein are administered by a variety of routes, which can vary between subjects, e.g., patients, based on subject preference, comorbidities, side effect profiles, pharmacokinetic and pharmacodynamic considerations, and other factors. In embodiments, there are other substances with the primary and / or secondary biologically active molecules known to those skilled in the art, such as modifications in the formulation to facilitate absorption by various routes (e.g., gastrointestinal, transdermal, etc.), to prolong the effect of the drug, and / or to achieve higher or more stable serum levels or to enhance the therapeutic effect of the primary and / or secondary biologically active molecules disclosed herein.

[0438] In an embodiment, the pharmaceutical composition is suitable for oral solid or oral liquid dosage forms, sublingual, buccal, rectal, vaginal, ophthalmic, otic, nasal, cutaneous, topical and transdermal administration; or intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular and subcutaneous injection, wherein such injections include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0439] In an embodiment, the pharmaceutical composition can be administered enterally or parenterally, wherein enteral modes include, but are not limited to, oral solid and oral liquid dosage forms, sublingual and buccal administration, and rectal administration; and parenteral modes of administration include, but are not limited to, bolus injection or continuous infusion, intravenous, intraarterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, vaginal, ocular, nasal, dermal, topical, otic, transdermal, and subcutaneous administration; in addition to other equivalent means known to those skilled in the art.

[0440] Enteral administration includes administration involving any part of the gastrointestinal tract. Non-limiting examples include those of oral administration, including oral solid and oral liquid dosage forms, and rectal administration, and in some embodiments can preferably be formulated into tinctures. Parenteral administration refers to administration in any manner not involving the gastrointestinal tract, including intravenous (into a vein), intraarterial (into an artery), intraosseous infusion (into the bone marrow), intramuscular (into a muscle), intracerebral (into the brain parenchyma), intraventricular (into the ventricular system), intrathecal (injection into the spinal canal), ear (through the ear), eye (through the eye), vaginal (into the vagina) and subcutaneous (subcutaneous). In embodiments, parenteral administration may include sublingual and / or buccal administration. In embodiments, the pharmaceutical composition may be administered to a subject via injection. In embodiments, the pharmaceutical composition may be administered via the nasal system or by, for example, oral solid and / or oral liquid dosage forms; inhaled via nasal spray or oral inhaler; atomized, from a nebulizer, such as a machine that turns liquid medicine into mist; or oral / sublingual administration. In embodiments, the pharmaceutical composition may be administered to a subject by a combination of modes of administration. In embodiments, the pharmaceutical composition can be administered to a subject by enteral administration. In embodiments, the pharmaceutical composition can be administered to a subject by parenteral administration. In embodiments, the composition can be administered to a subject by at least one enteral administration and at least one parenteral administration. In embodiments, equivalent administration routes known to those skilled in the art are utilized.

[0441] In some embodiments, the therapeutic combination can be administered via multiple routes of administration. For example, in embodiments, the fungal portion of the disclosed combination is administered via one route of administration, and the plant part (one or more) and algae portion are administered via different routes of administration. In embodiments, the plant part of the disclosed combination is administered via one route of administration, and the fungal and algae portions are administered via different routes of administration. In embodiments, the algae portion of the disclosed combination is administered via one route of administration, and the plant part (one or more) and fungal portion are administered via different routes of administration.

[0442] Administration of different (fungal, plant, or algae) portions of the disclosed combination to different tissues can maximize the therapeutic effect of the combination, resulting in reduced side effects, reduced patient discomfort, and / or increased bioavailability. In one illustrative example, the disclosed combination comprises: a plant portion comprising a cannabinoid (e.g., THC) or a Cannabis extract, which is administered to the oral mucosa by spray; while the remaining ingredients (e.g., fungal, plant, and / or algae portions) are delivered to the epithelial cells in the lungs via a soft mist inhaler. In some embodiments, administration according to this exemplary procedure results in reduced throat irritation (e.g., in individuals sensitive to inhaled Cannabis or cannabinoids), maximizes the bioavailability of the remaining ingredients (e.g., fungal, plant, and / or algae portions), and improves the pharmacokinetic profile of the components of the therapeutic combination; for example, by accelerating the uptake of the longer-lasting plant portion (e.g., THC or Cannabis extract) while slowing the uptake of the shorter-lasting plant portion.

[0443] In another example, the disclosed combination includes an algae portion comprising Pyropia or a Pyropia extract that is administered to the oral mucosa via an oral spray, while the remaining ingredients (e.g., fungal, plant, and / or algae portions) are delivered to the epithelial cells in the lungs via a soft mist inhaler. In some embodiments, administration according to this exemplary procedure results in reduced throat irritation, maximizes the bioavailability of the ingredients (e.g., fungal, plant, and / or algae portions), and improves the pharmacokinetic profile of the components of the therapeutic combination, for example, by accelerating the uptake of the long-lasting portion while slowing the uptake of the shorter-lasting algae portion (e.g., Pyropia or a Pyropia extract).

[0444] B. Method of administration

[0445] In some aspects, methods of administration or administration of 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. Such terms will be understood to include people with indications for which the combinations, compositions, or methods described herein may be effective, or who may otherwise benefit from the present invention. Generally, all combinations, compositions, and methods of the present invention will be understood to work for all individuals, although individual variations are expected and will be understood.

[0446] The present invention provides methods of using a therapeutically effective amount of a pharmaceutical composition of the present invention containing a major and / or minor biologically active molecule disclosed herein in a mammal, preferably a human. These methods include methods for treating movement disorders, including methods for treating movement disorders in healthy individuals.

[0447] 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 biologically active molecules that is sufficient to provide the desired therapeutic effect, e.g., to alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of the disease or condition, or any other desired alteration in a biological system. A "therapeutically effective amount" includes, for example, a prophylactically effective amount.

[0448] An "effective amount" of a primary and / or secondary biologically active molecule disclosed herein is an amount effective to achieve the 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 the metabolism of a compound, such as a primary and / or secondary biologically active molecule disclosed herein, age, weight, 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 condition being treated or the health benefit being sought, the weight and age of the subject, the severity of the disease condition or the extent of the health benefit being sought, the mode of administration, etc., all of which can be readily determined by a skilled artisan. In addition, pharmacogenomic (the effect of genotype on the pharmacokinetics, pharmacodynamics, or efficacy of a therapeutic agent) information about a particular patient may affect the dosage used.

[0449] As used herein, "therapeutic effect" or "therapeutic efficacy" refers to a response in a mammal, preferably a human, that is judged to be desirable and beneficial following treatment. Thus, these responses will vary depending on the condition being treated or the improvement in physiological or psychological function being sought, as well as on the specific component(s) of the compositions of the present invention being considered, but will be readily understood by those skilled in the art. For example, in embodiments, a "therapeutic effect" may refer to an effect caused by a disclosed composition, or its use in a method of the present invention, such as the treatment of movement disorders disclosed herein.

[0450] "Therapeutically effective dose" refers to the dose necessary to elicit a desired outcome in a patient undergoing treatment. Thus, in embodiments, a therapeutically effective dose may refer to the dose of a pharmaceutical composition or therapeutic combination necessary to deliver a measurable, patient-specific biological effect in treating or preventing a condition or disorder. "Therapeutically effective dose" may be used interchangeably with "therapeutically effective amount" or "effective amount."

[0451] H. Dosage

[0452] 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 symptoms being treated, the desired clinical endpoint, previous, concurrent or subsequent therapy, the general health, age, sex and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other conditions or diseases in the subject, and other factors that will be appreciated by those skilled in the art (e.g., medical or family history).

[0453] In embodiments, wherein the combination and / or composition comprises a major and / or minor bioactive molecule from a fungus, the major and / or minor 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 greater 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.

[0454] In all embodiments herein including a dose of less than about 1 mg, such dose will be understood to include further specific doses 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.

