Therapeutic combinations for mitochondrial and other disorders

Abstract

Therapeutic combinations, pharmaceutical compositions, and pharmaceutical kits are provided, comprising fungi (e.g., Psilocybe spp.), plants (e.g., Cannabis spp., Dipteryx spp.), and algae (e.g., from the family Bangiaceae, including Pyropia spp. and Porphyra spp.), including extracts thereof and bioactive molecules derived therefrom. Also provided are methods for producing the combinations, compositions, and kits such as through natural, biosynthetic, or synthetic means. Further provided are methods of use for treating medical conditions, particularly mitochondrial and other disorders, wherein the disclosed combinations and compositions exhibit synergistic effects and therapeutic and other advantages.

Description

[0001] THERAPEUTIC COMBINATIONS FOR MITOCHONDRIAL AND OTHER DISORDERS

[0002] CROSS-REFERENCE

[0003]

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Appl. No. 63 / 565,498, filed March 14, 2024, and hereby incorporated by reference for all purposes as if fully set forth herein.

[0004] FIELD OF THE INVENTION

[0005]

[0002] Therapeutic combinations comprising bioactive molecules from fungi, plants, and algae are disclosed, as well as pharmaceutical compositions and kits thereof, and methods of their use in medicine, including to treat mitochondrial and other disorders, such as metabolic disorders, pain disorders, autoimmune disorders, mental health disorders, endocrine disorders, viral disorders, and degenerative disorders.

[0006] BACKGROUND OF THE INVENTION

[0007]

[0003] According to the United Mitochondrial Disease Foundation (UMDF), every 30 minutes a child is born who will develop a mitochondrial disorder by age 10 (Ahuja AS. PeerJ. travel2018;6:e4790). Overall, approximately 1 in every 4,000 individuals in the U.S. has a mitochondrial disorder (id.). In fact, it is estimated that between about 1 ,000 to 4,000 children are born each year nationwide with a mitochondrial disorder (id. .

[0008]

[0004] Mitochondrial disorders present with a wide range of manifestations, making diagnosis challenging and often leading to misdiagnosis. In most cases, no single symptom is definitive for a mitochondrial disorder; rather, diagnosis is based on the specific combination of symptoms and their progression over time.

[0009]

[0005] Many mitochondrial disorders remain incurable, and treatment is generally limited to managing symptoms or slowing disease progression. Moreover, mitochondrial dysfunction can contribute to the onset or exacerbation of various other conditions, including metabolic, autoimmune, pain, mental health, endocrine, viral, and degenerative disorders. There is a critical need for novel therapies capable of mitigating symptoms, preventing the emergence of new complications, and reversing disease progression in mitochondrial disorders and other conditions, whether directly linked to mitochondrial dysfunction or arising from other etiologies.

[0010]

[0006] Provided herein are therapeutic combinations, pharmaceutical compositions, and kits, along with methods of their use to treat mitochondrial and other disorders, that these needs and others, and have such advantages and improvements over existing treatment options as will be readily apparent from the disclosure.

[0011] INCORPORATION BY REFERENCE

[0012]

[0007] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference comes from an area that is analogous or directly applicable to the invention, nor should a citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or forms part of the common general knowledge in the art. BRIEF SUMMARY OF THE INVENTION

[0013]

[0008] A simplified summary of some aspects and embodiments follows, to provide a basic understanding of the invention. This summary is not an extensive overview, nor is it intended to identify every key or critical element of the invention or to delineate the complete scope of the invention. Its sole purpose is to present some exemplary embodiments in a simplified form as a prelude to the more detailed description below.

[0014]

[0009] In some exemplary aspects are provided methods of preventing or treating a medical condition in a subject, comprising administering to the subject a combination comprising: (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion; wherein the medical condition is any of a mitochondrial disorder, a metabolic disorder, an autoimmune disorder, a pain disorder, a mental health disorder, an endocrine disorder, a viral disorder, or a degenerative disorder.

[0015]

[0010] In embodiments, the fungal portion is from a psilocybin-producing species. In embodiments, the psilocybin-producing species is from any of the genera Psilocybe, Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, and Pluteus. In embodiments, the psilocybin-producing species is from the genus Psilocybe. In embodiments, the psilocybin-producing species from the genus Psilocybe is any of P. cubensis, P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and P. liniformans. In embodiments, the first plant portion is from a species in the Cannabis genus. In embodiments, the species in the Cannabis genus is any of C. sativa, C. indica, and C. ruderalis.

[0016]

[0011] In embodiments, the second plant portion is from a species in the Dipteryx genus. In embodiments, the species in the Dipteryx genus is D. odorata. In embodiments, the algal portion is from a species of marine algae. In embodiments, the species of marine algae is from the family Bangiaceae. In embodiments, the species of marine algae is from the genus Pyropia or Porphyra. In embodiments, the species of marine algae is any of P. yezoensis, Pyropia perforata, and Porphyra umbilicalis. In embodiments, the fungal portion, first plant portion, second plant portion, and algal portion are administered in separate compositions. In embodiments the fungal portion, first plant portion, second plant portion, and algal portion are administered simultaneously. In embodiments, the fungal portion, first plant portion, second plant portion, and algal portion are administered in a single composition. In embodiments, the fungal portion comprises a P. cubensis extract; the first plant portion comprises a C. sativa extract; the second plant portion comprises a D. odorata extract; and the algal portion comprises a P. yezoensis extract. In embodiments, the P. cubensis extract is obtained by ultrasonic extraction or Soxhlet extraction. In embodiments, the P. cubensis extract comprises a mixture of a P. cubensis extract obtained by ultrasonic extraction and a P. cubensis extract obtained by Soxhlet extraction in a weight ratio from about 0.5:1 to about 5:1. In embodiments, the weight ratio of the P. cubensis extract obtained by ultrasonic extraction and the P. cubensis extract obtained by Soxhlet extraction is 2:1. In embodiments, the P. cubensis extract comprises psilocybin and psilocin. In embodiments, the P. cubensis extract comprises psilocybin and psilocin in a weight ratio from about 1 :5 to about 5:1. In embodiments, the P. cubensis extract comprises psilocybin and psilocin in a weight ratio of about 5:3. In embodiments, the P. cubensis extract comprises from about 50 pg to about 500 pg of psilocybin and from about 20 pg to about 200 pg of psilocin. In embodiments, the P. cubensis extract comprises about 250 pg of psilocybin and about 150 pg of psilocin. In embodiments, the C. sativa extract is obtained by Soxhlet extraction. In embodiments, the C. sativa extract comprises A9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In embodiments, the C. sativa extract comprises THC and CBD in a weight ratio from about 1 :5 to about 5:1. In embodiments, the C. sativa extract comprises THC and CBD in a weight ratio of about 1 :1 . In embodiments, the C. sativa extract comprises from about 0.1 mg to about 5 mg of THC and from about 0.1 to 5 mg of CBD. In embodiments, the

[0017] C. sativa extract comprises about 1 mg of THC and about 1 mg of CBD.

[0018]

[0012] In embodiments, the D. odorata extract is obtained by anhydrous ethanol percolation. In embodiments, the D. odorata extract comprises coumarin. In embodiments, the D. odorata extract comprises from about 1 mg to about 10 mg of coumarin. In embodiments, the D. odorata extract comprises about 1 mg of coumarin.

[0019]

[0013] In embodiments, the combination comprises from about 1 mg to about 20 mg of P. yezoensis extract. In embodiments, the combination comprises about 8 mg of P. yezoensis extract. In embodiments, the P. yezoensis extract is obtained by ultrasonic extraction. In embodiments, the P. yezoensis extract comprises porphyran. In embodiments, the P. cubensis extract, C. sativa extract, D. odorata extract, and P. yezoensis extract are administered in separate compositions. In embodiments, the P. cubensis extract, C. sativa extract,

[0020] D. odorata extract, and P. yezoensis extract are administered simultaneously. In embodiments, the P. cubensis extract, C. sativa extract, D. odorata extract, and P. yezoensis extract are administered in a single composition. In embodiments, the P. cubensis extract constitutes from about 20% to about 60% by volume of the single composition. In embodiments, the P. cubensis extract constitutes about 45% by volume of the single composition. In embodiments, the C. sativa extract constitutes from about 5% to about 30% by volume of the single composition. In embodiments, the C. sativa extract constitutes about 15% by volume of the single composition. In embodiments, the D. odorata extract constitutes from about 1 % to about 5% by volume of the single composition. In embodiments, the D. odorata extract constitutes about 2% by volume of the single composition. In embodiments, the P. yezoensis extract constitutes from about 5% to about 30% by volume of the single composition. In embodiments, the P. yezoensis extract constitutes about 15% by volume of the single composition. In embodiments, the single composition further comprises any of a flavorant, colorant, and diluent. In embodiments, the flavorant or colorant comprises ginger or bay laurel. In embodiments, the flavorant or colorant is ethanol infused with ginger and bay leaf. In embodiments, the flavorant or colorant constitutes from about 5% to about 30% by volume of the single composition. In embodiments, the flavorant or colorant constitutes about 15% by volume of the single composition. In embodiments, the diluent is water. In embodiments, the water constitutes from about 5% to about 15% by volume of the single composition. In embodiments, the water constitutes about 8% by volume of the single composition. In embodiments, between about 10 and 200 mg of the single composition are administered per single dose. In embodiments, between about 50 mg of the single composition are administered per single dose.

[0021]

[0014] In embodiments, between 1 and 8 doses of the single composition are administered per day. In embodiments, between 1 and 8 doses of the single composition are administered per day for at least one week, two weeks, three weeks, 1 month, 2 months, or 3 months. In embodiments, the subject experiences a reduction in the severity of a symptom of the mitochondrial or other disorder. In embodiments, the reduction in the severity of the symptom is durable for at least one week, two weeks, three weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or at least 12 months, when measured from baseline.

[0022]

[0015] The mitochondrial disorder may be any of myopathy with exercise intolerance; eyelid ptosis; ophthalmoparesis; pigmentary retinopathy; sensorineural hearing loss; hypertrophic cardiomyopathy; migraine disorder; mitochondrial disease NOS; demyelination due to mitochondrial disease; mitochondrial cytopathy; a liver disease due to a mitochondrial disorder; a disorder of mitochondrial oxidative phosphorylation; a multiple mitochondrial DNA deletion syndrome; a mitochondrial protein translation defect; a mitochondrial myopathy; a glomerular disease associated with a mitochondrial disease; myoclonus due to a mitochondrial cytopathy; a disorder of mitochondrial membrane transport; epilepsy due to a mitochondrial disorder; an intestinal congenital motility disorder due to a mitochondrial disease; mitochondrial diabetes; mitochondrial ocular myopathy; congenital muscular dystrophy with mitochondrial structural abnormalities; a disorder of mitochondrial fatty acid oxidation; ataxia due to a mitochondrial mutation; mitochondrial isocitrate dehydrogenase deficiency; chorea due to mitochondriopathy; mitochondrial thiamine pyrophosphate carrier deficiency; dystonia due to a mitochondrial cytopathy; dilated cardiomyopathy due to a mitochondrial myopathy; mitochondrial disease with hypertrophic cardiomyopathy; mitochondrial myopathy with sideroblastic anemia; and mitochondrial 2-methylacetoacetyl-coA thiolase (MAT) deficiency, potassium-stimulated. The mitochondrial disorder may be myopathy with exercise intolerance. In embodiments, the subject experiences a reduction in the severity of a myopathy with exercise intolerance symptom. The mitochondrial disorder may be eyelid ptosis. In embodiments, the subject experiences a reduction in the severity of an eyelid ptosis symptom. The mitochondrial disorder may be ophthalmoparesis. In embodiments, the subject experiences a reduction in the severity of an ophthalmoparesis symptom. The mitochondrial disorder may be pigmentary retinopathy. In embodiments, the subject experiences a reduction in the severity of a pigmentary retinopathy symptom. The mitochondrial disorder may be sensorineural hearing loss. In embodiments, the subject experiences a reduction in the severity of a sensorineural hearing loss symptom. The mitochondrial disorder may be hypertrophic cardiomyopathy. In embodiments, the subject experiences a reduction in the severity of a hypertrophic cardiomyopathy symptom.

[0023]

[0016] The mitochondrial disorder may be migraine disorder. In embodiments, the subject experiences a reduction in the severity of a migraine disorder symptom. In embodiments, the symptom of migraine disorder is the frequency, intensity, and duration of a migraine symptom. The mitochondrial disorder may be a primary mitochondrial disorder or a secondary mitochondrial disorder. The mitochondrial disorder may be a primary mitochondrial disorder. In embodiments, the primary mitochondrial disorder is any of Barth syndrome; growth delay, amino aciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome); chronic progressive external ophthalmoplegia (CPEO); oculopharyngeal muscular dystrophy (OPMD); Amish lethal microcephaly; optic atrophy; Leber hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh and Leigh-like syndrome; Sengers syndrome; maternally inherited deafness and diabetes (MIDD); a mitochondrial DNA depletion syndrome; encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); encephalopathy due to defective mitochondrial and peroxisomal fission; ethylmalonic encephalopathy; a mitochondrial myopathy; a mitochondrial complex deficiency; a mitochondrial DNA depletion syndrome; progressive external ophthalmoplegia (PEG); HSD10 mitochondrial disease; neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS); fatal infantile cardioencephalomyopathy; a combined oxidative phosphorylation deficiency; a POLG-related disorder; a mitochondrial trifunctional protein deficiency; a mitochondrial phosphate carrier deficiency; a pyruvate dehydrogenase complex deficiency; mitochondrial short-chain enoyl-CoA hydratase 1 deficiency; and Pearson syndrome. The mitochondrial disorder may be a secondary mitochondrial disorder. In embodiments, the secondary mitochondrial disorder is any of Wolfram syndrome; muscular dystrophy; Alzheimer’s disease; Charcot-Marie-Tooth disease; 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL); myopathic carnitine deficiency; early infantile epileptic deficiency; sensorineural hearing loss or deafness; hyperornithinemia-hyperammonemia- homocitrullinuria syndrome (HHH syndrome); 3-methylglutaconic aciduria; a carnitine palmitoyltransferase deficiency; ophthalmoplegic neuromuscular disorder with abnormal mitochondria; pyruvate carboxylase deficiency; reticular dysgenesis; cardiomyopathy; infantile mitochondrial striatonigral degeneration; retinitis pigmentosa-deafness syndrome; infantile cerebellar-retinal degeneration; muscle atrophy; a deficiency in mitochondrial import-stimulating factor; cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome; and a mitochondrial HMG-CoA synthase-2 deficiency. In embodiments, the metabolic disorder is any of hyperlipidemia; dyslipidemia; hypercholesterolemia; hypertriglyceridemia; metabolic syndrome; metabolic syndrome X; Fabry disease; Gaucher’s disease; phenylketonuria (PKU); hyperglycemia; insulin resistance; impaired glucose tolerance; hyperinsulinism; hypertension; Hunter syndrome; Hurler syndrome; Krabbe disease; maple syrup urine disease; metachromatic leukodystrophy; Niemann-Pick disease; galactosemia; Tay-Sachs disease; a glycogen storage disease; a peroxisomal disorder; a metal metabolism disorder; an organic acidemia; a urea cycle disorder; an inborn error of metabolism; a disorder of metabolite absorption or transport; a disorder of lipoprotein metabolism or certain specified lipidemias; and a metabolic or transporter liver disease.

[0024]

[0017] In embodiments, the autoimmune disorder is any of achalasia; Addison’s disease; adult Still’s disease; agammaglobulinemia; alopecia areata; amyloidosis; Ankylosing spondylitis; anti-GBM / anti-TBM nephritis; antiphospholipid syndrome; autoimmune angioedema; autoimmune dysautonomia; autoimmune encephalitis; autoimmune inner ear disease (Al ED); autoimmune myocarditis; autoimmune oophoritis; autoimmune orchitis; autoimmune pancreatitis; autoimmune retinopathy; autoimmune urticaria; axonal and neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; benign mucosal pemphigoid (mucous membrane pemphigoid); bullous pemphigoid; Castleman disease (CD); Chagas disease; chronic inflammatory demyelinating polyneuropathy (Cl DP); chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA); cicatricial pemphigoid; Cogan’s syndrome; cold agglutinin disease; complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); congenital heart block; Coxsackie myocarditis; dermatitis herpetiformis; dermatomyositis; Devic’s disease (neuromyelitis optica); Dressier’s syndrome; eosinophilic esophagitis (EoE); eosinophilic fasciitis; erythema nodosum; essential mixed cryoglobulinemia; Evans syndrome; fibrosing alveolitis; giant cell arteritis (temporal arteritis); giant cell myocarditis; glomerulonephritis; Goodpasture’s syndrome; granulomatosis with polyangiitis; Graves’ disease; hemolytic anemia; Henoch-Schonlein purpura (HSP); herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (acne inversa); IgA nephropathy; lgG4-related sclerosing disease; immune thrombocytopenic purpura (ITP); inclusion body myositis (IBM); interstitial cystitis (IC); juvenile myositis (JM); Lambert-Eaton syndrome; lichen planus; lichen sclerosus; ligneous conjunctivitis; linear IgA disease (LAD); Meniere’s disease; microscopic polyangiitis (MPA); mixed connective tissue disease (MCTD); Mucha-Habermann disease; multifocal motor neuropathy (MMN) or MMNCB; MS; myasthenia gravis; myelin oligodendrocyte glycoprotein antibody disorder; myositis; narcolepsy; neuromyelitis optica / devic disease; neutropenia; ocular cicatricial pemphigoid; optic neuritis; palindromic rheumatism (PR); PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); paraneoplastic cerebellar degeneration (PCD); paroxysmal nocturnal hemoglobinuria (PNH); Parsonage-Turner syndrome; pemphigus; perivenous encephalomyelitis; pernicious anemia (PA); disease affecting many nerves, organomegaly, abnormal enlargement of an organ, endocrinopathy, disease affecting certain hormone-producing glands that help to regulate sexual function, and certain metabolic functions, monoclonal gammopathy or M proteins, and skin abnormalities (POEMS syndrome); polyarteritis nodosa; polyglandular syndromes type I, II, III; polymyalgia rheumatica; polymyositis; postmyocardial infarction syndrome; postpericardiotomy syndrome; primary biliary cholangitis; primary sclerosing cholangitis; progesterone dermatitis; progressive hemifacial atrophy (PHA) (also known as Parry Romberg syndrome); pulmonary alveolar proteinosis (PAP); pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; relapsing polychondritis; retroperitoneal fibrosis; rheumatic fever; sarcoidosis; Schmidt syndrome or autoimmune polyendocrine syndrome type II; scleritis; stiff person syndrome (SPS); Susac’s syndrome; sympathetic ophthalmia (SO); Takayasu’s arteritis; temporal arteritis / giant cell arteritis; thrombocytopenic purpura (TTP); thrombotic thrombocytopenic purpura (Ttp); thyroid eye disease (TED); Tolosa-Hunt syndrome (THS); transverse myelitis; undifferentiated connective tissue disease (UCTD); vitiligo; Vogt-Koyanagi-Harada disease; and warm autoimmune hemolytic anemia.