[0455] In all embodiments herein including dosage amounts of at least about 1 mg or more, up to and including about 75 mg, such dosage amounts will be understood to include the following further specific dosage amounts (all such milligram dosage amounts will also be understood to be preceded 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 , 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, and amounts within these ranges.

[0456] In all embodiments herein including doses of 75 mg and greater than 75 mg, including 100 mg, 150 mg, 200 mg or greater than 200 mg, such doses will be understood to include 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. 01mg, 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, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 133 mg, 134mg, 137mg, 138mg, 139mg, 140mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 1 52mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg, 161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg In some embodiments, the dosage may be greater than 200 mg, including 225 mg, 250 mg, or greater than 250 mg.

[0457] In embodiments wherein the combinations and / or compositions comprise major and / or minor bioactive molecules from fungi, the major and / or minor bioactive molecules may be present in an amount such that a single dose (whether or not such dose is presented 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, and 5 μg or less), or at least about 100 μg, or greater, and greater than 1000 μg, including 1500 μg, 2000 μg, up to and including 5000 μg, and in some embodiments, greater than 5000 μg.

[0458] In all embodiments herein including a dose of about 100 μg or less, such embodiments will be understood to include further specific doses including about 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, and about 5 μg or less.

[0459] In all embodiments herein comprising a dosage amount of at least about 100 μg or more, and greater than 1000 μg, including 1500 μg, 2000 μg, up to and including 5000 μg, such embodiments will be understood to include further specific dosage amounts, including 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 0μg, 220μg, 230μg, 240μg, 250μg, 260μg, 270μg, 280μg, 290μg, 300μg, 310μg, 320μg, 330μg, 3 40μg, 350μg, 360μg, 370μg, 380μg, 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, 670μg, 680μg, 680μg, 700μg, 710μg, 720μ g, 730μg, 740μg, 750μg, 760μg, 770μg, 780μg, 780μg, 860μg, 870μg, 880μg, 890μg, 900μg, 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, greater than 5000 μg.

[0460] In some embodiments, wherein the primary bioactive molecule from the fungus is any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, or beta-carboline, it may be present in an amount such that a single dose (whether or not such dose is presented in a unit dosage form) is about 100 μg or less, at least about 100 μg or more, and greater than 1000 μg, including 1500 μg, 2000 μg, up to and including 5000 μg.

[0461] In embodiments, where the secondary bioactive molecule from a fungus is a polysaccharide, a peptide, a terpene or terpenoid, a phenolic compound, a mineral, a vitamin, an amino acid, a lipid, a choline, or a lactone, it 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 greater 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.

[0462] In embodiments, wherein the combination and / or composition comprises a major and / or minor bioactive molecule from a plant, the major and / or minor 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 greater 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.

[0463] For example, in some embodiments, the primary bioactive molecule from the plant is a cannabinoid, THC, CBD, a flavonoid or flavonoid, a terpene or terpene-like compound, a carbohydrate, a fatty acid or fatty acid ester (FAE), an amide, an amine, a phytosterol, a phenolic compound, a coumarin, a compound derived from coumarin, i.e., a coumarin derivative (e.g., phenylpropionic acid, coumarin or coumarin-like compound), a coumarin, an isoflavone, a lupeol derivative, a fatty acid ester, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxyretusin-8-methyl-ether, 5-methoxyanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, coumaroyl-β-glucoside, chrysin, salicylic acid, eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaroyl-β-D-glucose, methyl linolenate, methyl oleate, o-coumaric acid, o-hydroxycoumaric acid, odoratin, p-hydroxy-benzoic acid, retusin, retusin-8-methyl-ether, sulfuretin, salicylic acid, afrormisin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin and umbelliferone, which may be present in an amount such that a single dose (whether or not such dose is 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.

[0464] In embodiments, wherein the combination and / or composition comprises a major and / or minor bioactive molecule from algae, the major and / or minor 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 greater 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.

[0465] For example, in some embodiments, where the primary bioactive molecule from the algae is a porphyra polysaccharide or oligoporphyra polysaccharide, a polysaccharide, an oligopolysaccharide, a monosaccharide, a peptide, a phycobiliprotein, a mycosporin-like amino acid, an essential amino acid, a non-essential amino acid, a carotene or an intermediate carotenoid, a glycoprotein, an aminosulfonic acid (such as taurine), a mineral, a vitamin, a lipid, a phenolic compound, or a brown algae polyphenol, it can be present in an amount such that a single dose (whether or not the dose is in a unit dosage form) is less than about 1 mg, about 1 mg, or greater 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 greater than 200 mg.

[0466] In some embodiments, the disclosed therapeutic combinations (i.e., particularly those comprising a bioactive molecule from a fungus and a bioactive molecule from a plant) are administered at 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, 100 mg and 500 mg, and preferably 100 mg and 400 mg. In embodiments, each individual dose of the disclosed therapeutic combination is 5 mg to 500 mg, or 10 mg to 400 mg, or preferably 10 mg to 100 mg.

[0467] In embodiments, a therapeutically effective dose of the primary and / or secondary biologically active molecule will be administered to the patient on a regular or chronic basis, wherein the primary and / or secondary biologically active molecule is administered to the patient daily, several times a day (at least once, at least twice, at least three times, at least four times, or more than four times a day); on a repeating schedule wherein the patient is administered a therapeutically effective dose of the first and / or secondary biologically active molecule every other day, every third day, every fourth day, every fifth day, every sixth day, every seventh day, or more than every seventh day; or, in some embodiments, a varying schedule consisting of multiple "on" days (wherein a therapeutically effective dose of the primary and / or secondary biologically active molecule is administered) and multiple "off" days (wherein no administration occurs), e.g., one day two days off, two days three days off, three days four days off, or other such schedules apparent to those skilled in the art (see, e.g., the so-called Paul Stamets or James Fadiman microdosing regimens).

[0468] It should be understood that in embodiments, the actual dose administered will be determined by the physician based on the relevant circumstances, delivery method, age of the patient, weight of the patient, whether the patient has any comorbidities, other medications the patient is taking (regular or current), and any patient-specific aspects that may affect the way the primary and / or secondary bioactive molecules interact with the patient, such as changes in metabolism, changes in patient response, etc., and therefore any dosage ranges disclosed herein are not intended to limit the scope of the invention. In some cases, a dosage level below the lower limit of the disclosed range may be sufficient, while in other cases, a dosage above the range may be employed without causing any harmful side effects, provided that, for example, such a larger dose can also be divided into several smaller doses for administration together or separately.

[0469] In such embodiments, the primary and / or secondary biologically active molecules can be administered and dosed according to good medical practice, taking into account the method and timing of administration, prior and concomitant medications and medical 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 medical practitioner, as well as knowledge of the specific compound being used. Dosage levels may vary from patient to patient, over time for individual patients, and for different combinations and formulations, but should be determined by one of ordinary skill. Determination of appropriate dosages should include not only the determination of a single dose, but also the determination of the route of administration, the number and timing of the doses, and the time of day or one or more times during psychotherapy that are preferred for their administration.

[0470] In an embodiment, the patient may be on a dosing schedule as described above, but may administer the dose to themselves. In an embodiment, the combination and / or disclosed composition may be prescribed to a patient, where the patient obtains a therapeutically effective dose from a pharmacy or healthcare provider.

[0471] The dosage amount, frequency, or duration can be increased or decreased as indicated by the desired clinical outcome, the state of the pathology or symptoms, any adverse side effects of the treatment or therapy, or concomitant medications. The concentrations or concentration ratios of the components of the disclosed combinations and compositions can also be changed as indicated by the desired clinical outcome, the state of the pathology or symptoms, any adverse side effects of the treatment or therapy, or concomitant medications. For example, in some embodiments, the disclosed combinations contain tryptamines (such as psilocin and / or psilocybin, for example, as components of fungal parts, such as fungal extracts from fungi containing psilocin and / or psilocybin). In some such embodiments, a composition with a reduced concentration of tryptamine (e.g., psilocin and / or psilocybin) can be administered to patients taking monoamine oxidase inhibitor (MAOI) drugs, as MAOIs are expected to reduce the metabolic excretion of tryptamines, thereby affecting the ratio and synergistic effect of the bioactive molecules after administration of the disclosed compositions. In another example, the percentages of the components of the disclosed compositions can be increased or decreased based on individual tolerance. For example, individuals who frequently consume cannabis products often develop a tolerance to the effects of cannabinoids. Thus, in some embodiments, individuals with significant tolerance to Cannabis or cannabinoids (e.g., THC) can be administered a composition with an increased THC concentration to address this tolerance. In yet another example, individuals with certain medical conditions may be particularly sensitive or tolerant to the effects of the disclosed compositions. By way of example only, in some embodiments, individuals with Lewy body dementia (LBD) can be administered a disclosed composition comprising a reduced concentration of a cannabinoid (e.g., THC) or a Cannabis extract, for example, if there is reasonable suspicion (e.g., at the discretion of a physician or another medical practitioner) that the cannabinoid or Cannabis extract may exacerbate cognitive or psychiatric symptoms of LBD and / or increase the patient's sensitivity to the composition or any component thereof. In another merely illustrative example, individuals with clinical depression can be administered a disclosed composition with an increased concentration of a tryptamine (e.g., psilocin and / or psilocybin, e.g., as a component of a fungal portion, such as a fungal extract from a psilocin- and / or psilocybin-containing fungus), which can provide clinical advantages, such as promoting serotonin regulation, neuroplasticity, and connectivity.

[0472] Those skilled in the art, having the benefit of this disclosure, will understand the factors that can influence the dosage, frequency, and timing necessary to provide an amount sufficient or effective to provide a therapeutic effect or benefit, and depending on the type of therapeutic effect desired, as well as to avoid or minimize adverse effects.

[0473] In other embodiments, appropriate dosages to achieve a therapeutic effect, including the upper and lower limits of any dosage range, can be determined by individuals, including individuals who are not clinicians, by reference to available public information and knowledge, as well as by reference to subjective considerations of desired results and effects.

[0474] In an embodiment, 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 an embodiment, the biologically active molecules in the therapeutic combination can be formulated separately into pharmaceutical compositions, which are then administered to the patient separately, sequentially, or simultaneously.

[0475] In an embodiment, sequential administration refers to administering one combination drug immediately after administering another combination drug (e.g., within about 5 minutes of administering the first combination drug), simultaneous administration refers to administering each combination drug at substantially the same time, and separate administration refers to administering over time between administrations. In embodiments in which the combination drug is administered separately, such administration can include administering over a period of time between each administration of about 5 minutes to about 30 minutes, about 10 minutes to about 60 minutes, about 30 minutes to about 180 minutes, about 180 minutes to about 360 minutes, or more than 360 minutes, such as 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 duration therebetween, as readily understood by those skilled in the art.

[0476] The time that passes between administrations is not confused with the frequency with which administration occurs. As will be appreciated by those skilled in the art, the frequency of administration may depend on the disease and symptoms being treated, and by the administration of the primary and / or secondary bioactive molecules disclosed herein. As a non-limiting example, it may be desirable to administer the combination drug from about once to about eight times a day, including once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, and eight times a day; in some embodiments, one of the combination drugs (i.e., one of the bioactive compounds in the combination) may be administered twice a day or three times a day, while the other combination drug is administered once a day or twice a day, and any other combination drug is administered according to an applicable appropriate administration schedule.

[0477] In addition, the dosing schedule can continue for a specific duration, including 1-7 days, or greater than 7 days, including 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 days, in the same pattern or a modified pattern; and the manner in which dosing is accomplished (i.e., via separate, sequential, or simultaneous administration) can be adjusted as needed so that the entire dosing schedule can include only sequential, simultaneous, or separate administration; or can include a combination of two of sequential, simultaneous, or separate administration; or can include all sequential, simultaneous, or separate administration. That is, in embodiments, the frequency of dosing and the duration of time that elapses between administrations will depend on the specific primary and / or secondary biologically active molecules utilized and the condition for which treatment is sought.

[0478] In embodiments, administration may comprise separate, sequential or simultaneous oral administration, sublingual administration, buccal administration, intravenous injection, intraarterial injection, intraperitoneal injection, intraosseous injection, intramuscular injection, intrathecal injection, intracerebroventricular injection, rectal administration, vaginal administration, ocular administration, nasal administration, dermal administration, topical administration, otic administration, transdermal administration or a combination thereof, as will be apparent to one skilled in the art, depending on the desired therapeutic effect. Furthermore, as mentioned, in embodiments, the combination drug is administered to a patient by more than one administration, wherein each administration is not by the same means of administration. As disclosed herein, this may be advantageous in cases where the primary and / or secondary biologically active molecules have different durations of action and maximum plasma concentrations.

[0479] In embodiments, the primary and / or secondary biologically active molecules disclosed herein are administered separately. In embodiments, the primary and / or secondary biologically active molecules disclosed herein are administered sequentially. In embodiments, the primary and / or secondary biologically active molecules disclosed herein are administered simultaneously. In embodiments, the timing of administration of the primary and / or secondary biologically active molecules disclosed herein (including whether more than one administration of the primary and / or secondary biologically active molecules is desired) will depend on the specific primary and / or secondary biologically active molecules administered to the individual and the indication for which treatment is sought.

[0480] a.Drug kit

[0481] In an embodiment, particularly where the formulation is prepared in a single unit dosage form, the recommended dose should be known by reference to the form of the formulation itself. In other embodiments, the recommended dose may be known by reference to the mode of administration or by reference to the packaging and labeling, package inserts, sales materials, training materials, or other information and knowledge available to those skilled in the art or the public. Therefore, another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present invention, a recommended administration guide or its prescription information, and a suitable container. A single unit dosage form may be included in a multi-dose kit or container. The pharmaceutical composition may also be packaged into a single or multiple unit dosage form to make the dosage uniform and easy to administer. Therefore, another aspect of the present disclosure provides a pharmaceutical kit comprising a pharmaceutical composition or formulation of the present invention, a recommended administration guide or its prescription information, and a suitable container. A single unit dosage form may be included in a multi-dose kit or container. The pharmaceutical composition may also be packaged into a single or multiple unit dosage form to make the dosage uniform and easy to administer.

[0482] In an exemplary pharmaceutical kit, capsules, tablets, caplets, or other unit dosage forms are packaged in a blister pack. "Blister pack" refers to any of several types of preformed containers, especially plastic packaging, which contains individual containers (e.g., cavities or pockets) for individual unit doses, wherein such individual containers are individually sealed and can be opened individually.

[0483] Blister packs include such pharmaceutical packaging known to those skilled in the art, including Rx160, Rx20e, SupRx and UltRx 2000, 3000, 4000 and 6000 (Honeywell). Within the definition of multidose container, and also commonly referred to as blister pack, are blister trays, blister cards, strip packs, press-through packs, and the like. Preferably, information regarding dosage and proper administration (if desired) is printed directly on the multidose kit (e.g., on a blister pack or other inner packaging containing the disclosed combination or composition); however, the kits of the invention may further comprise a package insert and other printed instructions (e.g., on the outer packaging) for administering the disclosed combination or composition and its appropriate therapeutic use.

[0484] In an embodiment, the patient will have the option of using online software such as a website or downloadable software such as a mobile application to help with compliance or provide data related to the treatment. Such software can be used, for example, to track the last dose taken and the total dose taken, provide reminders and alarms for upcoming doses, provide feedback to prevent taking doses outside the set schedule, and allow recording of specific subjective effects, or provide means for unstructured logging. This data collection can help individual patient compliance, can be used to improve or customize individual patient care plans, and can be anonymized, aggregated and analyzed (including by AI or natural language processing means) to allow research into the effects of various treatments.

[0485] I. Treatment Methods

[0486] In some aspects are methods of preventing or treating movement disorders comprising administering to a patient a disclosed therapeutic combination or pharmaceutical composition.