[0025]

[0018] In embodiments, the pain disorder is any of acute pain; episodic pain; phantom pain; soft tissue pain; nociceptive pain; functional pain; idiopathic pain; radicular pain; referred pain; breakthrough pain; herniated disc pain; perioperative pain; pre-operative pain; post-operative pain; neuropathic pain; post-herpetic neuralgia; trigeminal neuralgia; back pain; neck pain; phantom limb pain; chronic pelvic pain; vulvodynia; nerve pain; complex regional pain syndrome or a related neuralgia; pain associated with HIV; nerve injury; root avulsion; erythromelalgia; paroxysmal extreme pain disorder; burning mouth syndrome; a central pain syndrome; a post-surgical pain syndrome; bone and / or joint pain; repetitive motion pain; dental pain; polymyositis / myofascial pain; a muscular injury; chronic pain; dysmenorrhea; pain associated with angina; pain due to inflammation; pain due to a rheumatic disease; pain due to teno-synovitis; bursitis; polymyalgia rheumatica; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; pain caused by central sensitization; chronic arthritic pain or a related neuralgia; migraine disorder; headache pain; a cluster headache; a non-vascular headache; traumatic nerve injury; nerve compression or entrapment; neuroma pain; testicular pain (orchialgia); lasting pain in scar tissue; herpes zoster or shingles; frozen shoulder; pain due to a bone fracture; pain due to sickle cell disease; pain due to kidney stones; pain due to appendicitis; CRPS; pain due to gout; pain due to acute pancreatitis; pain due to a stomach or peptic ulcer; pain due to a heart attack; Munchausen syndrome; pain due to another injury or medical condition; an arthritis; a sexual pain disorder; dysmenorrhea disorder; painful periods disorder; abdominal pain disorder; emporomandibular joint disorder; chronic temporomandibular disorder pain; cold impediment disorder; painful impediment disorder; chronic primary headache or orofacial pain; chronic primary temporomandibular disorder pain; puerperal abdominal pain disorder; chest impediment disorder; heart pain disorder; true heart pain disorder; Lumbago disorder; low back pain disorder; wind impediment disorder; migrating painful movement disorder; growth pain disorder; hypochondrium pain disorder; an abdominal pain-related functional Gl disorder in a child; chronic headache or orofacial pain associated with non-vascular intracranial disorder; acute whiplash associated disorder with complaint of neck pain with neurological signs; chronic headache or orofacial pain associated with disorders of homoeostasis; headache or orofacial pain associated with chronic secondary temporomandibular disorders; chronic headache or orofacial pain associated with cranial or cervical vascular disorder; acute whiplash associated disorder with complaint of neck pain with musculoskeletal signs; and acute whiplash associated disorder with complaint of neck pain, stiffness or tenderness only.

[0026]

[0019] In embodiments, the mental health disorder is any of a neurodevelopmental disorder; schizophrenia or another primary psychotic disorder; catatonia; a mood disorder; an anxiety or fear-related disorder; an obsessive-compulsive or related disorder; a disorder specifically associated with stress; a dissociative disorder; a feeding or eating disorder; an elimination disorder; a disorder of bodily distress or bodily experience; a disorder due to substance use or addictive behaviors; an impulse control disorder; a disruptive behavior or dissocial disorder; a personality disorder or related trait; a paraphilic disorder; a factitious disorder; a neurocognitive disorder; a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium; a sleep-wake disorder; a sexual dysfunction; gender incongruence; a bipolar or related disorder; a depressive disorder; a trauma- or stressor-related disorder; a somatic symptom or related disorder; gender dysphoria; and a substance-related or addictive disorder.

[0027]

[0020] In embodiments, the neuropsychiatric disorder is a psychosis. In embodiments, the subject experiences a reduction in the severity of a psychosis symptom. In embodiments, the symptom of a psychosis is any of a hallucination; a delusion; and disordered thinking. In embodiments, the neuropsychiatric disorder is in a juvenile subject. In embodiments, the neuropsychiatric disorder in a juvenile subject is any of a seizure disorder; an attention deficit disorder; a cognitive deficit disorder; a palsy; uncontrolled anger; a migraine headache; an addiction; an eating disorder; depression; and anxiety. In embodiments, the subject experiences a reduction in the severity of a juvenile neuropsychiatric disorder symptom. In embodiments, the neuropsychiatric disorder is in an elderly subject. In embodiments, the neuropsychiatric disorder in an elderly subject is any of Alzheimer’s disease, dementia, stroke, depression, addiction, and PTSD. In embodiments, the subject experiences a reduction in the severity of an elderly neuropsychiatric disorder symptom.

[0028]

[0021] In embodiments, the endocrine disorder is any of premenstrual dysphoric disorder (PMDD); premenstrual syndrome (PMS); and a complication or symptom arising from perimenopause (e.g., vasomotor symptoms, symptoms affecting sleep or mood, adhesive capsulitis). In embodiments, the endocrine disorder is premenstrual dysphoric disorder. In embodiments, the subject experiences a reduction in the severity of premenstrual dysphoric disorder symptom. In embodiments, the symptom of premenstrual dysphoric disorder is any of mood or sleep problems, anxiety, and pain. In embodiments, the endocrine disorder is premenstrual syndrome. In embodiments, the subject experiences a reduction in the severity of premenstrual syndrome. In embodiments, the endocrine disorder is a complication or symptom arising from perimenopause. In embodiments, the subject experiences a reduction in the severity of a complication or symptom arising from perimenopause. In embodiments, the symptom of a complication or symptom arising from perimenopause is any of vasomotor symptoms (e.g., hot flashes); fatigue; mood or sleep problems; and adhesive capsulitis. In embodiments, the endocrine disorder is any of PMDD; PMS; a complication or symptom arising from perimenopause; acromegaly; Addison's disease; adrenal cancer; adrenoleukodystrophy; benign adrenal tumors; cancer; carcinoid tumors; chronic kidney disease; congenital adrenal hyperplasia; Cushing syndrome; cystic fibrosis; diabetic nephropathy (kidney disease); end-stage renal disease; erectile dysfunction; galactorrhea; gender dysphoria; gestational diabetes; goiter; Graves' disease; high cholesterol; high potassium (hyperkalemia); hirsutism; Hurthle cell cancer; hypercalcemia; hypereosinophilic syndrome; hyperparathyroidism; hyperthyroidism (overactive thyroid); hypoglycemia; hypoparathyroidism; hypopituitarism; hypothyroidism (underactive thyroid); infertility; an inherited metabolic disorder; insulinoma; Klinefelter syndrome; low potassium (hypokalemia); male hypogonadism; male infertility; metabolic bone disease; multiple endocrine neoplasia, type 1 (MEN 1); multiple endocrine neoplasia, type 2 (MEN 2); neuroblastoma; neuroendocrine tumors; osteomalacia; osteopenia; osteopetrosis; osteoporosis; Paget's disease of bone; Paget's disease of the breast; pheochromocytoma; a pituitary tumor; POEMS syndrome; polycystic ovary syndrome (PCOS); primary aldosteronism; prolactinoma; Sheehan's syndrome; thyroid cancer; thyroid disease; thyroid eye disease; thyroid nodules; Turner syndrome; varicocele; and Whipple's disease.

[0029]

[0022] In embodiments, the viral disorder is any of SARS; COVID; and Lyme disease. In embodiments, the viral disorder is SARS. In embodiments, the subject experiences a reduction in the severity of a symptom arising from SARS. In embodiments, the viral disorder is COVID. In embodiments, the subject experiences a reduction in the severity of a symptom arising from COVID. In embodiments, the viral disorder is Lyme disease. In embodiments, the subject experiences a reduction in the severity of a symptom arising from Lyme disease. In embodiments, the viral disorder is any of the common cold (usually caused by rhinovirus); the flu (influenza); COVID-19; respiratory syncytial virus (RSV); human metapneumovirus (hMPV); parainfluenza; norovirus, rotavirus, astrovirus, a hepatitis virus; human immunodeficiency virus (HIV); genital herpes (HSV); Fifth disease; Mpox; viral myocarditis; acute viral myocarditis; chronic viral myocarditis; cytomegaloviral disease; lentivirus; filovirus; Lassa fever; arenavirus; orthopoxvirus; arbovirus; viral keratitis; and flavivirus. In embodiments, the viral disorder is a post viral infection. In embodiments, the post viral infection is triggered by any of the common cold; the flu; herpes; and HIV.

[0030]

[0023] In embodiments, the degenerative disorder is any of muscle degeneration; lung degeneration; vascular degeneration; artery degeneration; aortic degeneration; Monckeberg's degeneration; degeneration of sinus; cortex degeneration; kidney degeneration; corneal degeneration; degeneration of the uterus; fatty degeneration; brain degeneration; vitreous degeneration; conjunctival or subconjunctival degenerations or deposits; breast degeneration; lenticular degenerative disease; cerebromacular degeneration; multidegenerative joint disease; ovarian degeneration; placental degeneration; degeneration of turbinate; degeneration of penis; degeneration of iris or ciliary body; a degenerative condition of the spine; degenerative knee disease; follicular degeneration syndrome; degenerative rupture of tendon; hyaloid degeneration; lens degeneration; pulp degeneration; a degenerative disorder of the spleen; degeneration of meniscus; hereditary retinal degeneration; peripheral retinal degeneration; cystic degeneration of ovary; neovascular late-stage age-related macular degeneration; a degenerative spinal instability; a degenerative myelopathic disorder; corticobasal degeneration; pituitary gland degeneration; polypoid sinus degeneration; fatty degeneration of aorta; dystonia associated with heredodegenerative disorders; thyroid degeneration; cochlea degeneration; degenerative or vascular disorders of the ear; degeneration of cervix uteri; another specified degeneration of macula or posterior pole; degenerative mitral valve prolapse; pineal gland degeneration; degenerative dementia; cardiovascular degeneration; suprarenal gland degeneration; lymph gland degeneration; juvenile macular degeneration-hypotrichosis; colloid degeneration of the skin; and choroidal degeneration. In embodiments, the combination further comprises an additional active agent.

[0031]

[0024] In some aspects are provided methods of preventing or treating a medical condition in a subject, comprising administering to the subject a combination comprising: a fungal portion; a first plant portion; optionally, a second plant portion; and optionally, an algal portion; wherein the medical condition is any of a mitochondrial disorder, a metabolic disorder, an autoimmune disorder, a pain disorder, a mental health disorder, an endocrine disorder, a viral disorder, or a degenerative disorder.

[0032]

[0025] The foregoing is a general overview of certain aspects of the disclosure to facilitate understanding of the detailed description and to highlight the contribution to the art. It is a high-level introduction to only some of the disclosed aspects and embodiments, offered solely for a reader’s convenience and not to limit the scope or or range of equivalents, to which the claims are entitled. Additional aspects and embodiments are described herein. It will be understood by those in the art that the specific combinations, compositions, and methods disclosed are exemplary and may be adapted or modified to achieve similar objectives. Such variations and equivalents fall within the scope and spirit of the invention as defined by the claims. The headings in this document are provided for ease of reference only and should not be read to limit the disclosed invention.

[0033] BRIEF DESCRIPTION OF THE FIGURES

[0034]

[0026] To further clarify various aspects of the invention, certain exemplary embodiments are illustrated in the figures. The figures depict only illustrated embodiments of the invention and should not be considered limiting of its scope. Certain aspects of the invention are therefore further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying figures in which:

[0035]

[0027] FIG. 1 illustrates the production of an exemplary composition according to certain embodiments.

[0036]

[0028] FIGS. 2-4, previously included in Applicant’s priority application, and published as Figures in Applicant’s earlier-filed international application, are fully incorporated by reference in the present application.

[0037]

[0029] FIG. 5 illustrates total antioxidant capacity of Cannabis Stock, measured via Folin-Ciocalteu assay, wherein the calculated GAEs of Cannabis Stock in mg are plotted per mL / L of a given solution.

[0038]

[0030] FIG. 6 illustrates total antioxidant capacity of Psilocybe Stock, using Folin-Ciocalteu assay, with the calculated GAEs of Psilocybe Stock in mg plotted per mL / L of a given solution.

[0039]

[0031] FIG. 7 illustrates total antioxidant capacity of Pyropia Stock, using Folin-Ciocalteu assay, with the calculated GAEs of Pyropia Stock in mg plotted per mL / L of a given solution.

[0040]

[0032] FIG. 8 illustrates total antioxidant capacity of Tonka Concentrate, using Folin-Ciocalteu assay, with calculated GAEs of Tonka Concentrate in mg plotted per mL / L of a given solution.

[0041]

[0033] FIG. 9 illustrates the total antioxidant capacity of Cannabis Stock (Ca Stock), Psilocybe Stock (Ps Stock), and the 2-ingredient blend of Cannabis / Psilocybe (Ca / Ps), using (i.e., obtained via) Folin-Ciocalteu assay. The 2-ingredient Ca / Ps blend had a higher antioxidant capacity than each ingredient alone, and these data suggest an additive effect, where the 2 ingredients contributed to the capacity of the 2-ingredient blend.

[0042]

[0034] FIG. 10 illustrates the total antioxidant capacity of Cannabis Stock (Ca Stock), Pyropia Stock (Py Stock), and the 2-ingredient blend of Cannabis / Pyropia (Ca / Py), obtained via Folin-Ciocalteu assay. The 2-ingredient blend of Cannabis and Pyropia had a higher antioxidant capacity than each ingredient alone, and these data suggest a synergistic effect, since the antioxidant capacity of the 2-ingredient blend was more than what would be expected by adding the numbers for the two ingredients together.

[0035] FIG. 11 illustrates the total antioxidant capacity of Cannabis Stock (Ca Stock), Tonka Stock (To Stock), and the 2-ingredient blend of Cannabis / Tonka (Ca / To), obtained via Folin-Ciocalteu assay. The 2-ingredient blend of Cannabis and Tonka had a similar antioxidant capacity as the Cannabis ingredient. Tonka provided a slight enhancement of the antioxidant capacity, despite its relatively low proportion in the blend.

[0043]

[0036] FIG. 12 illustrates the total antioxidant capacity of Psilocybe Stock (Ps Stock), Pyropia Stock (Py Stock), and the 2-ingredient blend of Psilocybe / Pyropia (Ps / Py), obtained via Folin-Ciocalteu assay. The 2-ingredient blend of Psilocybe and Pyropia had slightly lower antioxidant capacity than Psilocybe alone. This suggests that compounds in the Pyropia stock solution interacted in a way that reduced the antioxidant capacity, i.e., the ability to donate electrons to the chemical reaction in the assay.

[0044]

[0037] FIG. 13 illustrates the total antioxidant capacity of Psilocybe Stock (Ps Stock), Tonka Stock (To Stock), and the 2-ingredient blend of Psilocybe / Tonka (Ps / To), obtained via Folin-Ciocalteu assay. The 2-ingredient blend of Psilocybe and Tonka had a lower antioxidant capacity than Psilocybe alone. This suggests that compounds in Tonka interacted with compounds in Psilocybe in a way that reduced the antioxidant capacity, i.e., the ability to donate electrons to the chemical reaction in the assay.

[0045]

[0038] FIG. 14 illustrates the total antioxidant capacity of Pyropia Stock (Py Stock), Tonka Stock (To Stock), and the 2-ingredient blend of Pyropia / Tonka (Py / To), using Folin-Ciocalteu assay. The 2-ingredient Py / To blend of had a similar antioxidant capacity as Py alone. To effects alone were undetectable at the dose range tested.

[0046]

[0039] FIG. 15 illustrates the total antioxidant capacity for the blend of Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To) compared to matching doses of Cannabis Stock (Ca Stock), Psilocybe Stock (Ps Stock), Pyropia Stock (Py Stock), and Tonka Stock (To Stock), obtained via Folin-Ciocalteu assay. The Ca / Ps / Py / To blend demonstrates a larger antioxidant capacity than any single ingredient, suggesting synergistic effects.

[0047]

[0040] FIG. 16 illustrates the total antioxidant capacity for the blend of Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To) compared to matching doses of each of the 2-ingredient blends, including Cannabis / Psilocybe (Ca / Ps), Cannabis / Pyropia (Ca / Py), Cannabis / Tonka (Ca / To), Psilocybe / Pyropia (Ps / Py), Psilocybe / Tonka (Ps / To), and Pyropia / Tonka (Py / To), obtained via Folin-Ciocalteu assay. The Ca / Ps / Py / To blend demonstrates a larger antioxidant capacity than any 2-ingredient blend, further suggesting synergistic effects.