[0487] Without being bound by theory, the disclosed combinations, compositions, and methods may be used in some embodiments to treat movement disorders due to their redundant, promiscuous effects on CNS signaling capabilities. In some embodiments, such effects include improvements in neuronal cytoarchitecture integrity and density, neurotransmitter synthesis and regulation, enhanced neuroprotection, and active utilization of plasticity mechanisms (e.g., BDNF, serotonergic muscle control, and glial networks).

[0488] In some embodiments, the disclosed combinations, compositions, and methods can be used to address malfunctions within these neural systems and address multiple contributors to the pathophysiology of movement disorders such as Parkinson's disease. In embodiments, each component of the disclosed combinations and compositions can affect these neural circuits in multiple ways, such as having different pharmacodynamics, a wide range of activities supported by privileged access and provision of exogenous inputs from natural sources. In one example, the disclosed combinations and compositions affect multiple immune and mitochondrial interfaces, which, combined with their effects on CNS signaling capacity, collectively and synergistically produce effective therapeutics for movement disorders such as Parkinson's disease.

[0489] In some aspects, the disclosed combinations, compositions and methods are useful for treating movement disorders due to their redundant, promiscuous negative regulation of pro-inflammatory cycles, for example by directly and indirectly (amplifying) reducing the interference of the cytokines TNF-α and IL-1β with the NF-Kβ and AP-1 transduction machinery, reducing oxidative ROS, NO and MPO, and activating the anti-inflammatory networks PPAR-γ and NRf2.

[0490] In some aspects, the disclosed combinations, compositions and methods can be used to treat inflammation and oxidative systems that contribute to movement disorders, such as the pathophysiology of Parkinson's disease. For example, neurodegeneration in movement disorders has been proposed to be characterized by metal homeostasis disorders and oxidative stress (Trist et al., 2018). Oxidative stress has been well documented in Parkinson's disease and is attributed to dopamine oxidative metabolism (Ahlskog, 2005). Oxidative mechanisms are associated with substantia nigra cell death in Parkinson's disease (Jenner, 1998). In embodiments, the disclosed combinations interact synergistically with inflammation and oxidative systems by, for example, collaboratively avoiding receptor depletion, activating self-regulatory compensatory measures and / or inducing immune responses. In some embodiments, the disclosed combinations have antioxidant properties, which are not subject to theoretical constraints and directly or indirectly treat or prevent movement disorders, such as by mediating or reducing the oxidative stress associated with the disorder.

[0491] In some embodiments, the disclosed combination can be used to treat inflammation and oxidative systems. As an illustrative example, Parkinson's disease is generally consistent with a significant loss of dopaminergic neurons in the substantia nigra (Meiser et al., 2013). Oxidative stress is associated with the loss of dopaminergic neurons, and dopamine metabolism itself is considered to be closely related to oxidative stress because its degradation produces reactive oxygen species (ROS), and dopamine oxidation can lead to endogenous neurotoxins (ibid.). Therefore, without being bound by theory, dopamine metabolism is of particular importance for neuronal redox homeostasis and viability. In embodiments, the disclosed combination plays an antioxidant effect that can be used to treat or prevent Parkinson's disease or another movement disorder. In embodiments, the antioxidant effect of the disclosed combination, for example, prevents or reduces the loss of dopaminergic neurons in individuals with Parkinson's disease or another movement disorder by reducing oxidative stress. In embodiments, reducing oxidative stress includes reducing the concentration of ROS associated with dopamine metabolism. In embodiments, reducing oxidative stress includes neutralizing (e.g., chemically reducing) ROS associated with dopamine metabolism. In embodiments, the antioxidant effect of the disclosed combination reduces the concentration of endogenous neurotoxins associated with dopamine oxidation. In embodiments, the antioxidant effect of the disclosed combination promotes neuronal redox homeostasis. In embodiments, the antioxidant effect of the disclosed combination promotes neuronal viability.

[0492] In addition, in some embodiments, the antioxidant effect of the disclosed combination can be measured by changes in biomarkers of movement disorders (e.g., Parkinson's disease), for example, changes in iron levels (e.g., reduction), and / or reductions in the concentrations of enzymes and substrates associated with oxidative stress. Several biomarkers of oxidative stress are associated with Parkinson's disease (Frijhoff, 2015). In embodiments, the biomarkers are substantia nigra cell death, free iron, glutathione (GSH), glutathione disulfide (GSSG), nuclear factor erythroid 2-related factor 2 (NRF2), advanced glycation end products (AGE), aldehyde 4-hydroxynonenal (HNE), malondialdehyde (MDA), F2-isoprostane, iso-L-adenosine (isoLG), nitrotyrosine (NO 2-Tyr) or a combination thereof. In embodiments, the biomarker is substantia nigra cell death. In 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 (AGE). In embodiments, the biomarker is the aldehyde 4-hydroxynonenal (HNE). In embodiments, the biomarker is malondialdehyde (MDA). In embodiments, the biomarker is F2-isoprostane. In embodiments, the biomarker is iso-L-adenosine (isoLG). In embodiments, the biomarker is nitrotyrosine (NO2-Tyr).

[0493] In some embodiments, the antioxidant effect of the disclosed combination can lead to a reduction in biomarkers of oxidation (e.g., biomarkers of oxidative stress). In embodiments, the concentration of a biomarker is reduced by about at least 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 the range between these values. In embodiments, the concentration of a biomarker is reduced by at least 99%. In embodiments, the concentration of a biomarker is reduced by about 99%. In embodiments, the concentration of a biomarker is reduced by about 98%. In embodiments, the concentration of a biomarker is reduced by about 95%. In embodiments, the concentration of a biomarker is reduced by about 90%. In embodiments, the concentration of a biomarker is reduced by about 85%. In embodiments, the concentration of a biomarker is reduced by about 80%. In embodiments, the concentration of a biomarker is reduced by about 75%. In embodiments, the concentration of a biomarker is reduced by about 70%. In embodiments, the concentration of a biomarker is reduced by about 65%. In embodiments, the concentration of a biomarker is reduced by about 60%. In embodiments, the concentration of a biomarker is reduced by about 55%. In embodiments, the concentration of a biomarker is reduced by about 50%. In embodiments, the concentration of a biomarker is reduced by about 45%. In embodiments, the concentration of a biomarker is reduced by about 40%. In embodiments, the concentration of a biomarker is reduced by about 35%. In embodiments, the concentration of a biomarker is reduced by about 30%. In embodiments, the concentration of a biomarker is reduced by about 25%. In embodiments, the concentration of a biomarker is reduced by about 20%. In embodiments, the concentration of a biomarker is reduced by about 15%. In embodiments, the concentration of a biomarker is reduced by about 10%. In embodiments, the concentration of a biomarker is reduced by about 5%. In embodiments, the concentration of a biomarker is reduced by about 4%. In embodiments, the concentration of a biomarker is reduced by about 3%. In embodiments, the concentration of a biomarker is reduced by about 2%. In embodiments, the concentration of a biomarker is reduced by about 1%. In embodiments, the concentration of a biomarker is reduced by less than 1%.

[0494] In some embodiments, the antioxidant properties and antioxidant effects of the disclosed combinations can be measured by total antioxidant assays, as disclosed in Apak, 2007. In embodiments, the total antioxidant assay is the Folin-Ciocalteu assay. In embodiments, the total antioxidant assay is the 2,2-diphenyl-1-picryl (DPPH) assay. In embodiments, the total antioxidant assay is the Trolox equivalent antioxidant capacity (TEAC) assay. In embodiments, the total antioxidant assay is the ferric iron reducing antioxidant power (FRAP) assay. In embodiments, the total antioxidant assay is the total antioxidant capacity (TAC) assay. In embodiments, the total antioxidant assay is the superoxide dismutase (SOD) assay. In embodiments, the total antioxidant assay is the lipid peroxidation assay. In embodiments, the total antioxidant assay is the hydroxyl radical scavenging assay. In embodiments, the total antioxidant assay is the copper ion reducing antioxidant power (CUORAC) assay.

[0495] 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. In embodiments, the synergistic effect is, for example, a synergistic effect in antioxidant capacity, potency, bioactivity, bioaccessibility, bioavailability, therapeutic effect, or a combination thereof.

[0496] "Treatment" encompasses 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 susceptible to the disorder but has not yet been diagnosed with the disorder; (b) inhibiting the disorder, i.e., preventing its development (including, for example, prevention); (c) alleviating the disorder, i.e., causing regression of the disorder or its clinical symptoms; (d) protecting against or alleviating symptoms or pathology caused by or associated with the disorder; (e) reducing, lowering, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency, or probability of one or more symptoms or pathologies associated with the disorder; and (f) preventing or inhibiting the worsening or progression of symptoms or pathologies associated with the disorder. It should be understood that the therapeutic amount necessary to achieve treatment for the purposes of the present invention will be an amount that, for example, provides an objective marker of improvement in a patient with clinically diagnosable symptoms. The effect may be prophylactic in terms of completely or partially preventing the disorder or its symptoms, and / or therapeutic in terms of partially or completely curing the disorder and / or the side effects attributable to the disorder.

[0497] It can be determined whether a patient has a movement disorder based on common techniques. Without being bound by theory, movement disorders are typically diagnosed after the presence of movement symptoms. Examples of methods for diagnosing movement disorders include genetic tests that detect known abnormalities that may indicate movement disorders, tests of blood, urine, and cerebrospinal fluid; a disease-specific drug trial that can be used to alleviate disease symptoms, nuclear imaging, magnetic resonance imaging (MRI), computed tomography (CT), observation of current symptoms (including observation of facial expressions), observation of limbs for tremors and gait for any abnormalities, assessment of neck stiffness, assessment of balance (including the time required to restore balance), patient medical history information, and additional testing to exclude any similar diseases. Because a variety of diseases and conditions have characteristic symptoms of movement disorders, diagnosis can include a combination of the above methods and can include other methods known to those skilled in the art.

[0498] In embodiments, measures of treatment effectiveness include outcome measures (primary or secondary), endpoints, effect measures, and effect measures within clinical or medical practice or research that can be used to assess the effects of an intervention or treatment (positive and / or negative), whether or not reported by the patient (e.g., questionnaires); based on other patient data (e.g., patient monitoring); by laboratory tests such as those collected from blood or urine; by medical examination by a physician or other healthcare professional, or by digital means, such as by using electronic tools such as online tools, smartphones, wireless devices, biosensors, or health apps.

[0499] In embodiments, measures of therapeutic efficacy include (a) symptom severity, (b) motor control, (c) MDS-UPDR, (d) UPDR, and (e) UPDRS-8.

[0500] In the embodiment, the measurement of the therapeutic effect includes (a) DaTscan to measure dopamine transporter system dysfunction, and (b) αSyn-SAA (α-synuclein seed amplification assay). DaTscan involves injecting technetium-99m (a tropane derivative) into the blood, where the tropane derivative binds to the dopamine transporter in the brain. A gamma camera then detects the radiation and creates an image detailing the distribution and density of dopamine transporters in the brain. The integrity of dopamine-producing cells in specific areas of the brain can then be assessed according to known methods. αSyn-SAA studies the aggregation and propagation of abnormal α-synuclein protein structures, which may play a role in the progression of neurodegenerative diseases such as Parkinson's disease. αSyn-SAA includes seed formation (e.g., the production or isolation of abnormal α-synuclein), propagation, amplification, and detection (e.g., immunohistochemistry, immunofluorescence, or ELISA).

[0501] In embodiments, movement disorders refer to a group of neurological (neurological) conditions that cause abnormal increases, decreases, reductions, or slowing of movements, which may be voluntary or involuntary (Mayo Clinic, 2017). In embodiments, movement disorders include amyotrophic lateral sclerosis (ALS), ataxias, including ataxias, congenital ataxias, hereditary ataxias (e.g., Friedreich's ataxia, ataxia due to cerebrotendinous xanthomatosis, ataxia due to refsum disease, ataxia due to abetalipoproteinemia, hereditary episodic ataxias, ataxias due to mitochondrial mutations, and spinocerebellar ataxias), non-hereditary degenerative ataxias (e.g., late-onset cerebellar cortical atrophy), acquired ataxias (e.g., ataxia due to alcoholic cerebellar degeneration), cervical dystonias, chorea forms of the disorder, including chorea chorea, benign hereditary chorea, secondary chorea (e.g., chorea due to Wilson disease, chorea due to infectious or parainfectious causes, chorea due to systemic lupus erythematosus, drug-induced chorea, and rheumatic chorea), dystonias, including dystonia, primary dystonias (e.g., benign essential blepharospasm), secondary dystonias (e.g., drug-induced dystonia, dystonia+, and dystonia associated with genetic degenerative disorders), paroxysmal dystonias and functional dystonias or spasticity, functional movement disorders, Huntington disease, multiple system atrophy, myoclonus, Parkinson disease, including sporadic Parkinson disease and familial Parkinson disease Parkinson's disease, including atypical Parkinson's disease (e.g., progressive supranuclear palsy, infectious or post-infectious Parkinson's disease, vascular Parkinson's disease, drug-induced Parkinson's disease, post-traumatic Parkinson's disease, and Parkinson's disease due to structural lesions) and functional Parkinson's disease, atypical Parkinson's disease, young-onset Parkinson's disease (YOPD), restless legs syndrome, tardive dyskinesia, L-dopa-induced dyskinesia, tremor-related disorders, including 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 Specific central nervous system disorders causing tremor) and functional tremor, tic disorders, including primary tics or tic disorders (e.g., Tourette syndrome, chronic motor tic disorder, chronic vocal tic disorder, and transient motor tics), secondary tics (e.g., infectious or post-infectious tics and tics associated with developmental disorders), myoclonic disorders (e.g., primary myoclonus, segmental myoclonus, focal myoclonus such as palatal myoclonus and chronic hiccups), Wilson disease, hemifacial spasm, certain specific movement disorders (e.g., stereotypies such as primary stereotypies and secondary stereotypies), Rett syndrome, akathisia and exaggerated startle reflex, sleep-related movement disorders,These include restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism, sleep-related rhythmic movement disorder, benign sleep myoclonus of infancy, propriospinal myoclonus at sleep onset, sleep-related movement disorders due to a medical condition, sleep-related movement disorders due to medications or substances, and REM sleep behavior disorder, and hereditary spastic paraplegia, including autosomal dominant hereditary spastic paraplegia, autosomal recessive hereditary spastic paraplegia, and X-linked hereditary spastic paraplegia.

[0502] In some embodiments, the movement disorder is ataxia, ataxia disorder, a specific movement disorder, cervical dystonia, chorea, choreiform disorder, dystonia, dystonia, essential tremor, Friedreich's ataxia, functional movement disorder, hemifacial spasm, hereditary spastic paraplegia, Huntington's disease, L-dopa-induced movement disorder, multiple system atrophy (MSA), myoclonus, myoclonic disorder, Parkinson's disease, atypical parkinsonism, parkinsonism, secondary parkinsonism, progressive supranuclear palsy (PSP), restless legs syndrome, Rett's syndrome, sleep-related movement disorder, spasticity, tardive dyskinesia (TD), In some embodiments, the movement disorder is Parkinson's disease (PD).

[0503] Parkinson's disease is a disorder that primarily affects dopamine-producing (dopaminergic) neurons in a specific area of ​​the brain called the substantia nigra. PD symptoms typically develop slowly over several years (although some aggressive forms of PD are known, and the disclosed invention is also applicable to treating such aggressive forms) (Elkouzi, n.d.).

[0504] Without being bound by theory, motor control is achieved through numerous interactions between various neural cell groups in the CNS, one such group being in the substantia nigra (SN). Substantia nigra neurons generate an extensive network of axonal projections that innervate the basal ganglia, establishing primarily symmetrical synapses with the dendritic spines and shafts of medium spiny projection neurons (Triarhou, 2002). SN neurons communicate with neurons of the basal ganglia by releasing the neurotransmitter dopamine (DA).