[0048]

[0041] FIG. 17 illustrates the total antioxidant capacity of the 4-ingredient blend of Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To) in comparison to Applicant’s “4+” Blend (i.e., Applicant’s final product disclosed herein as ABS-108 and NIM-01, and as the composition of EXAMPLE 6) obtained via Folin-Ciocalteu assay. The 4+ blend showed a higher antioxidant capacity than the 4-ingredient blend of Ca / Ps / Py / To. This shows the additional ingredients in the 4+ blend contribute to the antioxidant properties of the final product.

[0049]

[0042] FIG. 18 illustrates the total cellular antioxidant protection of Cannabis in Soy Lecithin emulsifier. FIG. 18 shows the percent inhibition of cellular oxidative damage per mL / L of solution used.

[0050]

[0043] FIG. 19 illustrates the total cellular antioxidant protection of Psilocybe Stock. FIG. 19 shows the percent inhibition of cellular oxidative damage per mL / L of solution used.

[0044] FIG. 20 illustrates the total cellular antioxidant protection of Pyropia Concentrate. FIG. 20 shows the percent inhibition of cellular oxidative damage per mL / L of solution used.

[0051]

[0045] FIG. 21 illustrates the total cellular antioxidant protection of Tonka Concentrate. FIG. 21 shows the percent inhibition of cellular oxidative damage per mL / L of solution used.

[0052]

[0046] FIG. 22 illustrates the total cellular antioxidant protection of Cannabis Stock (Ca Stock) compared with related 2-ingredient blends, namely Cannabis / Psilocybe (Ca / Ps), Cannabis / Pyropia (Ca / Py), and Cannabis Tonka (Ca / To), along with Soy Lecithin. FIG. 22 shows the percent inhibition of cellular oxidative damage per mL / L of solution used. FIG. 22 depicts data as the average ± std. deviation of duplicate data points for each dose. The table under the graph shown in FIG. 22 depicts the statistical significance of Ca Stock to Ca / Ps versus Ca Stock to Ca / Py versus Ca Stock to Ca / To, and is indicated by asterisks (P<0.10: (*), P<0.05: *, P<0.01 : **). Cannabis alone provided a slightly better cellular antioxidant protection than any of the 2-ingredient blends containing Cannabis.

[0053]

[0047] FIG. 23 illustrates the total cellular antioxidant protection of Psilocybe Stock (Ps Stock) compared with the related 2-ingredient blends, namely Cannabis / Psilocybe (Ca / Ps), Psilocybe / Pyropia (Ps / Py), and Psilocybe / Tonka (Ps / To). Psilocybe alone provided a mild cellular antioxidant protection at the highest dose. In contrast, the 2-ingredient blends did not provide cellular antioxidant protection at the dose range tests.

[0054]

[0048] FIG. 24 illustrates the total cellular antioxidant protection of Pyropia Stock (Py Stock) compared with related 2-ingredient blends, namely Cannabis / Pyropia (Ca / Py), Psilocybe / Pyropia (Ps / Py) and Pyropia / Tonka (Py / To). The 2-ingredient blends showed a higher cellular antioxidant protection than Pyropia alone, and these data suggest an additive effect, where the 2 ingredients contributed to the capacity of the 2-ingredient blends.

[0055]

[0049] FIG. 25 illustrates the total cellular antioxidant protection of the 4-ingredient blend, namely Cannabis / Psilocybe / Pyropia / Tonka (Ca / Ps / Py / To), Applicant’s “4+” Blend, and ethanol. Applicant’s “4+” blend showed similar cellular antioxidant protection at a dose of 10.42 mL / L. The ethanol control showed cellular damage at a dose of 20.83 mL / L, and no cellular antioxidant protection at lower doses.

[0056]

[0050] FIG. 26 illustrates the total cellular energy production in peripheral blood mononuclear cell (PBMC) cultures following treatment with Cannabis Stock, Cannabis / Psilocybe / Pyropia / Tonka, Applicant’s “4+” Blend, and Soy Lecithin emulsifier. Cannabis Stock and Soy Lecithin emulsifier result in increased cellular energy production at higher doses. The highest doses of the Cannabis / Psilocybin / Pyropia / Tonka blend are associated with increased cellular energy production. A steep decline in cellular metabolic activity was observed at the 1 .6 mL / L dose of the 4+ blend treatment. The Cannabis / Psilocybin / Pyropia / Tonka blend and Applicant’s “4+” blend were well-tolerated by the cells at doses at or lower than 0.01 mL / L.

[0057]

[0051] FIG. 27 illustrates the total cellular energy production in peripheral blood mononuclear cell (PBMC) cultures following treatment with Psilocybe Stock, Pyropia Stock, and Tonka Stock. Psilocybe Stock and Pyropia Stock, but not Tonka Stock, resulted in increased cellular metabolic activity.

[0058]

[0052] FIG. 28 illustrates the total cellular energy production in peripheral blood mononuclear cell (PBMC) cultures following treatment with Cannabis / Psilocybe, Cannabis / Pyropia, and Cannabis / Tonka. The 2-ingredient Cannabis blends were associated with increased mitochondrial activity at medium doses, and decreased activity at higher doses. An exception is the Cannabis / Tonka blend, which is associated with a large increase in mitochondrial activity at 100 mL / L.

[0059]

[0053] FIG. 29 illustrates the total cellular energy production in peripheral blood mononuclear cell (PBMC) cultures following treatment with Psilocybe / Pyropia and Psilocybe / Tonka. The 2-ingredient blends containing Psilocybe were associated with increased mitochondrial activity.

[0060]

[0054] FIG. 30 illustrates the total cellular energy production in peripheral blood mononuclear cell (PBMC) cultures following treatment with Py / To. The Py / To blend was associated with increased mitochondrial activity.

[0061]

[0055] FIG. 31 illustrates the percent of viable PBMC cultures following treatment with Cannabis Stock, Cannabis / Psilocybe / Pyropia / Tonka, Applicant’s “4+” Blend, and Soy Lecithin emulsifier. FIG. 31 shows the percent of live lymphocytes per mL / L of solution used. Cannabis and the Soy Lecithin emulsifier were well tolerated by the PBMC cultures at all doses tested. The Ca / Ps / Py / To blend was well tolerated at doses at or lower than 0.8 mL / L. Applicant’s “4+” Blend was well tolerated at doses at or lower than 0.2 mL / L.

[0062]

[0056] FIG. 32 illustrates the percent of viable PBMC cultures following treatment with Psilocybe Stock, Pyropia Stock and Tonka Stock. Psilocybe was well tolerated at doses at or lower than 12.5 mL / L. Pyropia was well tolerated at doses at or lower than 50 mL / L. Tonka was well tolerated at all doses tested.

[0063]

[0057] FIG. 33 illustrates the percent of viable PBMC cultures following treatment with Pyropia / Tonka, Psilocybe / Tonka, Psilocybe / Pyropia, Cannabis / Tonka, Cannabis / Pyropia, and Cannabis / Psilocybe. Cannabis / Pyropia showed similar tolerability to Cannabis alone. Cannabis / Psilocybe was better tolerated by the cell cultures than Cannabis alone. Cannabis / Tonka was slightly less tolerated by the cell cultures than Cannabis alone. Tonka did not have much activity at the low dose tested, suggesting a synergistic effects of the 2-ingredient blend. The Psilocybe / Pyropia and the Psilocybe / Tonka blends were tolerated in a similar manner as Psilocybe alone. Psilocybe / Cannabis was slightly less tolerated by the cell cultures than Psilocybe alone, while Pyropia / Tonka was tolerated in a similar manner as Pyropia alone.

[0064]

[0058] FIG. 34 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Cannabis Stock, per mL / L of solution used. It was inconclusive whether Cannabis contributed to the increased mitochondrial activity.

[0065]

[0059] FIG. 35 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Soy Lecithin emulsifier, per mL / L of solution used. The effects of Cannabis and Soy Lecithin emulsifier were similar.

[0066]

[0060] FIG. 36 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Psilocybe Stock, per mL / L of solution used. The area shown inside the rounded frame as depicted in FIG. 36 details the doses where cell viability was excellent, and where mitochondrial activity was increased, illustrating that Psilocybe Stock supports mitochondrial function and cellular energy production. Psilocybe stock showed definitive support of mitochondrial function.

[0067]

[0061] FIG. 37 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Pyropia Stock, per mL / L of solution used. The area shown inside the rounded frame as depicted in FIG. 37 details the doses where cell viability was excellent, and where mitochondrial activity was increased, illustrating that Pyropia Stock supports mitochondrial function and cellular energy production. Pyropia stock showed definitive support of mitochondrial function.

[0068]

[0062] FIG. 38 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Tonka Stock, per mL / L of solution used.

[0069]

[0063] FIG. 39 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Cannabis / Psilocybe / Pyropia / Tonka, per mL / L of solution used.

[0070]

[0064] FIG. 40 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMCs following treatment with Applicant’s “4+” Blend, per mL / L of solution used.

[0071]

[0065] FIG. 41 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Cannabis / Psilocybe, per mL / L of solution used. The area shown inside the rounded frame as depicted in FIG. 41 details the doses where cell viability was excellent, and where mitochondrial activity was increased, illustrating that Ca / Ps supports mitochondrial function and cellular energy production.

[0072]

[0066] FIG. 42 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Cannabis / Pyropia, per mL / L of solution used. The area shown inside the rounded frame as depicted in FIG. 42 details the doses where cell viability was excellent, and where mitochondrial activity was increased, illustrating that Ca / Py supports mitochondrial function and cellular energy production.

[0073]

[0067] FIG. 43 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Cannabis / Tonka, per mL / L of solution used.

[0074]

[0068] FIG. 44 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Psilocybe / Pyropia, per mL / L of solution used. The area shown inside the rounded frame as depicted in FIG. 44 details the doses where cell viability was excellent, and where mitochondrial activity was increased, illustrating that Ps / Py supports mitochondrial function and cellular energy production.

[0075]

[0069] FIG. 45 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Psilocybe / Tonka, per mL / L of solution used. The effect of Psilocybe / Tonka on mitochondrial function was extremely mild and judged to be inconclusive.

[0076]

[0070] FIG. 46 illustrates the relative mitochondrial metabolic activity and the percent of viable PBMC cultures following treatment with Pyropia / Tonka, per mL / L of solution used. The area shown inside the rounded frame as depicted in FIG. 46 details the doses where cell viability was excellent, and where mitochondrial activity was increased, illustrating that Pyropia / Tonka supports mitochondrial function and cellular energy production.

[0077] DETAILED DESCRIPTION OF THE INVENTION

[0078]

[0071] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates some exemplary embodiments in further detail to enable one having ordinary skill in the art to which the invention belongs (equivalently as shorthand, “one of skill”) to practice such embodiments and to make and use the full scope of the invention claimed.

[0079]

[0072] Many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention illustrated herein can be made by one of skill 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. Thus, the invention is not intended to be limited to the aspects presented, but is to be accorded the widest scope consistent with the principles and features disclosed. The description below is designed to make such embodiments apparent to one of skill, in that the embodiments shall be both readily cognizable and readily creatable without undue experimentation, solely using the teachings herein together with the general knowledge in the art.

[0080] / . General Definitions and Terms

[0081]

[0073] The singular articles “a,” “an,” and “the” encompass both singular and plural referents unless context explicitly dictates otherwise. For instance, “an excipient” may refer to one or more excipients, and “a bioactive molecule” may denote one or more bioactive molecules. “A bioactive molecule” may include bioactive molecule(s) present within another substance, such as an extract, unless expressly or contextually limited to purified or isolated forms. Even in such cases, the term may still encompass the bioactive molecule(s) in combination with another substance, provided that the molecule(s) maintain the specified degree of purity.

[0082]

[0074] “Or” means, and is interchangeable with, “and / or” unless context clearly indicates otherwise. The specific use of the term “and / or” does not signify that any uses of “or” are disjunctive only; rather, such use simply underscores the possibility that the term “and / or” may be conjunctive in particular embodiments, but otherwise may be disjunctive, like “or.” The term “and” will be understood to be conjunctive.

[0083]

[0075] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[0084]

[0076] Compositions “consisting of’ specific bioactive molecules may include only the bioactive molecules recited, and those “consisting essentially of’ specific bioactive molecules may include the recited bioactive molecules, optionally together with additional compounds or other elements that do not materially affect the basic and novel characteristic(s) of the claimed combination, composition, or method. While the term “one or more” may be used, its absence (or its replacement by the singular) does not signify the singular only; rather, such use simply underscores the possibility of multiple agents or ingredients in particular embodiments.

[0085]

[0077] Where ranges are used, the disclosure includes embodiments in which the endpoints are included, embodiments in which both endpoints are excluded, and embodiments in which one endpoint is included and the other is excluded. It should be assumed that both endpoints are included unless indicated otherwise. It is also understood that unless otherwise indicated or otherwise evident from the context and understanding of one of skill, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. It is further understood that where a series of numerical values is stated herein, the disclosure includes embodiments that relate analogously to any intervening value or range defined by any two values in the series, and that the lowest value may be taken as a minimum and the greatest value may be taken as a maximum. Numerical values, as used herein, include values expressed as percentages.

[0086]

[0078] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, will be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers will be understood as not being modified by the term “about.” In embodiments, the numerical parameters are approximations that can vary depending on the particular embodiment or the properties sought to be obtained. In embodiments, “about” includes numbers that fall within a range of ±10% of a number, in embodiments within ±5% of a number, in embodiments within ±2% of a number, in embodiments within ±1 % of a number, in embodiments within ±0.5% of a number, and in embodiments within ±0.1% of a number, unless otherwise stated or evident from the context (such as where a number would impermissibly exceed 100% of a possible value).

[0087]

[0079] Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, “about 1, 2, or 3” means “about 1 , about 2, or about 3” and “about 1 to 10” means “about 1 to about 10.”

[0088]

[0080] The term “substantially,” where used to modify a feature or limitation, must be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, such as by using a standard recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill.

[0089]

[0081] Numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the examples are reported as precisely as practicable. Numerical values in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0090]

[0082] A comprehensive list of the abbreviations used by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry, typically presented in a table entitled Standard List of Abbreviations; the current list as of the date of this filing is incorporated by reference.

[0091]

[0083] Unless explicitly defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one of skill. Further definitions that may assist a reader in understanding the disclosed and exemplary embodiments are below; however, it will be appreciated that such definitions are not intended to limit the scope of the disclosure, which shall be properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill) in view of the language used in the claims. Terminology is for the purpose of describing particular embodiments and not intended to be limiting.

[0084] Terms having a specific meaning within the regulatory law of a jurisdiction in which this application is filed or may be in force generally should be given such meaning unless context dictates otherwise. For example, “Botanical Drug Substance” may refer to the term as defined through FDA implementing rules and regulations, and as described in the Guidance for Industry Botanical Drug Products, December 2016 (Docket No. FDA-2000-D-0103), U.S. Department of Health and Human Services, FDA ODER (FDA. Botanical drug development guidance for industry. 2016. ODER pharmaceutical quality. CMC). Other such terms, including “Botanical Drug Product” and “Botanical Raw Materials,” shall be known similarly.

[0092]

[0085] For avoidance of doubt, even though “botanical” is commonly used to mean “relating to plants,” for purposes herein “botanical,” as in a “botanical” drug substance or drug product, may include compounds, substances, and products (e.g., extracts) obtained or derived from fungal material, or present therein, such as psilocybin-containing or other fungi, such as defined by the FDA. A “botanical” drug substance or drug product also may include compounds, substances, and products (e.g., extracts) obtained or derived from algal material, or present therein, wherein “algal material” refers broadly to any material from the polyphyletic group of diverse photosynthetic eukaryotic organisms that is referred to or understood in the field as “algae,” and especially those parts comprising the bioactive molecules of interest, as known by those of skill.

[0093]

[0086] Botanical drug substances and drug products, and compositions comprising them, may be available by prescription or over-the-counter (OTC), as nutritional or dietary supplements, as “nutraceuticals,” or under any other regulatory regime; they also may be unregulated (e.g., “natural products”).

[0094]

[0087] Herein, “plant material” encompasses whole plants and also parts thereof, such as parts which contain the bioactive molecules sought, e.g., the aerial parts of a plant or isolated leaves, stems, flowers, fruits, roots, or combinations of any of the foregoing, as may depend on the plant, but will be known in view hereof by those of skill. For example, with cannabis plant material, plant material may preferably comprise the inflorescences of the flowering female plant, such as generally comprise the greatest concentration of bioactive molecules, for example terpenoids and cannabinoids. Other plant parts however, for cannabis and for other plants, also shall be able to be used in the disclosed compositions and methods, as will be appreciated by those of skill.

[0095]

[0088] Where fungal material is used (e.g., in extraction), it may be from any part of fungal fruiting bodies (“mushrooms”), from fungal sclerotia (“truffles”), as well as from mycelia or other material (e.g., bioreactor biomass), unless context indicates otherwise, and any or all such parts, as well as combinations thereof, may be referred to as “fungal material.” Preferably, fungal material containing the bioactive molecule(s) is selected.

[0096]

[0089] “In embodiments” is equivalent to, and used only as shorthand for, “in some embodiments.”

[0097]

[0090] Terms used and other disclosure also may be more fully understood in view of Applicant’s International Application Nos. PCT / US2023 / 032444, published as WO2024 / 054688, and PCT / US2024 / 016584, published as WO2024 / 173954, the complete contents of which are incorporated by reference as if fully set forth herein.

[0098]

[0091] Generally, the nomenclature and terminology used and the procedures performed herein are those known in fields relating to that of one or more aspects of the disclosure, such as biology, chemistry, natural products extraction, botany, mycology, phycology, pharmacology, and medicine, and that are well-known and commonly employed in one or more of such fields. Standard techniques and procedures are those generally performed according to conventional methods in the art. While any materials and methods similar or equivalent to those described can be used in some embodiments, certain materials and methods are described herein.

[0099] / / . Components of Therapeutic Combinations, Compositions, and Formulations

[0100]

[0092] In some aspects are provided therapeutic combinations comprising a fungal portion, a plant portion, and an algal portion. A "therapeutic combination,” useful for example in methods of treating subjects, such as human and other mammalian subjects, including where used according to disclosed methods, will be referred to herein equivalently and simply for shorthand as a “combination,” and a “combination” consequently refers to a “therapeutic combination” according to the disclosure, unless context clearly indicates otherwise.

[0101]

[0093] In embodiments, a combination comprises a fungal portion, a plant portion, and an algal portion. In embodiments, a combination comprises a fungal portion, a first plant portion, an optional second plant portion, and an algal portion. In embodiments, a combination comprises a fungal portion, a first plant portion, a second plant portion, and an algal portion. Combinations are useful to prevent or treat disorders, such as when administered according to disclosed methods. In embodiments, a combination is useful to prevent or treat a mitochondrial disorder. In embodiments, a combination is useful to prevent or treat a metabolic disorder. In embodiments, a combination is useful to prevent or treat an autoimmune disorder. In embodiments, a combination is useful to prevent or treat a pain disorder. In embodiments, a combination is useful to prevent or treat a mental health disorder. In embodiments, a combination is useful to prevent or treat an endocrine disorder. In embodiments, a combination is useful to prevent or treat a viral disorder. In embodiments, a combination is useful to prevent or treat a degenerative disorder.

[0102]

[0094] In embodiments, a fungal, a plant, or an algal portion comprises an extract (i.e., a fungal, plant, or algal extract, respectively). In embodiments, a combination comprises a fungal extract, a plant portion, and an algal portion. In embodiments, a combination comprises a fungal extract, a first plant portion, an optional second plant portion, and an algal portion. In embodiments, a combination comprises a fungal extract, a first plant portion, a second plant portion, and an algal portion. In embodiments, a combination comprises a fungal portion, a first plant extract, an optional second plant extract, and an algal portion. In embodiments, a combination comprises a fungal portion, a first plant extract, a second plant extract, and an algal portion. In embodiments, a combination comprises a fungal portion, a first plant portion, an optional second plant portion, and an algal extract. In embodiments, a combination comprises a fungal portion, a first plant portion, a second plant portion, and an algal extract. In embodiments, a combination comprises a fungal extract, a first plant extract, an optional second plant extract, and an algal portion. In embodiments, a combination comprises a fungal extract, a first plant extract, a second plant extract, and an algal portion. In embodiments, a combination comprises a fungal extract, a first plant portion, an optional second plant portion, and an algal extract. In embodiments, a combination comprises a fungal extract, a first plant portion, a second plant portion, and an algal extract. In embodiments, a combination comprises a fungal extract, a plant extract, and an algal extract. In embodiments, a combination comprises a fungal extract, a first plant extract, an optional second plant extract, and an algal extract. In embodiments, a combination comprises a fungal extract, a first plant extract, a second plant extract, and an algal extract.

[0103]

[0095] In embodiments, the combination comprises a bioactive molecule from a fungus, a plant, and / or an algae. In embodiments, a combination comprises a bioactive molecule from a fungus, and a bioactive molecule from a plant. In embodiments, a combination comprises a bioactive molecule from a plant, and a bioactive molecule from an algae. In embodiments, a combination comprises a bioactive molecule from a fungus, a bioactive molecule from a plant, and a bioactive molecule from an algae. In embodiments, a combination comprises a bioactive molecule from a fungus, a bioactive molecule from a plant, a bioactive molecule from an algae, and a bioactive molecule from a fungus, a plant, and / or an algae. In embodiments, a combination comprises a bioactive molecule from a fungus, a first bioactive molecule from a plant, a second bioactive molecule from a plant, and a bioactive molecule from an algae.

[0104]

[0096] In embodiments, a combination comprises a bioactive molecule from Psilocybe cubensis, a bioactive molecule from Cannabis sativa, a bioactive molecule from Pyropia yezoensis, and / or a bioactive molecule from Dipteryx odorata. In embodiments, a combination comprises two or more of a bioactive molecule from P. cubensis, a bioactive molecule from C. sativa, a bioactive molecule from P yezoensis, and a bioactive molecule from D. odorata. In embodiments, a combination comprises three or more of a bioactive molecule from P. cubensis, a bioactive molecule from C. sativa, a bioactive molecule from P yezoensis, and a bioactive molecule from D. odorata. In embodiments, a combination comprises all four of a bioactive molecule from P. cubensis, a bioactive molecule from C. sativa, a bioactive molecule from P. yezoensis, and a bioactive molecule from D. odorata.

[0105]

[0097] In embodiments, a combination is a botanical formulation, comprising whole extracts of P. cubensis, C. sativa, P. yezoensis, and D. odorata. In embodiments, a combination is a botanical formulation comprising whole extracts of two or more of P. cubensis, C. sativa, P. yezoensis, and D. odorata. In embodiments, a combination is a botanical formulation comprising whole extracts of three or more of P. cubensis, C. sativa, P. yezoensis, and D. odorata. In embodiments, a combination is a botanical formulation comprising whole extracts of all four of P. cubensis, C. sativa, P. yezoensis, and D. odorata.

[0106]

[0098] A bioactive molecule may be provided in an extract, such as in a whole extract, in a fraction or subtraction thereof, or may be provided as an isolated compound, a substantially purified compound, or a purified compound, including one produced by biosynthetic or synthetic means, and combinations thereof.

[0107]

[0099] In embodiments, a bioactive molecule from a fungus is not also a bioactive molecule from a plant, nor is it a bioactive molecule from an algae (i.e., the bioactive molecule from a fungus is only found in fungi). In embodiments, a bioactive molecule from a plant is not also a bioactive molecule from a fungus, nor is it a bioactive molecule from an algae (i.e., the bioactive molecule from a plant is only found in plants). In embodiments, a bioactive molecule from an algae is not also a bioactive molecule from any fungus, nor is it a bioactive molecule from any plant (i.e., the bioactive molecule from an algae is only found in algae).

[0108]

[0100] In embodiments, a bioactive molecule from a fungus is also either a bioactive molecule from a plant, or a bioactive molecule from an algae (i.e., it is also found in plants or algae, but not both). In embodiments, a bioactive molecule from a plant is also either a bioactive molecule from any fungus, or a bioactive molecule from an algae (i.e., it is also found in fungi or algae, but not both). In embodiments, a bioactive molecule from an algae is also either a bioactive molecule from any fungus, or a bioactive molecule from a plant (i.e., it is also found in fungi or plants, but not both).

[0109]

[0101] In 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 found in plants or algae). In 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 found in fungi or algae). In 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 found in fungi or plants).

[0110]

[0102] Herein, “secondary,” as in “secondary bioactive,” may be used interchangeably with the terms “second” or “additional,” and is not intended to necessarily signify any specific degree of priority when compared to the term “primary,” as in “primary bioactive,” and does not necessarily imply a lower degree of importance or significance, such as importance or significance in any specific combination, composition, kit, or method; in providing or contributing to any specific advantage, benefit, or synergy; or for any specific use.

[0111] A. Fungi

[0112]

[0103] “Fungi” refers to organisms that do not contain chlorophyll and are saprophytic, parasitic, and / or symbiotic, and which may reproduce both sexually and asexually through spores. Fungi include what are commonly referred to as yeasts, rusts, smuts, mildews, molds, and mushrooms. Exemplary fungi include the classes Phycomycetes, Ascomycetes, and Basidiomycetes. Herein, “fungi” refers to both filamentous and non-filamentous fungi, and use of the word “fungi” may include other words, including “fungal” and “fungus.”

[0113]

[0104] In some exemplary embodiments, the fungi are psilocybin-producing fungi. A “psilocybin-producing” fungus is any fungus that produces or is capable of producing psilocybin. Over 100 species in the Psilocybe genus of fungi produce psilocybin. Psilocybin-producing species are also in other genera, including Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, and Pluteus. In embodiments, a psilocybin-producing species is from any of these genera. In embodiments, a psilocybin-producing species is from any of the Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe genera. In embodiments, a psilocybin-producing species is from Psilocybe.

[0114]

[0105] Other genera, species, and strains of psilocybin-producing fungi will be readily known or identifiable.

[0115]

[0106] In embodiments, the psilocybin-producing fungus is a Psilocybe spp. fungus. In embodiments, the Psilocybe spp. fungus is a P. acutipilea, P. alien!!, P. alutacea, P. angulospora, P. antioquiensis, P. araucariicola, P. atlantis, P. aquamarina, P. armandii (Mexicana), P. aucklandiae, P. aztecorum, P. azurescens, P. baeocystis, P. banderillensis, P. bispora, P. brasiliensis, P. bmnneocystidiata, P. caeruleoannulata, P. caenilescens, 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. guatapensis, 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. 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. pseudo- aztecorum, 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. subaeniginascens, P. subaeruginosa, P. subcaerulipes, P. subcubensis, P. subpsilocybioi- des, P. subtropicalis, P. tampanensis, P. thaicordispora, P. thaiaeivgineomaculans, P. thaiduplicatocystidiata, P. uruguayensis, P. uxpanapensis, P. venenata, P. villarrealiae, P. weilii, P. weldenii, P. weraroa, P. wrightii, P. yungensis, P. zapotecoantillarum, P. zapotecocaribaea, or P. zapotecorum species, including strains thereof.

[0116]

[0107] In embodiments, the psilocybin-producing fungus is not a Psilocybe spp. fungus. Other psilocybin-producing fungi, not of the Psilocybe genus, will be readily known to those in the art. Non-limiting examples include Conocybe siligineoides, Conocybe velutipes, Copelandia tropica, Inocybe aeruginascens, Inocybe caerulata, Inocybe coelestium, Inocybe corydalina, Inocybe haemacta, Inocybe tricolor, Galerina steglichii, Gymnopilus aeruginosus, Gymnopilus braendlei, Gymnopilus cyanopalmicola, Gymnopilus dilepis, Gymnopilus dunensis, Gymnopilus intermedius, Gymnopilus lateritius, Gymnopilus luteofolius, Gymnopilus luteoviridis, Gymnopilus luteus, Gymnopilus palmicola, Gymnopilus purpuratus, Gymnopilus subpurpuratus, Gymnopilus subspectabilis, Gymnopilus validipes, Gymnopilus viridans, Panaeolus venezolanus, Panaeolus tropicalis, Panaeolus tirunelveliensis, Panaeolus rubricaulis, Panaeolus olivaceus, Panaeolus moellerianus, Panaeolus microsporus, Panaeolus lentisporus, Panaeolus fimicola, Panaeolus cyanescens, Panaeolus cinctulus, Panaeolus chlorocystis, Panaeolus cambodginiensis, Panaeolus bisporus, Panaeolus axfordii, Panaeolus africanus, Panaeolus affinis, Pholiotina cyanopus, Pholiotina smithii, Pluteus albostipitatus, Pluteus americanus, Pluteus cyanopus, Pluteus glaucus, Pluteus glaucotinctus, Pluteus nigroviridis, Pluteus phaeocyanopus, Pluteus salicinus, Pluteus saupei, Pluteus velutinornatus, and Pluteus villosus.

[0117]

[0108] In embodiments, a bioactive molecule from a fungus is any in Venturella et al. Int J Mol Sci. 2021 ;22 (2):634; Anusiya et al. Bioeng’g. 2021 ; 12(2): 11239-11268; Thu et al. Molecules. 2020;25(8):1972; Muszynska et al. Food Chem. 2018;243:373-381 ; and Mishraki-Berkowitz et al. J Forensic Sci. 2020;65(5): 1450-1457.

[0118] 1. Primary and Secondary Bioactive Molecules from Fungi

[0119]

[0109] In embodiments, a combination comprises a fungal portion. In embodiments, the fungal portion comprises a fungal extract. In embodiments, the fungal portion comprises a bioactive molecule from a fungus. In embodiments, the fungal extract comprises a bioactive molecule from a fungus. In embodiments, a combination comprises a bioactive molecule from a fungus. A "bioactive molecule” herein may be used as shorthand, and refers equivalently to and should be understood as meaning a “primary bioactive molecule and / or a secondary bioactive molecule” or a “primary and / or secondary bioactive molecule” according to the disclosure, unless context clearly indicates otherwise. “Molecule” also may be used herein alone as shorthand.

[0120]

[0110] In embodiments, the fungal portion is from a psilocybin-producing fungus. The fungus can be any psilocybin-producing fungus known or ascertainable by those of skill, including, as non-limiting examples, certain species from the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, and Psilocybe.

[0121]

[0111] In some embodiments wherein the fungal portion is described as being “from” a fungus, it will be understood that the fungal portion comprises matter derived from the fungus, including, as non-limiting examples, fungal material such as raw (i.e., unprocessed) fungal biomass, a fungal extract (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or a molecule that is naturally occurring in the fungus (e.g., a primary or secondary bioactive molecule described in embodiments herein), whether or not said molecule is actually obtained by isolating the molecule from the fungus, or another means (e.g., by chemical synthesis).

[0122]

[0112] In embodiments, the fungal portion of a combination is from a psilocybin-producing species. In embodiments, the fungal portion of a combination is from a species of the genera Athelia, Conocybe, Copelandia, Fibularhizoctonia, Galerina, Gymnopilus, Inocybe, Mycena, Panaeolus, Pholiotina, Pluteus, or Psilocybe. In embodiments, the fungal portion comprises a fungal extract from a psilocybin-producing species. In 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, or Psilocybe. In embodiments, the fungal portion comprises a bioactive molecule from a psilocybin-producing species. In 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, or Psilocybe. In embodiments, the fungal portion is from a species of Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, or Psilocybe. In embodiments, the fungal portion comprises a fungal extract from a species of Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, or Psilocybe. In embodiments, the fungal portion comprises a bioactive molecule from a species of Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, or Psilocybe.

[0123]

[0113] In embodiments, the fungi is a Psilocybe spp. fungi. In embodiments, the fungal portion is from a Psilocybe spp. fungi. In embodiments, the fungal portion is from any of P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and P. liniformans. In embodiments, the fungal portion comprises a fungal extract from a Psilocybe spp. fungi. In embodiments, the fungal portion comprises a fungal extract from any of P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyano- fibrillosa, and / or P. liniformans. In embodiments, the fungal portion comprises a fungal extract from a Psilocybe spp. fungi. In embodiments, the fungal portion comprises a bioactive molecule from any of P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofib llosa, and P. liniformans.

[0124]

[0114] In embodiments, the fungal portion comprises any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aeruginascin. In embodiments, the fungal portion comprises a fungal extract comprising any of psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, and aeruginascin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus that is any 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 a primary bioactive molecule from a fungus, wherein the molecule is psilocybin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus, wherein the molecule is psilocin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus, wherein the molecule is baeocystin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus, wherein the molecule is norbaeocystin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus, wherein the molecule is norpsilocin. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus, wherein the molecule is aeruginascin.

[0125]

[0115] In embodiments, the fungal portion comprises two bioactive molecules from a fungus, which may be any two bioactive molecules. In embodiments, the fungal portion comprises psilocybin and psilocin. In embodiments, the fungal portion comprises a fungal extract comprising psilocybin and psilocin. In embodiments, the fungal portion comprises, as primary bioactive molecules from a fungus, psilocybin and psilocin. A fungal portion may comprise another number of bioactive molecules, such as 3, 4, 5, or more than 5.

[0126]

[0116] In embodiments, the fungal portion comprises two bioactive molecules from a fungus in a defined weight ratio or molar ratio, including from one or more psilocybin-producing species, from different fungal species, and from different fungal genera. Psilocybin and psilocin are used in exemplary embodiments, but any two bioactive molecules from a fungus may be provided, including primary and / or secondary bioactive molecules described herein. In embodiments, the fungal portion comprises both psilocybin and psilocin in a weight ratio of between about 100:1 and 1 :100, 50:1 and 1 :50, 10:1 and 1 :10, 5:1 and 1 :5, 2:1 and 1 :2, 5:3 and 3:5, or 3:2 and 2:3, all ranges inclusive. In embodiments, fungal portion comprises psilocybin and psilocin in a molar ratio of 100:1 and 1 :100, 50:1 and 1 :50, 10:1 and 1 :10, 5:1 and 1 :5, 2:1 and 1 :2, 5:3 and 3:5, or 3:2 and 2:3, all ranges inclusive. In embodiments, the fungal portion comprises both psilocybin and psilocin in a weight ratio of about 100:1 , 50:1 , 10:1, 5:1, 2:1, 5:3, 3:2, or 1 :1. In embodiments, the fungal portion comprises both psilocybin and psilocin in a molar ratio of about 100:1 , 50:1 , 10:1, 5:1 , 2:1 , 5:3, 3:2, or 1 :1. In embodiments, the fungal portion comprises both psilocybin and psilocin in a weight ratio of about 1 :100, 1 :50, 1 :10, 1 :5, 1 :2, 3:5, 2:3, or 1 :1. In embodiments, the fungal portion comprises both psilocybin and psilocin in a molar ratio of about 1 :100, 1 :50, 1 :10, 1 :5, 1 :2, 3:5, 2:3, or 1 :1. In embodiments, the fungal portion comprises both psilocybin and psilocin in a weight ratio of about 5:3, 3:2, 1 :1 , 2:3, or 3:5. In embodiments, the fungal portion comprises both psilocybin and psilocin in a molar ratio of about 5:3, 3:2, 1 :1 , 2:3, or 3:5. In embodiments, a fungal portion, a fungal extract, or a mixture of bioactive molecules from a fungus comprises psilocybin and psilocin in a weight ratio of about 5:3, 3:2, or 1 :1. In embodiments, a fungal portion, a fungal extract, or a mixture of bioactive molecules from a fungus comprises psilocybin and psilocin in a molar ratio of about 5:3, 3:2, or 1 :1. In embodiments, a fungal portion, a fungal extract, or a mixture of bioactive molecules from a fungus comprises psilocybin and psilocin in a weight ratio of about 5:3. In embodiments, a fungal portion, a fungal extract, or a mixture of bioactive molecules from a fungus comprises psilocybin and psilocin in a molar ratio of about 5:3.