[0505] Those with PD typically experience damage and / or death of dopamine-producing nerve cells in the basal ganglia, which leads to a reduction and cessation of dopamine production, respectively. This prevents the signaling cascade and downstream effects caused by dopamine release, and therefore prevents fine motor control. Brain cells in PD patients also frequently contain Lewy bodies, which are clumps of alpha-synuclein that, while poorly understood, are hypothesized to regulate neurotransmitter release. Patients with Lewy bodies may develop Lewy body dementia (LBD), which is associated with a depletion of acetylcholine (affecting memory and thinking) and dopamine (further affecting movement) in the brain.

[0506] Furthermore, PD is often characterized by a loss of nerve endings that produce norepinephrine, the primary chemical messenger of the sympathetic nervous system, which may explain the non-motor features of PD. As therapeutic combinations gradually interfere with inflammation-mediated PD progression, synergistic functions, including activation of alternative signaling networks and improved cell viability / energetics provided by BDNF-mediated plasticity, may work synergistically to deliver systemic, low-dose, disease-modifying treatments or adjunctive therapies to address Parkinson's disease.

[0507] In embodiments, the therapeutic combination effectively increases endogenous dopamine, serotonin, and norepinephrine. In embodiments, the therapeutic combination effectively increases endogenous dopamine, serotonin, and norepinephrine by any of the following: activation and mediation of the se...

Claims

1. A therapeutic combination for preventing or treating movement disorders, comprising: a. Fungal part; b. the first plant part; c. optionally a second plant part; and d. Algae part.

2. The therapeutic combination according to claim 1, comprising: a. Fungal part; b. the first plant part; c. a second plant part; and d. Algae part.

3. The therapeutic combination of claim 2, wherein the fungal portion is from a species that produces psilocybin.

4. The therapeutic combination of claim 3, wherein the psilocybin-producing species is from any one of the following genera: Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe.

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

6. The therapeutic combination of claim 5, wherein the psilocybin-producing species from the genus Psilocybe is any one of the following: 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.

7. The therapeutic combination according to claim 2, comprising: a. Fungal parts from species of the genus Psilocybe; b. the first plant part; c. a second plant part; and d. Algae part.

8. The therapeutic combination according to claim 2, wherein the first plant part is from a species of the genus Cannabis.

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

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

11. The therapeutic combination according to claim 10, comprising: a. Fungal parts from species of the genus Psilocybe; b. a first plant part from a species of the genus Cannabis; c. a second plant part; and d. Algae part.

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

13. The therapeutic combination according to claim 12, wherein the Dipteryx species is Dipteryx odorata.

14. The therapeutic combination according to claim 2, comprising: a. Fungal part; b. the first plant part; c. a second plant part from a species of the genus Dipteryx; and d. Algae part.

15. The therapeutic combination according to claim 14, comprising: a. Fungal parts of species of the genus Psilocybe; b. a first plant part from a species of the genus Cannabis; c. a second plant part from a species of the genus Dipteryx; and d. Algae part.

16. The therapeutic combination of claim 2, wherein the algae portion is from a marine algae species.

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

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

19. The therapeutic combination of claim 18, wherein the marine algae species is any one of Pyropiayezoensis, Pyropiaperforata, and Porphyra umbilicalis.

20. The therapeutic combination according to claim 2, comprising: a. Fungal part; b. the first plant part; c. a second plant part; and d. Algal parts from the genera Pyropia or Porphyra.

21. The therapeutic combination according to claim 20, comprising: a. Fungal parts from species of the genus Psilocybe; b. a first plant part from a species of the genus Cannabis; c. a second plant part from a species of the genus Dipteryx; and d. Algal parts from the genera Pyropia or Porphyra.

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

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

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

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. The therapeutic combination of claim 8, wherein the first plant part comprises a Cannabis plant extract from a species of the genus Cannabis.

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

28. The therapeutic combination according to claim 27, wherein the Cannabis plant extract is obtained by Soxhlet extraction.

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

30. The therapeutic combination according to claim 29, wherein the Dipteryx plant extract is from Dipteryxodorata.

31. The therapeutic combination according to claim 30, wherein the Dipteryx plant extract is obtained by diafiltration against anhydrous ethanol.

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

33. The therapeutic combination of claim 32, wherein the algae extract is from Pyropiayezoensis, Pyropiaperforata, or Porphyra umbilicalis.

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

35. The therapeutic combination according to claim 2, comprising: a. Fungal extracts from species of the genus Psilocybe; b. Cannabis plant extracts from species of the genus Cannabis; c. Dipteryx plant extracts from species of the genus Dipteryx; and d. Algae extracts from the genera Pyropia or Porphyra.

36. The therapeutic combination according to claim 35, comprising: 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 diafiltration into anhydrous ethanol; and d. Algae extract obtained by ultrasonic extraction.

37. The therapeutic combination according to claim 35 or 36, comprising: a. Fungal extracts containing psilocybin and psilocin; b. Contains Δ 9 -Cannabis plant extracts of THC (THC) and cannabidiol (CBD); c. Dipteryx plant extract containing coumarin; and d. Algae extract containing Porphyra polysaccharide.

38. The therapeutic combination according to claim 21, comprising: a. The part of the fungus that contains psilocybin and psilocin; b. Contains Δ 9 - a first plant part containing THC (THC) and cannabidiol (CBD); c. a second plant part comprising coumarin; and d. Algal fraction comprising Porphyra polysaccharide.

39. The therapeutic combination of any one of claims 1-36, wherein the fungal portion comprises a bioactive molecule from a fungus.

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

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

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

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

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

45. The therapeutic combination of claim 44, wherein the weight ratio of psilocybin to psilocin is about 5:

3.

46. ​​The therapeutic combination of claim 41, wherein the one or more beta-carbolines is any one of harmane, harmine, harmol, pinoline, harmaline, cordysinin C, cordysinin D, norharmane, and perlolyrine.

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

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

49. The therapeutic combination according to any one of claims 1-36, wherein the first plant part comprises a bioactive molecule from Cannabis.

50. The therapeutic combination of claim 49, wherein the bioactive molecule from Cannabis is the predominant bioactive molecule from the Cannabis species.

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

52. The therapeutic combination of claim 51, wherein the one or more cannabinoids are 9 -THC-type cannabinoids, Δ 8 - Any one 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-type cannabinoids.

53. The therapeutic combination of claim 52, wherein the one or more cannabinoids are 9 -THC (THC) or cannabidiol (CBD).

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

55. The therapeutic combination of claim 54, wherein the weight ratio of THC to CBD is about 1:

1.

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

57. The therapeutic combination of claim 56, wherein the secondary bioactive molecule from the Cannabis species is any one of a flavonoid 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. The therapeutic combination of any one of claims 1-36, wherein the second plant part comprises a biologically active molecule from Dipteryx.

59. The therapeutic combination of claim 58, wherein the biologically active molecule from Dipteryx is the principal biologically active molecule from Dipteryx odorata.

60. The therapeutic combination of claim 59, wherein the major biologically active molecule from Dipteryx odorata is coumarin.

61. The therapeutic combination of claim 58, wherein the biologically active molecule from Dipteryx is a secondary biologically active molecule from Dipteryx odorata.

62. The therapeutic combination of claim 61, wherein the secondary bioactive molecule from Dipteryx odorata is any of the following: cumaru, a coumarin derivative, an isoflavone, a lupeol derivative, a fatty acid ester, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxyretusin-8-methyl-ether, 5-methoxyanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, betulin, butin, coumaric acid-β-glucoside, dipteryxin, dipteryxic acid, eriodictyol, ferulic acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p-coumaryl-β-d-glucose, methyl linolenate, methyl oleate, O-coumaric acid, O-hydroxycoumaric acid, odoratin, P-hydroxy-benzoic acid, retusin, retusin-8-methyl-ether, sulfuretin, salicylic acid, afrormisin, castinin, linoleic acid, oleic acid, 3',4',7'-trihydroxyflavone, luteolin, and umbelliferone.