[0127]

[0117] In embodiments, the fungal portion comprises a p-carboline (beta-carboline). In embodiments, the fungal portion comprises a fungal extract comprising a p-carboline. In embodiments, the fungal portion comprises a primary bioactive molecule from a fungus, wherein the primary bioactive molecule is a P-carboline. In embodiments, the p-carboline is harmane, harmine, harmol, harmalol, harmaline, tetrahydroharmine, pinoline, cordysinin C, cordysinin D, norharmane, perlolyrine, p-carboline (9H-pyrido[3,4- b]indole), or another L-tryptop han-derived p-carboline. Although “P-carboline” may refer to both the individual compound and the class of related compounds, use of the term herein will be understood as referring to the class of compounds (including when recited as “a p-carboline”) unless context demonstrates otherwise.

[0128]

[0118] In embodiments, the secondary bioactive molecule from a fungus is a polysaccharide (including a and P-glucans and polysaccharide-protein complexes), a peptide (including proteins such as lectins), a terpene or terpenoid (including mono and sesquiterpene oils, diterpenes, triterpenoids and sterols, and carotenoid pigments), a phenolic compound (including phenolic acids, hydroxycinnamic acids, hydroxybenzoic acids, ligans, tannins, flavonoids, stilbenes, and oxidized polyphenols), a mineral (including potassium, phosphorous, sodium, calcium, magnesium, copper, selenium, iron, and zinc), a vitamin (including ascorbic acid, vitamin D, riboflavin, folate, thiamine, pantothenic acid, and niacin), an amino acid (including the 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, linoleic, and linolenic acids), a choline, or a lactone. B. Plants

[0129]

[0119] “Plants” refers to photosynthetic eukaryotes of the kingdom Plantae. In embodiments, a combination comprises a plant portion. In embodiments, the plant portion comprises a plant extract. In embodiments, the plant portion comprises a bioactive molecule from a plant. In embodiments, the plant extract comprises a bioactive molecule from a plant. In embodiments, a combination comprises a bioactive molecule from a plant.

[0130]

[0120] In embodiments wherein the plant portion is described as being “from” a plant, it will be understood that the plant portion comprises matter derived from the plant, including, as non-limiting examples, plant material such as raw (i.e., unprocessed) plant biomass, a plant extract (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or a molecule that is naturally occurring in the plant (e.g., a primary or secondary bioactive molecule described in embodiments herein), whether or not said molecule is actually obtained by isolating the molecule from the plant, or another means (e.g., by chemical synthesis).

[0131]

[0121] In embodiments, a combination comprises a plant extract. In embodiments, a combination comprises a bioactive molecule from a plant. In embodiments, a combination comprises a Cannabis extract and / or Dipteryx extract. In embodiments, a combination comprises a Cannabis extract. In embodiments, a combination comprises a Dipteryx extract. In embodiments, a combination comprises a Cannabis extract and a Dipteryx extract. In embodiments, the combination comprises a bioactive molecule from a plant in the genera Cannabis and / or Dipteryx. In embodiments, the combination comprises a molecule from a plant in the genera Cannabis.

[0132] 1. Cannabis

[0133]

[0122] Cannabis is a genus of flowering plant in the family Cannabaceae, including from any of C. sativa, Cannabis indica, and Cannabis ruderalis, or generally from C. sativa L as a single undivided species. Herein, “cannabis” refers to all such encompassed species, subspecies, cultivars, varieties, variants, strains, chemovars, and the like, comprising the genus Cannabis, independent of any such terminology. “Cannabis" herein includes C. sativa, C. indica, and C. ruderalis, and genetic crosses, self-crosses, and hybrids thereof.

[0134]

[0123] In embodiments, the plant portion of a combination is from Cannabis. Where the plant portion is “from” Cannabis, it will be understood that the plant portion comprises matter derived from Cannabis, including, as non-limiting examples, Cannabis material such as raw (i.e., unprocessed) Cannabis biomass, a Cannabis extract (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or a molecule that is naturally occurring in Cannabis (e.g., a primary or secondary bioactive molecule), whether or not said molecule is actually obtained by isolating the molecule from Cannabis, or another means (e.g., by chemical synthesis).

[0135]

[0124] In embodiments, a combination comprises a Cannabis extract. In embodiments, a combination comprises a primary bioactive molecule from Cannabis. In embodiments, a combination comprises a secondary bioactive molecule from Cannabis. a. Primary and Secondary Bioactive Molecules from Cannabis

[0136]

[0125] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from Cannabis. In embodiments, the primary bioactive molecule from Cannabis is a cannabinoid. A “cannabinoid” may refer to any of the classes of small molecules that act on cannabinoid receptors, including cannabinoid receptor 1 (CB and cannabinoid receptor 2 (CB2) receptors. Cannabinoids will be generally known in the art.

[0137]

[0126] Exemplary cannabinoids are described in Radwan et al. Molecules. 2021 May 8;26(9):2774 (“Radwan”), incorporated by reference as if fully set forth herein. Without being limited thereby, cannabinoids according to Radwan include compounds with a C21 terpenophenolic backbone, including from 11 cannabinoid sub-classes, namely: cannabichromene (CBC)-type, cannabidiol (CBD) type, cannabielsoin (CBE) type, cannabigerol (CBG) type, cannabicyclol (CBL) type, cannabinol (CBN) type, cannabinodiol (CBND) type, cannabitriol (CBT) type, (-)-A8-frans- tetrahydrocannabinol (A8-THC) type, (-)-A9-trans-tetrahydrocannabinol (A9-THC) type, and miscellaneous-type cannabinoids. Non-limiting examples of cannabinoids, which will be understood to be useful in the practice of the disclosure, are known by reference to the disclosure of Radwan and the below. In embodiments, the primary bioactive molecule from Cannabis is any such cannabinoid.

[0138]

[0127] In embodiments, the primary bioactive molecule from Cannabis is any of a A9-THC-type cannabinoid, a A8-THC-type cannabinoid, a CBG-type cannabinoid, a CBD-type cannabinoid, a CBND-type cannabinoid, a CBE-type cannabinoid, a CBL-type cannabinoid, a CBN-type cannabinoid, a CBC-type cannabinoid, a CBT-type cannabinoid, or a miscellaneous-type cannabinoid. Exemplary cannabinoids include the following.

[0139]

[0128] A9-THC-type cannabinoids include A9-THC-C5, A9-THCAA-C5, A9-THCAB-C5, A9-THC-C4, A9-THCAA-C4, A9-THCV, A9-THCVAA, A9-THCO, A9-THCOAA, A9-THC-aldehyde, p-fenchyl (-)-A9-frans- tetrahydrocannabinolate, a-fenchyl (-)-A9-frans-tetrahydrocannabinolate, epi-bornyl (-)-A9-frans-tetrahydro- cannabinolate, bornyl (-)-A9-frans-tetrahydrocannabinolate, a-terpenyl (-)-A9-frans- tetrahydrocannabinolate, 4-terpenyl (-)-A9-frans-tetrahydrocannabinolate, a-cadinyl (-)-A9-frans-tetrahydro- cannabinolate, y-eudesmyl (-)-A9-frans-tetrahydrocannabinolate, 8a-hydroxy-(-)-A9-frans-tetrahydro- cannabinol, 80-hydroxy-(-)-A9- frans-tetrahydrocannabinol, 11-acetoxy-(-)-A9-frans-tetrahydro- cannabinolic acid A, 8-oxo-(-)-A9-frans-tetra- hydrocannabinol, cannabisol, (-)-A9-frans-tetrahydrocannabiphorol, and (-)-A9-trans-tetrahydrocannabihexol.

[0140]

[0129] A8-THC-type cannabinoids include A8-THC, A8-THCA, 10a-OH-A8-THC, 10p-OH-A8-THC, and 10a-a-hydroxy-10-oxo-A8-THC. 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-frans-epoxy- cannabigerolic acid, (±)-6,7-c / s- epoxycannabigerolic acid, (±)-6,7-c / s-epoxycannabigerol, (±)-6,7-frans-epxoy- cannabigerol, camagerol, and sesquicannabigerol.

[0141]

[0130] CBD-type cannabinoids include CBD-C5, CBDA-C5, CBDM-C5, CBD-C4, CBDV, CBDVA, CBD-C^ CBDH, CBDP, and CBDD. CBND-type cannabinoids include CBND-C3and CBND-C5. CBE-type cannabinoids include CBE-C5, CBEAA-C5, CBEAB-C5, CBE-C3, and CBEAB-C3. CBL-type cannabinoids include CBL, CBLA, and CBLV. CBC-type cannabinoids include CBC, CBCA, ±CBCV, -+CBCV, CBCVA, 4-acetoxy-CBC, (±)-3”-hydroxy-A4”-cannabichromene, (-)-7-hydroxy-canna- bichromene, and CBC-C3. CBN-type cannabinoids include CBN-C5, CBNA-C5, CBN-C4, CBN-C3, CBN-C2, CBN-C^ CBNM-C5, 8-OH-CBN, 8-OH-CBNA, 1’S-OH-CBN, and 4-terpenyl-cannabinolate. CBT-type cannabinoids include (-)-frans-CBT-C5, (+)-frans-CBT-C5, (±)-c / s-CBT-C5, (±)-frans-CBT-C3, CBT-C3-homologue, (-)-trans-CBT- OEt-C5, (-)-frans-CBT-OEt-C3, 8,9-Di-OH-CBT-C5, CBDA-C5, and 9-OH-CBT-C5ester.

[0142]

[0131] Miscellaneous-type cannabinoids include DCBF-C5, CBF-C5, OH-iso- HHCV-C3OTHC, cannabicitran, c / s-A9-THC, CBCON-C5, CBR, CBTT, CBCN-C5, CBCN-C3, c / s-iso-A7-THCV, frans-iso- A7-THCV, frans-iso-A7-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, 10a-hydroxy-A9 11-hexahydrocannabinol, 90, 100-epoxy- hexahydrocannabinol, 9a-hydroxyhexahydrocannabinol, 7-oxo-9a-hydroxyhexahydrocannabinol, 10a-hydroxy- hexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, and 9a-hydroxy-10-oxo-A6a 10a-THC.

[0143]

[0132] In embodiments, the primary bioactive molecule from Cannabis is any of the foregoing cannabinoids.

[0144]

[0133] In embodiments, a cannabinoid also includes cannabinoid carboxylic acids and their carboxylate salts (see U.S. Pat. No. 9,376,367). In embodiments, a cannabinoid also includes its isomers, such as structural isomers and stereoisomers (including enantiomers), the -A and -B isomers for each cannabinoid, double bond isomers, and other such isomers known to those of skill. Thus, “THC” will, in embodiments, include THC-A and THC-B. In embodiments, reference to a cannabinoid also includes the various alkyl chain lengths associated therewith, as illustrated by Cn, wherein “n” refers to the number of carbon atoms in each alkyl chain. Thus, in embodiments, “THC” also includes THC-C1 , THC-C2, THC-C3, THC-C4, THC-C5, THC-C6, and THC-C7. Reference to a given cannabinoid also will include all possible isomers, such as but not limited to, its -A and -B isomers, together with all possible combinations of alkyl chain lengths, including chains comprised of 1 , 2, 3, 4, 5, 6, or 7 carbon atoms. So, herein, reference to “THC” will include THC-C1 A, THC-C1 B, THC-C2 A, THC-C2 B, THC-C3 A, THC-C3 B, THC-C4 A, THC-C4 B, THC-C5 A, THC-C5 B, THC-C6 A, THC-C6 B, THC-C7 A, and THC-C7 B. As will be apparent to one of skill, such logic applies to all cannabinoids disclosed herein; THC is merely used to illustrate such logic, and should not be construed as limiting.

[0145]

[0134] In embodiments, a cannabinoid may further comprise an additional chemical moiety substituted thereon, including methyl, alkyl, alkenyl, methoxy, alkoxy, acetyl, carboxyl, carbonyl, oxo, ester, hydroxyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, heterocyclyl- alkenyl, heteroarylalkenyl, arylalkenyl, heterocyclyl, aralkyl, cycloalkylalkyl, heterocyclylalkyl, heteroarylalkyl, and the like. In embodiments, a cannabinoid includes a “synthetic cannabinoid.”

[0146]

[0135] In embodiments, the plant portion comprises two bioactive molecules from a plant, which may be any two bioactive molecules, including from Cannabis, from Dipteryx, and / or from other plants, including from different plant species and from different plant genera. In embodiments, the plant portion comprises THC and CBD. In embodiments, the plant portion comprises a plant extract comprising THC and CBD. In embodiments, the plant portion comprises, as primary bioactive molecules from a plant, THC and CBD. A plant portion may comprise another number of bioactive molecules, such as 3, 4, 5, or more than 5. In embodiments, the plant portion comprises two bioactive molecules from a plant in a defined weight ratio or molar ratio. THC and CBD are used in exemplary embodiments, but any two bioactive molecules from a plant may be provided, including primary and / or secondary bioactive molecules described herein.

[0147]

[0136] In embodiments, the plant portion comprises both THC and CBD. In embodiments, the plant portion comprises a plant extract comprising both THC and CBD. In embodiments, the plant portion comprises, as primary bioactive molecules from a plant (e.g., Cannabis), both THC and CBD. In embodiments, the plant portion comprises both THC and CBD in a weight ratio of between about 100:1 and 1 :100, 50:1 and 1 :50, 10:1 and 1 :10, 5:1 and 1 :5, 2:1 and 1 :2, 5:3 and 3:5, or 3:2 and 2:3, all ranges inclusive. In embodiments, the plant portion comprises both THC and CBD in a molar ratio of between about 100:1 and 1 :100, 50:1 and 1 :50, 10:1 and 1 :10, 5:1 and 1 :5, 2:1 and 1 :2, 5:3 and 3:5, or 3:2 and 2:3, all ranges inclusive. In embodiments, the plant portion comprises both THC and CBD in a weight ratio of about 100:1 , 50:1 , 10:1 , 5:1 , 2:1 , 5:3, 3:2, or 1 :1. In embodiments, the plant portion comprises both THC and CBD in a molar ratio of about 100:1, 50:1 , 10:1 , 5:1, 2:1 , 5:3, 3:2, or 1 :1. In embodiments, the plant portion comprises THC and CBD in a weight ratio of about 1 :100, 1 :50, 1 :10, 1 :5, 1 :2, 3:5, 2:3, or 1 :1. In embodiments, the plant portion comprises both THC and CBD in a 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 portion comprises both THC and CBD in a weight ratio of from about 1 :5 to 5:1 , including about 1 :5, 1 :4, 1 :3, 1 :2, 1 :1 , 2:1 , 3:1 , 4:1 , and 5:1. In embodiments, the plant portion comprises both THC and CBD in a molar ratio of from about 1 :5 to 5:1 , including about 1 :5, 1 :4, 1 :3, 1 :2, 1 :1 , 2:1 , 3:1 , 4:1 , and 5:1. In embodiments, the plant portion comprises both THC and CBD in a weight ratio of about 1 :1. In embodiments, the plant portion comprises both THC and CBD in a molar ratio of about 1 :1. In embodiments, the plant portion comprises a plant extract (e.g., a Cannabis extract) comprising both THC and CBD, including in any of the above weight ratios. In embodiments, the Cannabis extract comprises both THC and CBD in any of the above molar ratios. In embodiments, the Cannabis extract comprises both THC and CBD in any of the above molar ratios.

[0148]

[0137] In embodiments, a combination comprises a secondary bioactive molecule from Cannabis. In embodiments, the secondary bioactive molecule from Cannabis is a flavone and / or flavonoid, a terpene and / or terpenoid, a carbohydrate, a fatty acid or a fatty acid ester (FAE), an amide, an amine, a phytosterol, or a phenolic compound. Flavonoids are a broad class of water-soluble polyphenolic molecules (i.e., comprising a phenyl group (-C6H5) bonded to a hydroxy group (-OH)), of which about 20 are widely found in Cannabis. A primary function of flavonoids is to provide color pigmentation to plants, particularly flowers. In Cannabis, deep purple strains owe their coloration to the flavonoids, anthocyanins and anthoxanthins. Besides providing color, flavonoids also have been shown to provide health benefits through modulation of cell signaling pathways and through various anti-inflammatory, antioxidant, anti-fungal, anti-cancer, and other effects. For example, the Cannabis flavonoid, apigenin, has potent anti-anxiety, anti-inflammatory, and anti-cancer properties; butin has been shown to reduce oxidative stress-related cell dysfunction. Other bioactive flavonoids found in Cannabis include cannaflavins, kaempferol, orientin, luteolin, quercetin, silymarin, and vitexin.