63. The therapeutic combination of any one of claims 1-36, wherein the algae fraction comprises bioactive molecules from algae.

64. The therapeutic combination of claim 63, wherein the bioactive molecule from algae is a major bioactive molecule from Pyropia or Porphyra.

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

66. The therapeutic combination of claim 65, wherein the major bioactive molecule from Pyropia or Porphyra is Porphyra polysaccharide.

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

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

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

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

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

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

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

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 algae part further comprise a non-naturally occurring carrier, diluent, or excipient.

75. The therapeutic combination according to claim 21, comprising: a. Bioactive molecules from species of the genus Psilocybe; b. Bioactive molecules from species of the genus Cannabis; c. biologically active molecules from species of the genus Dipteryx; and d. Bioactive molecules from species of the genus Pyropia or Porphyra.

76. The therapeutic combination according to claim 75, comprising: a. Major bioactive molecules from Psilocybe species; b. Major bioactive molecules from Cannabis species; c. major bioactive molecules from species of the genus Dipteryx; and d. Major bioactive molecules from species of the genus Pyropia or Porphyra.

77. The therapeutic combination according to claim 76, comprising: a. one or more tryptamines from species of the genus Psilocybe; b. one or more cannabinoids from species of the genus Cannabis; c. Coumarin; and d. Porphyra polysaccharide.

78. The therapeutic combination according to claim 77, comprising: a. Psilocybin and psilocin; b.THC and CBD; c. Coumarin; and d. Porphyra polysaccharide.

79. The therapeutic combination according to claim 78, comprising: a. Psilocybin and psilocin in a weight ratio of 5:3; b. THC and CBD in a 1:1 weight ratio; c. Coumarin; and d. Porphyra polysaccharide.

80. The therapeutic combination according to any one of claims 75-79, further comprising: a. Minor bioactive molecules from species of the genus Psilocybe; b. Secondary bioactive molecules from species of the genus Cannabis; c. a secondary bioactive molecule from a species of the genus Dipteryx; and d. Secondary bioactive molecules from species of the genus Pyropia or Porphyra.

81. The therapeutic combination of any one of claims 75-79, wherein one of the biologically active molecules, two of the biologically active molecules, three of the biologically active molecules, four of the biologically active molecules, five of the biologically active molecules, six of the biologically active molecules, at least one of the biologically active molecules, at least two of the biologically active molecules, at least three of the biologically active molecules, at least four of the biologically active molecules, at least five of the biologically active molecules, at least six of the biologically active molecules, all of the biologically active molecules, six or fewer of the biologically active molecules, five or fewer of the biologically active molecules, four or fewer of the biologically active molecules, three or fewer of the biologically active molecules, two or fewer of the biologically active molecules, or none of the biologically active molecules are from or in an extract.

82. The therapeutic combination of any one of claims 75-79, wherein one of the biologically active molecules, two of the biologically active molecules, three of the biologically active molecules, four of the biologically active molecules, five of the biologically active molecules, six of the biologically active molecules, at least one of the biologically active molecules, at least two of the biologically active molecules, at least three of the biologically active molecules, at least four of the biologically active molecules, at least five of the biologically active molecules, at least six of the biologically active molecules, all of the biologically active molecules, six or fewer of the biologically active molecules, five or fewer of the biologically active molecules, four or fewer of the biologically active molecules, three or fewer of the biologically active molecules, two or fewer of the biologically active molecules, or none of the biologically active molecules are isolated molecules.

83. The therapeutic combination of any one of claims 75-79, wherein one of the biologically active molecules, two of the biologically active molecules, three of the biologically active molecules, four of the biologically active molecules, five of the biologically active molecules, six of the biologically active molecules, at least one of the biologically active molecules, at least two of the biologically active molecules, at least three of the biologically active molecules, at least four of the biologically active molecules, at least five of the biologically active molecules, at least six of the biologically active molecules, all of the biologically active molecules, six or fewer of the biologically active molecules, five or fewer of the biologically active molecules, four or fewer of the biologically active molecules, three or fewer of the biologically active molecules, two or fewer of the biologically active molecules, or none of the biologically active molecules is a pure or substantially pure molecule.

84. The therapeutic combination of any one of claims 75-79, wherein one of the biologically active molecules, two of the biologically active molecules, three of the biologically active molecules, four of the biologically active molecules, five of the biologically active molecules, six of the biologically active molecules, at least one of the biologically active molecules, at least two of the biologically active molecules, at least three of the biologically active molecules, at least four of the biologically active molecules, at least five of the biologically active molecules, at least six of the biologically active molecules, all of the biologically active molecules, six or fewer of the biologically active molecules, five or fewer of the biologically active molecules, four or fewer of the biologically active molecules, three or fewer of the biologically active molecules, two or fewer of the biologically active molecules, or none of the biologically active molecules is a synthetic molecule.

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

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

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

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

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

90. The therapeutic combination of claim 21, wherein: a. The fungal portion constitutes approximately 45% by volume of the total combination; b. said first plant part constituting about 15% by volume of the total combination; c. said second plant part constituting about 2% by volume of the total combination; d. The algae portion constitutes approximately 15% by volume of the total combination; e. The flavoring or coloring agent constitutes about 15% by volume of the total combination; and f. The diluent constitutes the remainder of the total composition.

91. The therapeutic combination according to any one of claims 21 or 90, wherein: a. The fungal portion 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 percolation of anhydrous ethanol; d. The algae portion comprises an algae extract obtained by ultrasonic extraction; e. The flavoring or coloring agent comprises ethanol impregnated with ginger and bay leaves; and f. The diluent includes water.

92. The therapeutic combination of claim 91, wherein: a. The fungal part 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 portion is a Cannabis plant extract obtained by Soxhlet extraction; c. The second plant part is a Dipteryx plant extract obtained by percolation of anhydrous ethanol; d. The algae portion is an algae extract obtained by ultrasonic extraction; e. The flavoring or coloring agent is ethanol infused with ginger and bay leaves; and f. The diluent is water.

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

94. A method of preparing the therapeutic combination of claim 35, comprising: a. obtaining the fungal extract by ultrasonic extraction and / or Soxhlet extraction; b. obtaining a Cannabis plant extract by Soxhlet extraction; c. Obtaining Dipteryx plant extract by diafiltration with anhydrous ethanol; d. obtaining an algae extract by ultrasonic extraction; e. analyzing the concentration of at least one bioactive molecule in each extract; f. calculating the blending percentage to achieve the target dose of each of at least one bioactive molecule in each extract; g. The calculated amount of each extract based on the mixing percentage is mixed into the mixture; h. Optionally, homogenizing the mixture; i. Optionally, adding flavoring or coloring agents; j. Optionally, add diluent to obtain the target volume.

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

96. The method of preparing a therapeutic combination according to claim 94, wherein the calculated amount of each extract based on the blend percentage comprises: a. 45% by volume of the fungal extract of the total combination; b. 15% by volume of the Cannabis plant extract of the total combination; 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 flavoring or coloring agent of the total combination; and f. 8% by volume of said diluent based on the total composition.

97. A pharmaceutical composition comprising the therapeutic combination of any one of claims 1-36 or 85 and a pharmaceutically acceptable carrier, diluent or excipient.

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

99. The pharmaceutical composition according to claim 97, suitable for enteral or parenteral administration.

100. The pharmaceutical composition of claim 97, prepared as any one of a tincture formulation, an oral spray formulation, an oromucosal spray formulation, a soft mist inhalation formulation, a vaporizer formulation, a tablet formulation, a scoreable dual-strength tablet formulation, a capsule formulation, a capsule formulation with an additional active agent, a suspension formulation, an intravenous solution formulation, an injectable solution formulation, a topical formulation for transdermal administration, a cut-matrix sublingual or buccal tablet formulation, a separately formed sublingual or buccal tablet formulation, and a formulation for intranasal delivery.