[0149]

[0138] 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. In embodiments, the flavonoid is any of orientin, orientin-O-glucoside, orientin-7-O-glucoside, orientin-7-O-rhamnoglucoside, vitexin, vitexin-O-glucoside, vitexin-7-O-glucoside, vitexin-7-O-rhamnoglucoside, cytisoside, cytisoside-glucoside, isovitexin, isovitexin-O- glucoside, isovitexin-7-O-glucoarbinoside, isovitexin-7-O-rhamnoglucoside, apigenin-7-O-glucoside, apigenin-7-O-glucuronoid, apigenin-7-O'P-coumaroyl-glucoside, 6-prenylapigenin, apigenin-6,8-di-gluco- pyranoside, luteolin-C-glucuronide, luteolin-7-O- glucuronide, canniflavin A, canniflavin B, canniflavin C, chrysoeriol, kaempferol-3-O-diglucoside, quercetin-3-O-glucoside, quercetin-3-O- diglucoside, kaempferol-3 -O-sophoroside, quercetin-3-O-sophoroside, rutin, quercetin, naringenin, and naringin.

[0150]

[0139] “Terpenes" refers to any of the class of organic hydrocarbon compounds containing one or more repeating units of a five-carbon building block known as an isoprene unit (i.e., 2-methyl-1 ,3-butadiene, having the molecular formula C5H8). Isoprene units may form linear chains, or be arranged in a ring structure (thus having the molecular formula (C5H8)n, where n is the number of linked isoprene units). Terpenes may be classified according to the number of isoprene units from which they are constituted: hemiterpenes (one unit), monoterpenes (two), sesquiterpenes (three), diterpenes (four), sesterterpenes (five), triterpenes (six), sesquarterpenes (seven), tetraterpenes (eight), and polyterpenes (nine or more). As isoprene polymers, terpenes may be referred to as “isoprenoids.” Terpenes also may be referred to as “terpenoids” after oxidation.

[0151]

[0140] In embodiments, the secondary bioactive molecule from Cannabis is any of a hemiterpene, a monoterpene, a sesquiterpene, a diterpene, a sesterterpene, a triterpene, a sesquiterpene, a tetraterpene, a polyterpene, a carbohydrate, a fatty acid or FAE, an amide, an amine, a phytosterol, and a phenolic compound.

[0152]

[0141] Monoterpenes include myrcene, cis-p-ocimene, trans-p-ocimene, p-cymene, a-terpinene, P-phellandrene, y-terpinene, a-terpinolene, a-phellandrene, 3-phenyl-2-methyl-prop-1 -ene, a-pinene, p-pinene, camphene, A3-carene, A4-carene, sabinene, a-thujene, linalool, citral B, nerol, geraniol, ipsienol, citronellol, 2-methyl-2-heptene-6-on, geranyl acetone, m-mentha- 1 ,8-(9)-dien-5-ol, carvacrol, carvone, a-terpineol, terpinene-4-ol, pulegone, dihydrocarvone, p-terpineol, dihydrocarveyl acetate, p-cymene-8-ol, p-cyclocitral, safranal, cis-linalool oxide, perillene, sabinol, thujyl alcohol, linalool oxide, cis-carveol, cis-sabinene hydrate, sabinene hydrate, 8-cineol, 1 ,4-cineol, piperitone oxide, piperitenone oxide, fenchyl alcohol, fenchone, borneol, bornyl acetate, camphor, camphene hydrate, a-pinene oxide, pinocarveol, and pinocarvone.

[0153]

[0142] Sesquiterpenes include a-caryophyllene, p-caryophyllene, caryophyllene oxide, curcumene, a-trans-bergamotene, a-selinene, p-farnesene, longifolene, humulene epoxide I, humulene epoxide II, caryophyllene alcohol (caryophyllenol), p-bisabolene, allo-aromadendrene, calamenene, a-copaene, nerolidol, a-gurjunene, iso-caryophyllene, p-selinene, selina-3,7(11)-diene, selina-4(14),7(11)-diene, a-bisabolol, a-cedrene, a-cubebene, 5-cadinene, epi-p-santalene, farnesol, y-cadinene, y-elemene, y-eudesmol, guaiol, ledol, trans-trans-a-farnesene, (Z)-p-farnesene, farnesyl acetone, a-cadinene, a-cis-bergamotene, a-eudesmol, a-guaiene, a-longipinene, a-ylangene, p-elemene, p-eudesmol, epi-a-bisabolol, y-cis-bisabolene, Y-curcumene, y-muurolene, Y-trans-bisabolene, viridiflorene, germacrene-B, and clovandiol.

[0154]

[0143] Diterpenes include phytol and neophytadiene. Triterpenes include friedeline and epifriedelanol. Miscellaneous terpenes include vomifoliol, dihydrovomifoliol, p-ionone, and dihydroactinidiolide.

[0155]

[0144] Phenolic compounds, in addition to those described as terpenes or flavonoids, include lignans, spiroindans, dihydrostilbenes, dihydrophenanthrene derivatives, stilbenoids, cannabispirans, denbinobin, catechin, chlorogenic acid, caffeic acid, epicatechin, luteolin-7-O-glucoside, p-coumaric acid, caffeoyl, tyramine, ferulic acid, quercetin-3-glucoside, kaempferols, apigenin-7-glucoside, luteolin, cannabisins, and apigenin.

[0156]

[0145] In embodiments, the secondary bioactive molecule from Cannabis may be any of a flavonoid, including orientin, orientin-O-glucoside, orientin-7-O-glucoside, orientin-7-O-rhamnoglucoside, vitexin, vitexin-O- glucoside, vitexin-7-O-glucoside, vitexin-7-O-rhamnoglucoside, cytisoside, cytisoside-glucoside, isovitexin, isovitexin-O-glucoside, isovitexin-7-O-glucoarbinoside, isovitexin-7-O-rhamnoglucoside, apigenin-7-O- glucoside, apigenin-7-O-glucuronoid, apigenin-7-O'P-coumaroylglucoside, 6-prenylapigenin, apigenin-6,8-di- gluco-pyranoside, luteolin-C-glucuronide, luteolin-7-O- glucuronide, canniflavin A, canniflavin B, canniflavin C, chrysoeriol, kaempferol-3-O-diglucoside, quercetin-3-O-glucoside, quercetin-3-O- diglucoside, kaempferol-3-O- sophoroside, quercetin-3-O-sophoroside, rutin, quercetin, naringenin, and naringin; a terpene, including myrcene, cis-p-ocimene, trans-p-ocimene, p-cymene, a-terpinene, p-phellandrene, Y-terpinene, a-terpinolene, a-phellandrene, 3-phenyl-2-methyl-prop-1-ene, a-pinene, p-pinene, camphene, A3-carene, A4-carene, sabinene, a-thujene, linalool, citral B, nerol, geraniol, ipsienol, citronellol, 2-methyl-2-heptene-6-on, geranyl acetone, m-mentha-1 ,8-(9)-dien-5-ol, carvacrol, carvone, a-terpineol, terpinene-4-ol, pulegone, dihydrocarvone, p-terpineol, dihydrocarveyl acetate, p-cymene-8-ol, p-cyclocitral, safranal, cis-linalool oxide, perillene, sabinol, thujyl alcohol, linalool oxide, cis-carveol, cis-sabinene hydrate, sabinene hydrate, 8-cineol, 1 ,4-cineol, piperitone oxide, piperitenone oxide, fenchyl alcohol, fenchone, borneol, bornyl acetate, camphor, camphene hydrate, a-pinene oxide, pinocarveol, pinocarvone, a-caryophyllene, p-caryophyllene, caryophyllene oxide, curcumene, a-trans-bergamotene, a-selinene, p-farnesene, longifolene, humulene epoxide I, humulene epoxide II, caryophyllene alcohol (caryophyllenol), p-bisabolene, allo-aromadendrene, calamenene, a-copaene, nerolidol, a-gurjunene, iso-caryophyllene, p-selinene, selina-3,7(11)-diene, selina-4(14),7(11)- diene, a-bisabolol, a-cedrene, a-cubebene, 5-cadinene, epi-p-santalene, farnesol, Y-cadinene, y-elemene, Y-eudesmol, guaiol, ledol, trans-trans-a-farnesene, (Z)-p-farnesene, farnesyl acetone, a-cadinene, a-cis- bergamotene, a-eudesmol, a-guaiene, a-longipinene, a-ylangene, p-elemene, p-eudesmol, epi-a-bisabolol, Y-cis-bisabolene, Y-curcumene, Y-muurolene, Y-trans-bisabolene, viridiflorene, germacrene-B, clovandiol, phytol, neophytadiene, friedeline, epifriedelanol, vomifoliol, dihydrovomifoliol, p-ionone, and dihydroactinidiolide; a carbohydrate; a fatty acid or its ester; an amide; an amine; a phytosterol; and a phenolic compound, including a lignan, a spiro-indan, a dihydrostilbene, a dihydrophenanthrene derivative, a stilbenoid, a cannabispiran, denbinobin, catechin, chlorogenic acid, caffeic acid, epicatechin, luteolin-7-O-glucoside, p-coumaric acid, caffeoyl, tyramine, ferulic acid, quercetin-3-glucoside, a kaempferol, apigenin-7-glucoside, luteolin, a cannabisin, and apigenin.

[0157]

[0146] In embodiments, bioactive molecules from Cannabis additionally include those outlined in Russo. Br J Pharmacol. 2011 ;163(7): 1344-1364; Gertsch et al. Br J Pharmacol. 2010;160(3):523-529; Tahir et al. J Cannabis Res. 2021 Mar 15;3(1):7; Thomas & ElSohly. Biosynthesis and pharmacology of phytocannabinoids and related chemical constituents. The Analytical Chemistry of Cannabis; Elsevier: Amsterdam, The Netherlands, 27-41; De Backer et al. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(32): 4115-4124; and Hazekamp et al. J Liq Chromatogr Relat Technol. 2004;27(15): 2421-2439).

[0158] 2. Dipteryx

[0159]

[0147] In embodiments, the plant portion of a combination is from Dipteryx. Where a plant portion is described as being “from” Dipteryx, it will be understood that the plant portion comprises matter derived from Dipteryx, including Dipteryx material such as raw (i.e., unprocessed) Dipteryx biomass, a Dipteryx extract (e.g., aqueous and / or ethanolic extracts as described herein), or a molecule that is naturally occurring in Dipteryx (e.g., a primary or secondary bioactive molecule), including isolated from Dipteryx, and obtained by other means (e.g., chemical synthesis). In embodiments, a combination comprises a Dipteryx extract. In embodiments, the combination comprises a primary and / or a secondary bioactive molecule from a species in the genus Dipteryx.

[0160]

[0148] In embodiments, the primary and / or secondary bioactive molecules are from Dipteryx, including from D. odorata, also referred to as the “Cumaru tree” or “Cumaru.” Dipteryx is a genus of trees in the family Fabaceae (previously Coumarouna). In embodiments, the primary bioactive molecule and / or secondary bioactive molecule are from Dipteryx. In other embodiments, the primary bioactive molecule and / or secondary bioactive molecule are from another genus from the tribe Dipterygeae, including the genera Monopteryx, Pterodon, and Taralea. In embodiments, a bioactive molecule, such as a coumarin, is from a plant of the genus Dipteryx, such as D. odorata, i.e., Cumaru. In embodiments, the combinations comprise primary and / or secondary bioactive molecules from the species D. odorata. D. odorata is known by many names, including Coumarouna odorata, Cumaru tree (Brazil), Tonka bean tree, Brazilian teak, Tonquin bean, rumara, Kumaru (Guyana), cumaruzeiro (Portuguese), charapilla (Peru), charapilla del murcielago (Peru), shihuahuaco (Peru), and sarapia (Venezuela, Columbia), all of which may be used interchangeably or viewed equivalently according to the disclosure herein. In other embodiments, a bioactive molecule, such as a coumarin, is from a plant of another genus, including any genera in the tribe Amburaneae, such as Amburana, Cordyla, Dupuya, Dussia, Mildbraediodendron, Myrocarpus, Myrospermum, Myroxylon, and Petaladenium. In embodiments, species from such other genera, and extracts and bioactive molecules therefrom, will be considered as equivalents of like extracts and bioactive molecules from Dipteryx.

[0161]

[0149] In embodiments, a disclosed combination (e.g., a “therapeutic combination,” the terms also including by implication a disclosed composition) comprising a bioactive molecule from Dipteryx, such as a coumarin, can exhibit antispasmodic, emmenagogue, cardiotonic, antiasthmatic, and anti-inflammatory effects. a. Primary and Secondary Bioactive Molecules from Dipteryx

[0162]

[0150] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from Dipteryx. In embodiments, the primary bioactive molecule from Dipteryx is coumarin (2H-chromen-2-one; 2H-1-benzopyran-2-one). In embodiments, a bioactive molecule is a compound derived from coumarin (e.g., a phenylpropanoid, a coumarin, or a coumarinoid) and which may be used in disclosed combinations, compositions, and methods; such compounds include, e.g., the bioactive molecules umbelliferone, aesculetin, herniarin, psoralen, dicoumarol, imperatorin, brodifacoum, bromadiolone, difenacoum, auraptene, ensaculin, phenprocoumon, PSB-SB-487, PSB-SB-1202, scopoletin, and warfarin (see, e.g., Laposata et al. N Engl J Med. 2007;356(2):174-182; Syah et al. Nat Prod Res. 2009;23(7):591-594).

[0163]

[0151] In embodiments, the secondary bioactive molecule from Dipteryx is any of coumarin, a coumarin, a courmarinoid, a coumarin derivative, an isoflavone, a lupeol derivative, a fatty acid ester, (±)-balanophonin, (— )-lariciresinol, 3'-hydroxyretusin-8-methyl-ether, 5-methoxyxanthocercin A, 6,4'-dihydroxy-3'-methoxyaurone, 7-hydroxy- chromone, 7,3'-dihydroxy-8,4'-dimethoxy-isoflavone, betulin, butin, coumaric-acid-beta-glucoside, dipteryxin, dipteryxic acid, eriodictyol, ferulic-acid, isoliquiritigenin, lupeol, melilotoside, melilotoside-1-p- coumaryl-beta-d-glucose, methyl-linolenate, methyl-oleate, O-coumaricacid, 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.

[0164]

[0152] In embodiments, bioactive molecules from Dipteryx additionally include those in Trincone, A. (Ed.). (2019). Enzymatic Technologies for Marine Polysaccharides (1st ed.). CRC Press; Jofre et al. Mar Drugs. 2020; 18(2):75; or Gomez-Zavaglia et al. Antioxidants (Basel). 2019;8(9):406.

[0165]

[0153] In embodiments, coumarin, a coumarin, a courmarinoid, or a coumarin derivative is extracted, isolated, or otherwise obtained from Dipteryx or D. odorata. In other embodiments, it is obtained from any other disclosed species, rather than from, or in addition to being from, Dipteryx or D. odorata. Coumarin may be obtained from plant species including vanilla grass (A. odoratum), sweet woodruff (G. odoratum), sweet grass (H. odorata), sweet-clover (genus Melilotus), cinnamon, including ceylon cinnamon or “true cinnamon” (C. verum), Chinese cinnamon or Chinese cassia (C. cassia), Indonesian cinnamon or Padang cassia (C. burmannii), Saigon cinnamon or Vietnamese cassia (C. loureiroi), deertongue (C. odoratissimus), Tilo (J. pectoralis), Mullein (genus Verbascum), many cherry blossom tree varieties of the genus Prunus, and in trace amounts in strawberries, black currants, apricots, and cherries.

[0166] 3. Algae

[0167]

[0154] In embodiments, a combination comprises an algal portion, i.e., a portion from algae. Algae broadly refers to a large, polyphyletic group of photosynthetic eukaryotic organisms. “Algae” herein includes species, from within any of a number of clades, that have chlorophyll as their primary photosynthetic pigment and lack a sterile covering of cells around their reproductive cells (Lee. Phycology. Cambridge University Press. 2008).

[0168]

[0155] Algae herein includes varieties capable of living in freshwater, and / or salt water, such as 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) (Baweja & Sahoo. (2015). Classification of algae. The algae world, 31-55).

[0169]

[0156] In embodiments, the algal portion comprises an algal extract. In embodiments, the algal portion comprises a bioactive molecule from an algae. In embodiments, the algal extract comprises a bioactive molecule from an algae. In embodiments, the algal portion comprises a primary bioactive molecule and / or a secondary bioactive molecule from an algae. In embodiments, the algal extract comprises a primary bioactive molecule and / or a secondary bioactive molecule from an algae. In embodiments, a combination comprises a primary bioactive molecule and / or a secondary bioactive molecule from an algae.

[0170]

[0157] In embodiments wherein the algae portion is described as being “from” an algae, it will be understood that the algae portion comprises matter derived from the algae, including, as non-limiting examples, algae material such as raw (i.e., unprocessed) algae biomass, an algae extract (e.g., extracts described herein, such as aqueous and / or ethanolic extracts), or a molecule that is naturally occurring in the algae (e.g., a primary or secondary bioactive molecule described in embodiments herein), whether or not said molecule is actually obtained by isolating the molecule from the algae, or another means (e.g., by chemical synthesis).

[0171]

[0158] In embodiments, a disclosed combination comprises a marine algae. In embodiments, the marine algae is any of a brown algae (Phaeophyta), a green algae (Chlorophyta), and a red algae (Rhodophyta). In embodiments, the marine algae is a marine red algae. In embodiments, the marine red algae is from the family Bangiacea. In embodiments, the marine red algae is from the genus Pyropia or Porphyra.

[0172]

[0159] In embodiments, the red algae is Porphyra umbilicalis. In embodiments, the red algae is Pyropia perforata. In embodiments, the red algae is Pyropia yezoensis (previously known as Porphyra yezoensis). Other species of Pyropia and Porphyra will be known, e.g., Pyropia tenera (previously Porphyra tenera). a. Primary and Secondary Bioactive Molecules from Algae

[0173]

[0160] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from algae.

[0174]

[0161] In embodiments, the primary bioactive molecule from an algae is a primary bioactive molecule from a genus in the family Bangiaceae. In embodiments, the primary bioactive molecule from an algae is a primary bioactive molecule from a species in the genus Pyropia or Porphyra. In embodiments, the primary bioactive molecule from an algae is a primary bioactive molecule from P. umbilicalis. In embodiments, the primary bioactive molecule from an algae is a primary bioactive molecule from P. perforata. In embodiments, the primary bioactive molecule from an algae is a primary bioactive molecule from P. yezoensis.

[0175]

[0162] In embodiments, the primary bioactive molecule from Pyropia or Porphyra is any of a porphyran or oligo-porphyran, a polysaccharide, a peptide (e.g., monopeptides, dipeptides, tripeptides, proteins); a phycobiliprotein (e.g., phycoerythrin, phycoerythrobilin, phycocyanin, allophycocyanin); a mycosporine amino acid (e.g., porphyra-334, shinorine); an essential amino acid (e.g., isoleucine, leucine, threonine, methionine, phenylalanine, lysine, histidine, valine, arginine, cysteine); a nonessential amino acid (e.g., aspartic acid, glutamic acid, glycine, tyrosine, serine, alanine, proline); a carotene (e.g., lutein, zeoxanthin, a-carotene, P-carotene, astaxanthin); an intermediate carotenoid (e.g., a-cryptoxanthin, zeinoxanthin, p-cryptoxanthin); a glycoprotein; and an amino sulfonic acid (e.g., taurine).

[0176]

[0163] In embodiments, the primary bioactive molecule from Pyropia or Porphyra is porphyran or oligo-porphyran. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a polysaccharide. In embodiments, the polysaccharide is any of glucose, fructose, galactose, and mannose. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a peptide. In embodiments, the peptide is any of a monopeptide, a dipeptide, a tripeptide, and a protein. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a phycobiliprotein. In embodiments, the phycobiliprotein is any of phycoerythrin, phycoerythrobilin, phycocyanin, and allophycocyanin. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a mycosporine amino acid. In embodiments, the mycosporine amino acid is any of porphyra-334 and shinorine. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is an essential amino acid. In embodiments, the essential amino acid is any of isoleucine, leucine, threonine, methionine, phenylalanine, lysine, histidine, valine, arginine, and cysteine. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a nonessential amino acid. In embodiments, the nonessential amino acid is any of aspartic acid, glutamic acid, glycine, tyrosine, serine, alanine, and proline. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a carotene. In embodiments, the carotene is any of lutein, zeoxanthin, a-carotene, p-carotene, and astaxanthin. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is an intermediate carotenoid. In embodiments, the intermediate carotenoid is any of a-cryptoxanthin, zeinoxanthin, and P-cryptoxanthin. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is a glycoprotein. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is an amino sulfonic acid. In embodiments, the amino sulfonic acid is taurine.

[0177]

[0164] In embodiments, a combination comprises a bioactive molecule from an algae, wherein the bioactive molecule, in embodiments, is a secondary bioactive molecule from an algae. In embodiments, the secondary bioactive molecule from an algae is a secondary bioactive molecule from a genus in the family Bangiaceae. In embodiments, the secondary bioactive molecule from an algae is a secondary bioactive molecule from a species in the genus Pyropia or Porphyra. In embodiments, the secondary bioactive molecule from an algae is a secondary bioactive molecule from P. umbilicalis. In embodiments, the secondary bioactive molecule from an algae is a secondary bioactive molecule from P. yezoensis.

[0178]

[0165] In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is a mineral, a vitamin, a lipid, a phenolic compound, or a phlorotannin. In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is a mineral, such as any of potassium, phosphorus, magnesium, sodium, calcium, manganese, iron, copper, and zinc. In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is a vitamin, such as any of vitamin K, ascorbic acid, folate, and cobalamin. In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is a lipid, such as a fatty acid, including eicosapentaenoic acid or palmitic acid. In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is a phenolic compound, such as a flavonoid, a phenolic acid, a polyphenolic amide, or another phenolic compound as will be known by one in the art. In embodiments, the secondary bioactive molecule from Pyropia or Porphyra is a phlorotannin, such as any of a fucol, a phloroethol, a fucophloroethol, an eckol, a fuhalol, and a carmalol.

[0179]

[0166] In embodiments, the algal portion comprises two bioactive molecules from algae, which may be any two bioactive molecules. In embodiments, the algal portion comprises an algal extract comprising two bioactive molecules. An algal portion may comprise another number of bioactive molecules, such as 3, 4, 5, or more than 5. In embodiments, the algal portion comprises two bioactive molecules from algae in a defined weight ratio or molar ratio, including from one or more algal species, from different algal species, and from different algal genera. Any two bioactive molecules from algae may be provided, including primary and / or secondary bioactive molecules described herein. In embodiments, the algal portion comprises two bioactive molecules in a weight ratio or a molar ratio of between about 100:1 and 1 :100, 50:1 and 1 :50, 10:1 and 1 :10, 5:1 and 1 :5, 2:1 and 1 :2, 5:3 and 3:5, or 3:2 and 2:3, all ranges inclusive. In embodiments, the algal portion comprises two bioactive molecules in a weight ratio or a molar ratio of about 100:1, 50:1 , 10:1 , 5:1 , 2:1 , 5:3, 3:2, or 1 :1. In embodiments, the algal portion comprises two bioactive molecules in a weight ratio or a molar ratio of about 1 :100, 1 :50, 1 :10, 1 :5, 1 :2, 3:5, 2:3, or 1 :1. In embodiments, the algal portion comprises two bioactive molecules in a weight ratio or a molar ratio of about 5:3, 3:2, 1 :1 , 2:3, or 3:5.

[0180] / / / . Obtaining Bioactive Molecules

[0181]

[0167] In embodiments, a bioactive molecule of a combination is commercially available, and can be commercially sourced (e.g., Cayman Chemical Co., Ann Arbor, Ml; Sigma-Aldrich, Burlington, MA).

[0182]

[0168] In embodiments, the disclosed primary and secondary bioactive molecules may be obtained via any of, as non-limiting examples: extraction, synthesis, biosynthesis methods, as a whole plant, as Cannabis flower, Cannabis biomass, a fruiting fungal body, fungal mycelium mass, bioreactor-produced fungal biomass, a truffle (a fungal sclerotia), a cumaru seed (tonka bean), or whole Porphyra or Pyropia algae, isolated, and / or gathered as fractions. Exemplary means of obtaining bioactive molecules are disclosed.

[0183] A. Extraction

[0184]

[0169] In embodiments, an extract (e.g., a fungal extract, a plant extract, or an algal extract) is obtained via extraction, such as an extraction technique disclosed herein or known to those of skill. Herein, “extract” may refer to a botanical extract (e.g., a fungal, Psilocybe, plant, Cannabis, Dipteryx, algal, or other extract) prepared, for example, from a botanical source (as “botanical” is defined herein). In embodiments, a primary and / or secondary bioactive molecule is provided in an extract obtained via extraction.

[0185]

[0170] Broadly, but without being bound by theory, an extraction system works by introducing a material, such as a fungal, plant material, and / or algal material containing primary and / or secondary bioactive molecule(s), to a solvent capable of separating the desired primary and / or secondary bioactive molecule(s) from the material to form a solution containing the solvent and the bioactive molecules (i.e., an extract). Various extraction systems exist, using different methods, and with different parameters (e.g., temperature, pressure, solvent) which may be tailored to extract a desired end product, for example, desired primary and / or secondary bioactive molecule(s). Such parameters will be known to those in the art. For example, and without being bound by theory, extraction systems generally follow the rule “like dissolves like.” Thus, when extracting a polar molecule, a polar solvent may be used; when extracting a nonpolar molecule, a nonpolar solvent may be used (Lowery & Richardson. Mechanism and Theory in Organic Chemistry. 3rd ed. Harper Collins Publishers; 1987).

[0186]

[0171] Methods of extracting primary and / or secondary bioactive molecules, of creating plant, algal, and fungal extracts thereof, and of generally obtaining purified products containing desired compounds free from undesired plant, algal, or fungal matter, chemicals, and other impurities will be known in view hereof and of the art, see e.g., U.S. Pat. Nos. 6,403,126, 8,846,409, 8,895,078, 10,059,684, 10,239,808, 10,246,431 , 10,300,494, 10,307,447, 10,406,453, 10,413,845, and 10,414,709; and U.S. App. Nos. 2003 / 0017216A1 and 2016 / 0038437A1 , and references cited, all of which are incorporated by reference as if fully set forth herein.

[0187]

[0172] Exemplary extraction methods and systems disclosed in such references and described herein should not be construed as being limiting, and many variations will be appreciated by those of skill. While exemplary extraction methods, including those described herein, are disclosed as a series of steps, other extraction methods useful in the practice of the disclosure and in obtaining bioactive molecules therefore may deviate from such steps, including by the modification to, removal of, addition of, or rearrangement of any such steps, as will be appreciated by those of skill, in view of the disclosure and general knowledge in the art.

[0188]

[0173] An extract may be used directly in a disclosed combination, composition, or method, or may be first further processed, such as by further extraction, filtration, distillation, fractionation, subfractionation, isolation, and / or purification, and other such methods known in the art, and including combinations thereof. In embodiments, an extract undergoes further processing to obtain a specific bioactive molecule(s) separate from other constituents, wherein such bioactive molecule(s) are found in the filtrate, fraction, subtraction, partially purified product, substantially purified product, completely purified product, isolate, or the like, and in some cases may be obtained separated from all other components as a single component or as single components.

[0189]

[0174] In embodiments, an extract does not undergo further processing to obtain a specific bioactive molecule(s) separate from other constituents, and is obtained as a whole plant, whole fungal, or whole algal extract, which may be referred to herein as a “whole extract.” In alternative embodiments of any exemplary disclosed embodiment herein, a whole extract is substituted with a fraction, subtraction, partially purified product, substantially purified product, completely purified product, isolate, or the like, as well as by a single bioactive molecule or one or more molecule(s) from an extract (including in an extract), or by molecule(s) produced synthetically, such as by partial or complete chemical synthesis, or by biosynthesis.

[0190]

[0175] Extracts include purified extracts. “Purified extract” may refer to a botanical extract that has undergone further processing after preparation, as understood in the art. In exemplary embodiments, purified extracts are the product of, e.g., soaking or heating the preparation in water and / or alcohol (e.g., depending on whether and to what degree the bioactive molecules sought are water soluble), agitating, cooling the resulting liquid, straining, filtering, and removing unwanted products (repeating if necessary), and evaporating sufficient liquid solvent to obtain a desired concentration (or entirely, e.g., to obtain an amorphous or crystalline precipitate), or using a spray dryer to create a purified dried powder. Other purification techniques will be known to one of skill, and in general, extraction and purification techniques for obtaining high purity bioactive compounds are known.

[0191]

[0176] A starch or other carrier can be added to a purified extract to maintain the purified dried powder as a free-flowing powder that is easy to work with during formulation, for instance if the dried powder will be added to capsules; however, when referring to the weight of a “purified extract,” any such carrier, diluent, or excipient is excluded from the total amount. In embodiments, extracts may be “standardized,” which refers to extracts that include a primary and / or secondary bioactive molecule in a specific concentration. Methods to produce standardized extracts, such as by quantifying the concentration of an extract, and then adding a carrier, diluent, or excipient to dilute the extract to a standardized concentration, or further concentrating an extract to increase its concentration, are known in the art. “Natural” may refer to a substance isolated or extracted from a natural source such as a fungi, plant, or algae. For example, a natural cannabinoid may be derived from a Cannabis plant. Thus, in embodiments, the compositions are obtained from botanical sources including fungi, plants, and algae, as extracts or by other means, and comprise a botanical and / or Cannab / s-derived drug product. In some embodiments, such compositions are substantially free of impurities.

[0192]

[0177] In embodiments, a disclosed combination or composition comprises multiple extracts (e.g., fungal extracts, plant extracts, algal extracts), and the concentration of bioactive molecules contained therein is quantified (e.g., according to disclosed or known methods). The concentrations of bioactive molecules in the extracts may vary, based on the concentration of bioactive molecules in the corresponding source material (e.g., raw fungal, plant, or algal biomass). In embodiments, the concentrations of bioactive molecules may vary from batch to batch, based on the variability of extraction. In conforming with FDA rules (FDA. Bot. Drug Dev. Guid. Indus. 2016. ODER Pharm. Qual. CMC), bioactive molecules (e.g., a primary and / or secondary bioactive molecule as disclosed herein) may be added to an extract disclosed herein (e.g., a fungal, plant, or algal extract); or to a disclosed composition comprising said extracts. This may be conducted for example to standardize a composition and ensure a fixed concentration of bioactive molecule(s) between batches, even when the source materials or extracts thereof vary in their concentrations of bioactive molecules.

[0193]

[0178] One exemplary extraction method applicable to the fungi, plants, and algae of the disclosure is ethanol extraction. In embodiments, the ethanol extraction is an ethanol percolation extraction, which may use anhydrous ethanol. In embodiments, the ethanol percolation extraction proceeds by first crushing, pulverizing, grinding, or macerating the fungal, plant, and / or algal material so that the ethanol solvent is capable of entering and exiting the material. In embodiments, the material is sufficiently reduced in size to increase the surface area for extraction, forming a collection of matter of reduced particle size. The matter is placed in a filter sitting atop a collection device. Ethanol is then poured over the matter, which then passes through the filter, and is collected in the collection device. In embodiments, this is completed until the color of the ethanol indicates substantially no additional bioactive molecules are being collected. Optionally, the excess ethanol is then evaporated. This may be completed by applying heat to the resultant solution, or utilizing ambient evaporation.

[0194]

[0179] One exemplary extraction method applicable to the fungi, plants, and algae of the disclosure is Soxhlet extraction. In embodiments, Soxhlet extraction, i.e., extraction with a Soxhlet extractor, is used to extract one or more primary and / or secondary bioactive molecules from fungi, plants, and / or algae. In embodiments, Soxhlet extraction is performed using an ethanol and water solvent (e.g., 80% ethanol and 20% water). In embodiments, the solvent is heated to reflux, and the solvent vapor travels up a distillation arm and floods into the chamber housing a thimble of the fungal, plant, and / or algal material. Broadly and in general, a condenser at the top of the Soxhlet device ensures that the solvent vapor cools, and drips back down into the chamber holding the fungal, plant, and / or algal material. As a result, the Soxhlet chamber containing the fungal, plant, and / or algal material slowly fills with warm solvent. When the chamber is almost full, the chamber is emptied by a siphon, and the solvent is returned to a distillation flask. In embodiments, using standard equipment known to those of skill, Soxhlet extraction is conducted for between about 6 and about 10 hours, including about 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours. In embodiments, Soxhlet extraction is conducted for about 7 hours. In other embodiments, Soxhlet extraction is conducted for less than 6 or greater than 10 hours.

[0195] 1. Exemplary Extraction of Molecules from Fungi

[0196]

[0180] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from a fungus. In embodiments, the bioactive molecule is obtained via extraction of fungal material.

[0197]

[0181] Without being bound by theory, exemplary fungal extraction methods can be generally described as follows. First, fungal material comprising the desired primary and / or secondary bioactive molecules is obtained, optionally dried (using, e.g., means such as a low-temperature oven, food dehydrator, and / or commercial drier), and optionally ground, pulverized, macerated, and / or milled to form a substantially fine powder (such as to increase the surface area available for a solvent to interact with a material and to increase the yield of bioactive molecules from the material), which is optionally then sieved, e.g., for consistency. In this exemplary extraction process, fungal material is then combined with a solvent capable of extracting the desired primary and / or secondary bioactive molecules (e.g., methanol, ethanol, water, or a mixture thereof) to form a slurry, and the slurry is agitated to facilitate extraction for a specified duration of time, for example about 24 hours. The solvent is then filtered and collected. In embodiments, filters may include a cheesecloth, filter paper, and / or a filtration system. Optionally, the extract may be evaporated, e.g., using ambient evaporation, rotary evaporation, vacuum evaporation, and evaporation methods where heat is applied, such as utilizing an oven, as well as combinations thereof, to create a more concentrated extract. In embodiments, the fungal material may be re-saturated with the same or different solvent after the initial filtration to complete a secondary, tertiary, or further extraction. Extraction methods and variations thereof may be chosen using ordinary skill.

[0198]

[0182] In embodiments, heat extraction is used. In embodiments, heat extraction follows a process as generally described above, except that, for example, the solvent is heated, the agitation is completed in a heated environment, or the extraction otherwise takes place at a raised temperature relative to ambient temperature. In embodiments, extraction is completed at temperatures at which psilocybin is substantially dephosphorylated to psilocin. In embodiments, heat extraction is completed in temperatures exceeding about 70 °C. In embodiments, extraction occurs at temperatures below which there is substantial dephosphorylation of psilocybin. In embodiments, extraction occurs at a temperature or temperature range chosen to produce a desired ratio of psilocybin to psilocin, e.g., based on the proportions in the starting material.

[0199]

[0183] In embodiments, ultrasonic extraction is used. In embodiments, mushrooms or other fungal matter is dried and cut and / or pulverized prior to ultrasonic extraction. In embodiments, an ultrasonic extraction machine is used to expose fungal material to ultrasonic vibrations via an ultrasonic probe, for example at 20 kHz or greater. In embodiments, the acoustic / ultrasonic cavitation in the sonicated liquid is sufficient to disrupt cell walls and release intracellular compounds, including the bioactive molecules.