101. The pharmaceutical composition according to claim 100, prepared as any one of a tincture preparation, an oral spray preparation, an oral mucosal spray preparation or a soft mist inhalation preparation.

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 Cannabis plant extract of the total combination; 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 flavoring or coloring agent of the total combination; and f. 8% by volume of said diluent based on the total composition.

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

104. The pharmaceutical composition of claim 97, wherein a single dose of psilocybin is about 0.5 μg to about 200 mg, about 5 μg to about 5 mg, or about 100 μg to about 600 μg.

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

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

108. The pharmaceutical composition of claim 97, wherein a 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. The pharmaceutical composition of claim 108, wherein a single dose of CBD is 1 mg.

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

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

112. The pharmaceutical composition of claim 97, wherein a single dose of coumarin 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.

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

114. The pharmaceutical composition of claim 97, wherein a single dose comprises a Pyropia yezoensis, Pyropia perforata, or Porphyraumbilicalis 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. The pharmaceutical composition of claim 114, wherein a single dose comprises the whole extract of Pyropia in an amount of 8 mg.

116. The pharmaceutical composition of claim 97, wherein a single dose comprises ginger and bay leaf infused ethanol 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. The pharmaceutical composition of claim 116, wherein a single dose comprises ethanol infused with ginger and bay leaves in an amount of 8 mg.

118. A pharmaceutical kit comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein: 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. The second pharmaceutical composition comprises the remainder of the therapeutic combination of claim 21 and a pharmaceutically acceptable carrier, diluent or excipient.

119. The pharmaceutical kit according to claim 118, wherein: a. The first pharmaceutical composition is prepared as a tincture preparation, an oral spray preparation, an oral mucosal spray preparation or a soft mist inhalation preparation; and b. The second pharmaceutical composition is prepared as a tincture preparation, an oral spray preparation, an oral mucosal spray preparation or a soft mist inhalation preparation.

120. A method of preventing or treating a movement disorder comprising administering to a patient in need thereof the therapeutic combination of any one of claims 1-36 or 85.

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

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

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

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

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

127. The method of claim 126, wherein the motor symptoms are hunched posture, masked facial expression, forward lean of the trunk, bent elbows and wrists, decreased arm swing, bent hips and knees, trembling limbs, shuffling gait, short-step gait, uncoordinated or awkward balance, altered speech, involuntary limb movements, irregular movements, prolonged contractions, intermittent contractions of the neck muscles, causing the head to turn in different ways; repetitive, irregular, involuntary movements involving the face, mouth, trunk and limbs; twisting, repetitive movements; twitching, tremors, stiffness, finger tapping, toe tapping, poor posture, slow, decreased or unbalanced movements of muscles or muscle groups; difficulty walking, random involuntary eye movements, involuntary blinking, involuntary grimacing, unpleasant, unusual sensations in the limbs that can be relieved by movement; any of involuntary sounds and rhythmic shaking of parts of the body, usually the hands and / or head.

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

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

130. The method of claim 129, wherein the non-motor symptom is any one of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain and other sensations, urinary problems, constipation problems, dizziness on standing, and fatigue.

131. The method of claim 129, wherein the non-motor symptoms are mood symptoms.

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

133. 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 the first administration of the pharmaceutical composition.

134. 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 the first administration of the pharmaceutical composition.

135. The method of claim 125, wherein the reduction in severity of at least one symptom of the movement disorder persists 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. The method of claim 124, wherein the improvement is an improvement in motor control.

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

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

140. The method of claim 124, wherein the improvement is an improvement in a clinical outcome assessment.

141. The method of claim 140, wherein the clinical outcome assessment is any one of the following: Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Movement Disorder Society Nonmotor Rating Scale (MDS-NMS), Corticobasal Ganglia Function Scale (SBFS), Gastrointestinal Dysfunction Rating Scale for Parkinson's Disease (GIDS-PD), Wilson's Disease Global Rating Scale (WD's GAS), Global Dystonia Severity Rating Scale (GDS), Modified Bradykinesia Rating Scale (MBRS), Nonmotor Symptom Questionnaire (NMSQ), Nonmotor Symptom Rating Scale for Parkinson's Disease (NMSS), Pantothenate Kinase-Associated Neurodegenerative Disease Rating Scale (PKAN-DRS), Progressive Supranuclear Palsy Clinician Deficit Scale (PSP-CDS), Idiopathic The tremor quality of life questionnaire, psychogenic movement disorder rating scale, Rasch movement disorder rating scale (RDRS), Rasch video-based Tic rating scale (RVBTRS), Parkinson's disease-autonomic dysfunction outcome scale (SCOPA-AUT), Parkinson's disease-diary card (SCOPA-DC), Parkinson's disease-psychiatric complications outcome scale (SCOPA-PC), Parkinson's disease-psychosocial function outcome scale (SCOPA-PS), Parkinson's disease outcome-sleep scale (SCOPA-Sleep; SCOPA-S), Parkinson's disease outcome-cognition scale (SCOPA-COG), Parkinson's disease short evaluation scale (SPES) / Parkinson's disease outcome-motor function scale (SPES / SCOPA-MOTOR), non-motor fluctuation assessment (NoMoFA) questionnaire, UFMG Sydenham Chorea Rating Scale (USCRS), Unified Movement Disorder Rating Scale (UDysRS), Unified Dystonia Rating Scale (UDRS), Unified Multiple System Atrophy Rating Scale (UMSARS), and Unified Parkinson's Disease Rating Scale-8 (UPDRS-8).

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

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

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

145. The method of claim 144, wherein the improvement of nM-EDL is for any one of cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, daytime sleepiness, pain and other sensations, urinary problems, constipation problems, dizziness on standing, and fatigue.

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

147. The method of claim 146, wherein the improvement in the M-EDL is an improvement in any of: speech, saliva and drooling, chewing and swallowing, eating tasks, dressing, hygiene, handwriting, performing hobbies and other activities, turning over in bed, tremors, getting out of bed, car, or deep chair; walking and balance, and freezing.

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

149. The method of claim 148, wherein the improvement in the motor test is an improvement in any of: speech, facial expression, rigidity, finger tapping, hand movement, pronation and supination of the hand, toe tapping, leg agility, chair-induced, gait, freezing of gait, postural stability, posture, global spontaneity of movement (body bradykinesia), postural tremor of the hand, kinetic tremor of the hand, resting tremor amplitude, constancy of resting tremor, Hoehn and Yahr stages, time spent with movement disorder, functional impact of movement disorder, time spent in the off state, functional impact of fluctuations, complexity of movement fluctuations, and painful off-state dystonia.

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

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

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

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

154. The method of claim 153, wherein the mental, behavioral and emotional improvement is any one of intellectual disability, thought disorder, depression and motivation / initiative.

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

156. The method of claim 155, wherein the improvement in ADLs is for any one of speech, salivation, swallowing, handwriting, cutting food and handling utensils, dressing, hygiene, turning over in bed and adjusting bedding, falls, freezing while walking, walking, tremors, and sensory complaints associated with Parkinson's disease.

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

158. The method of claim 157, wherein the improvement in the motor examination is an improvement in any of speech, facial expression, tremor at rest, hand movements or postural tremor, rigidity, finger tapping, hand movements, rapid alternating movements of the hands, leg agility caused by chair, posture, gait, postural stability, and body movement delays and hypokinesia.

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

160. The method of claim 159, wherein the improvement in the treatment complication is any one of daily duration of dyskinesia, severity of dyskinesia disability, painful dyskinesia, and proportion of waking days that the patient is on average "off." 161. The method of any one of claims 152-160, wherein the improvement is an improvement in score.

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

164. The method of claim 163, wherein the reduction is a reduction in at least 1 stage.

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

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

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

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

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

170. The method of any one of claims 140-149, wherein the improvement persists 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.

Images