[0200]

[0184] In embodiments, a Soxhlet extractor is used, and extraction is performed as disclosed or known. In embodiments, Soxhlet extraction is used to extract psilocybin or psilocin from fungal matter.

[0201]

[0185] Extracts of fungal material (comprising a primary and / or secondary bioactive molecule) produced according to different methods described herein or otherwise known to one of skill may be combined, including to provide various advantages. For example, fungal extracts produced according to different techniques may contain different concentrations of primary and / or secondary bioactive molecules, and combining such extracts in a combination may confer advantageous or synergistic properties.

[0202]

[0186] In embodiments, the fungal portion of a combination comprises a mixture of fungal extracts. In embodiments, the fungal portion of a combination comprises a mixture of an ultrasonic extract and a Soxhlet extract. In embodiments, the mixture comprises the ultrasonic extract and the Soxhlet extract in an ultrasonic: Soxhlet ratio (e.g., a volume ratio (v / v) or weight ratio (w / w) of the extract solutions, or a molar ratio, such as a molar ratio of the constituent bioactive molecule(s) in the extracts) of between about 0.5:1 to 10:1.

[0203]

[0187] In embodiments, the mixture comprises the ultrasonic extract and the Soxhlet extract in an ultrasonic: Soxhlet molar ratio (e.g., the molar ratio of the constituent bioactive molecule(s) in the extracts) of between about 0.5:1 to 10:1. In embodiments, the mixture of fungal extracts comprises the ultrasonic extract and the Soxhlet extract in an ultrasonic:Soxhlet volume ratio of between about 0.5:1 to 10:1. In embodiments, the mixture comprises the ultrasonic extract and the Soxhlet extract in a weight ratio from about 0.5:1 to about 5:1 .

[0204]

[0188] A ratio “of between about 0.5:1 to 10:1” includes ratios of 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 , ratios “less than” each of these values, ratios “greater than” each of these values, ratios “about” each of these values, and ranges in between these values.

[0205]

[0189] In embodiments, the mixture comprises the ultrasonic extract and the Soxhlet extract in an ultrasonic: Soxhlet weight ratio of about 2:1 .

[0206]

[0190] Advantages of combining different fungal extracts in disclosed combinations can include, for example, improved solution stability during extraction of a bioactive molecule from a fungus as described herein. For example, certain compositions disclosed herein comprise, as a component of a fungal portion, psilocin and / or psilocybin. The solution instability of psilocybin, and especially psilocin, has long been recognized. In embodiments, combining fungal extracts (e.g., as in disclosed combinations wherein the fungal portion comprises both an ultrasonic extract and a Soxhlet extract) protects the resulting combination against oxidative decomposition. Without being bound by theory, the differing levels of primary and / or secondary bioactive molecules in the different fungal extracts, which may include naturally occurring stabilizers and antioxidants, may in combination produce additive or synergistic effects that stabilize the resulting formulations against decomposition pathways, such as oxidative dimerization. In embodiments, oxidative decomposition of a composition can be monitored quantitatively (e.g., by chemical analysis methods, such as disclosed in Lenz et al., 2020 and Lenz et al., 2021 ; or otherwise known to one of skill) or qualitatively (e.g., by visual monitoring of the characteristic “blueing” reaction of psilocybin- and / or psilocin-containing extracts and materials).

[0207]

[0191] In embodiments, disclosed combinations wherein a fungal portion comprises multiple fungal extracts may also possess other advantageous properties when extracting a bioactive molecule from a fungus as disclosed herein, such as increased mixability with the other portions of the combination (e.g., plant and / or algal portions). By way of example, some disclosed compositions comprise components with high water solubility (e.g., a fungal extract comprising psilocybin and / or psilocin, or a fungal extract comprising these compounds) and 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 primary and / or secondary bioactive molecules and the solvent system. Without being bound by theory, differing levels of primary and / or secondary bioactive molecules in different fungal extracts may produce additive or synergistic effects that stabilize the resulting formulations against precipitation.

[0208]

[0192] In embodiments, disclosed combinations wherein the fungal portion comprises multiple different fungal extracts possess improved stability (e.g., against oxidation and / or precipitation) such that additional stabilizing excipients (e.g., antioxidants, stabilizers) are not necessary for the combination to have sufficient stability under ambient conditions. Reducing or eliminating the need for such additional stabilizing excipients may result in further advantages, such as improved bioavailability, as these ingredients may interfere with absorption of a primary and / or secondary bioactive molecule.

[0209] 2. Exemplary Extraction of Molecules from Cannabis

[0210]

[0193] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from a Cannabis species. In embodiments, the primary and / or secondary bioactive molecule may be obtained via extraction of Cannabis material. Without being bound by theory, Cannabis extraction methods can be generally described as follows. First, the Cannabis material comprising the desired primary and / or secondary bioactive molecules is obtained, optionally dried (using, e.g., means such as a low-temperature oven, food dehydrator, and / or commercial drier), and optionally ground, pulverized, macerated, and / or milled to form a substantially fine powder, which is optionally then sieved, e.g., for consistency.

[0211]

[0194] In embodiments, the dried, and optionally ground and / or pulverized Cannabis material is then placed into an extraction system generally containing a loop, wherein a solvent is circulated. Evaporation is used to remove solvent, followed by distillation and filtration to further concentrate the extract and remove impurities.

[0212]

[0195] In such an exemplary extraction system, the high temperature and pressure may yield decarboxylation (occurring at about 110 °C at standard pressure). In embodiments, a THC-free product is desired. In such embodiments, an extraction process with temperatures and pressures below the threshold for decarboxylation are used. In embodiments, column chromatography is used to remove THC after extraction. In an exemplary embodiment, the solvent is chilled ethanol (kept between -30 °C and -40 °C). In embodiments, the solvent is methanol or isopropyl alcohol. In embodiments, the extraction method is subcritical CO2extraction. In embodiments, the extraction method is supercritical CO2extraction. In embodiments, the extraction method is hydrocarbon extraction. In embodiments, the hydrocarbon extraction uses butane, propane, other hydrocarbon liquids and gasses as well as mixtures thereof in any proportions as the solvent.

[0213]

[0196] Other such extraction methods are known in the art, including variations thereof, e.g., to temperature, pressure, and equipment. While any such extraction methods may be used, it will be appreciated that certain extraction methods may provide specific benefits, depending on the desired composition of the extract; such will be known in view of the disclosure and ordinary skill in the art. As non-limiting examples, supercritical CO2extraction is useful for extracting cannabinoids and preserving terpenoids; warm alcohol extraction is useful for extracting and decarboxylating cannabinoids, but also extracts various pigments and impurities; cold alcohol extraction is more effective at isolating terpenes and cannabinoids from impurities than warm ethanol extraction, but is less efficient; hydrocarbon extraction is useful for reducing impurities and pigments in the extract, and may be more efficient than cold alcohol extraction; and the like.

[0214]

[0197] Primary and / or secondary bioactive molecules from Cannabis may be obtained via extraction of Cannabis plant material, and may be used to prepare Cannabis-dewed drug substances and drug products. “Cannabis-dewed drug substance” may refer to a botanical drug substance which is derived from Cannabis plants (including plant parts, plant part biomass, and plant exudates), as non-limiting illustrative examples, primary extracts prepared by processes including maceration, percolation, extraction with solvents such as C1-C5 alcohols (e.g., ethanol), hydrocarbons (e.g., propane, butane), and subcritical or supercritical carbon dioxide. “Cannabis-dewed drug product” may refer to a primary Cannabis extract that is further purified, for example by distillation or chromatography. It will be known to those of skill that when certain solvents are used to prepare primary extracts, the resultant extract may contain non-specific lipid-soluble material. Those of skill will know that such impurities can be removed by a variety of processes including winterization (e.g., chilling to -20° C followed by filtration to remove waxy ballast), further extraction or filtration, and distillation.

[0215] 3. Exemplary Extraction of Molecules from Dipteryx

[0216]

[0198] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from Dipteryx. In embodiments, the primary and / or secondary bioactive molecule may be obtained via extraction of cumaru seeds (tonka beans). In embodiments, a primary bioactive molecule in Dipteryx, such as coumarin, is extracted from cumaru seeds via extraction with a polar solvent, such as water, an alcohol (e.g., ethanol or methanol), and various ethers. Below, an exemplary extraction system utilizing ethanol is described.

[0217]

[0199] In embodiments, ethanol extraction is used to extract coumarin from cumaru seeds or other Dipteryx matter. In embodiments, the ethanol percolation extraction proceeds by first crushing the cumaru seeds so that the ethanol solvent is capable of entering and exiting the beans. In embodiments, the seeds are sufficiently ground to increase surface area for extraction, forming a collection of seed matter for extraction.

[0218]

[0200] In embodiments, ultrasonic extraction is used, such as to extract coumarin from cumaru seeds or other Dipteryx matter. In embodiments, ultrasonic extraction proceeds by first crushing / grinding the cumaru beans. In embodiments, an ultrasonic extraction machine is used to expose the cumaru beans to ultrasonic vibrations via an ultrasonic probe, for example at 20 kHz or greater.

[0219]

[0201] In embodiments, a Soxhlet extractor is used, and extraction is performed as disclosed or known. In embodiments, Soxhlet extraction is used to extract coumarin from cumaru seeds or other Dipteryx matter.

[0220]

[0202] Other bioactive molecules from cumaru may be extracted in the same or a similar manner, and is present in an extract when the exemplary ethanol extraction method is used. Other useful extraction methods will be known to those of skill. The concentration of a bioactive molecule may be determined as described.

[0221] 4. Exemplary Extraction of Molecules from Pyropia

[0222]

[0203] In embodiments, a combination comprises a primary and / or secondary bioactive molecule from Pyropia. A primary bioactive molecule in Pyropia is taurine or porphyran, which may, in embodiments, be extracted from Pyropia or algal material via extraction with a polar solvent, including water, alcohols, including ethanol and methanol; and various ethers. Below, an exemplary extraction system using ethanol is described.

[0223]

[0204] In embodiments, ethanol extraction is used, such as to extract taurine or porphyran from Pyropia or algal material. In embodiments, extraction of the algal material uses an ethanol percolation extraction system.

[0224]

[0205] In embodiments, ultrasonic extraction is used. In embodiments, Pyropia or algal material is ground or pulverized prior to ultrasonic extraction. In embodiments, an ultrasonic extraction machine is used to expose Pyropia or algal material to ultrasonic vibrations via an ultrasonic probe, for example at 20 kHz or greater.

[0225]

[0206] In embodiments, a Soxhlet extractor is used, and extraction is performed as disclosed or known. In embodiments, Soxhlet extraction is used to extract taurine or porphyran from Pyropia or algal material.

[0226]

[0207] Other extraction methods also may be used, as known to those of skill. Additionally, while taurine or porphyran is directly mentioned, it should be readily appreciated that, e.g., secondary bioactive molecules from Pyropia or algal material may additionally be extracted in the same or a similar manner, and is present in the extract when the exemplary ethanol extraction method is used. Moreover, the concentration of a primary and / or secondary bioactive molecule may be determined as disclosed herein. 5. Determining the Concentration of a Primary or Secondary Bioactive Molecule

[0227]

[0208] It will be appreciated that determining the concentration of a primary and / or secondary bioactive molecule within an extract or within fungi, plant, and / or algae material is within the ability of one of skill. Several such means are disclosed below, and may be used in embodiments.

[0228]

[0209] As a non-limiting example of such means, the concentration of primary bioactive molecules from various Psilocybe species are presented in TABLE 1 below (reproduced from Mahmood. Bioactive Alkaloids from Fungi: Psilocybin. In: Ramawat, K., Merillon, JM. (eds) Natural Products. Springer, 2013, and organized by psilocybin content; see also Stamets. Psilocybin Mushrooms of the World: An Identification Guide. Ten Speed Press. 1996) showing the w / w% of psilocybin, psilocin, and baeocystin in dried mushrooms (containing negligible water weight, or sometimes referred to as “cracker dry”), as is additionally discussed further herein:

[0229] TABLE 1 : Psilocybin, Psilocin, & Baeocystin Content of Exemplary Psilocybe Species by %

[0230]

[0210] Thus, an extract of 100 mg P. cubensis may, in some embodiments, contain approximately 0.63 mg of psilocybin. An extract of 275 mg P. azurescens may, in embodiments, contain approximately 4.895 mg.

[0231]

[0211] One will appreciate that growing conditions of organisms such as fungi (as well as plants and algae) may influence the concentration of bioactive molecules found therein. The concentration of bioactive molecules may differ depending on the organism part from which they are obtained (e.g., cap vs. stipe or mycelium; flower vs. leaves or stalk; etc.), as well as other variables known in the art. One will appreciate how to select such growing conditions, organism parts, and the like, and understand how to determine the concentration of bioactive molecules with disclosed methods or those generally known in the art.

[0232]

[0212] In embodiments, the concentration of a primary and / or secondary bioactive molecule in fungi, plants, and / or algae is determined utilizing liquid chromatography, such as high-performance liquid chromatography (HPLC). Broadly, HPLC works by using pumps to pass a pressurized liquid solvent containing the sample mixture (in this case, a fungal extract) through a column filled with a solid adsorbent material. As each individual component in the sample interacts differently with the adsorbent material, it causes different flow rates for different components leading to the separation of the components as they flow out of the column.

[0233]

[0213] In embodiments, the concentration of a primary and / or secondary bioactive molecule in fungi, plants, and / or algae is determined utilizing reversed-phase HPLC and single-wavelength detection, as disclosed in Samuelsson et al. Physiol Plant. 1977;40:315-319, which is incorporated herein by reference. Broadly, reverse-phase HPLC generally proceeds in the same manner as the exemplary HPLC method disclosed above, but has a hydrophobic rather than a hydrophilic stationary phase. Meaning, hydrophobic molecules will absorb to the column packing, while hydrophilic molecules will be eluted and detected first.

[0234]

[0214] In embodiments, the concentration of a primary and / or secondary bioactive molecule in fungi, plants, and / or algae is determined utilizing liquid chromatography and mass spectrometry (LC / MS), as illustrated by Goff et al. Anal Chim Acta. 2024; 1288:342161 , which is incorporated herein by reference.

[0235]

[0215] In embodiments, the concentration of a primary and / or secondary bioactive molecule in fungi, plants, and / or algae is determined utilizing hydrophilic interaction liquid chromatography (HILIC), described in Veress et al. The Applications Book. 2019;32(7):387-388, and incorporated herein by reference. Broadly, HILIC is a normal phase HPLC technique utilizing reversed-phase type eluents. The column has a hydrophilic stationary phase, and the eluent contains water, a buffer, and a high concentration of water-miscible organic solvent.

[0236]

[0216] In embodiments, the concentration of a primary and / or secondary bioactive molecule in fungi, plants, and / or algae is determined utilizing a rapid personal quantification means usable for determination of concentration, one example of which for fungi is the PSILO-QTest (Miraculix; Jena, Germany), useful for determining the concentration of psilocybin. The PSILO-QTest uses chemical color reaction to detect concentration, with color intensity proportional to the concentration of the bioactive molecule. In embodiments, characterization of the fungal, plant, and / or algal portion of a disclosed combination (e.g., characterization of the primary and / or secondary bioactive molecules) comprises characterizing free and / or bound amino acids using known chromatographic techniques (e.g., LC-MS, HPLC). In embodiments, the characterization comprises determining the concentration of taurine in the fungal, plant, and / or algal portion.

[0237] B. Synthesis

[0238]

[0217] In embodiments, the primary and secondary bioactive molecules disclosed herein may be synthetic, where “synthetic” herein may refer to a substance which is manufactured in a laboratory, by means of chemical synthesis (e.g., by a series of chemical processes or reactions using chemical substrates, reagents, and optionally a catalyst) or biosynthesis, discussed herein, (e.g., from a bioengineered organism, and thus including those compounds also referred to as “biosynthetic” or as involving “synthetic biology” or “synbio”).

[0239]

[0218] Generally, methods for chemical synthesis are well known in the art, including for the bioactive molecules disclosed herein. Methods for synthesis of the bioactive molecules and / or starting materials therefore will be readily apparent to the skilled artisan in view of general references known in the art (see, e.g., Greene & Wuts. Protective Groups in Organic Chemistry. 2nd ed. Wiley. 1991 ; Harrison et al. Compendium of Syn. Org. Methods. Vol. 1-8. John Wiley and Sons, 1971-1996; Beilstein. Beilstein Handbook of Org. Chem. 1990; Felser et al. Reagents for Organic Synthesis. Vol. 1-17. Wiley Intersci. 1967-1994. Trost & Fleming. Comprehensive Org. Syn. Pergamon Press. 1991 ; Theilheimer’s Synthetic Methods Org. Chem. Vols. 1-45. Karger. 1991 ; March. Advanced Organic Chemistry. Wiley Interscience. 1991; Larock. Comprehensive Organic Transformations. VCH Publishers. 1989; Paquette. Encyclopedia of Reagents for Org. Syn. John Wiley & Sons. 1995) and may be used to synthesize the bioactive molecules, where not otherwise obtained, such as by extraction. In general, methods for chemical synthesis will be adapted from the approaches used for similar compounds (Shulgin & Shulgin, PiHKAL, A chemical love story, Transform Press, Berkeley CA, 1992; Glennon et al., J Med Chem. 1986; 29(2): 194-199; Nichols et al. J Med Chem. 1991 ; 34(1):276-281 ; Kedrowski et al., Organic Letters. 2007;9(17):3205-3207; Heravi & Zadsirjan. Current Organic Syn. 2016; 13(6):780-833; Keri et al. Eur J Med Chem. 2017;138: 1002- 1033; Perez Silanes et al. J Heterocycl Chem. 2001 ;38(5): 1025-1030; and references therein), such adaptations being that known and understood to those of ordinary skill.

[0240]

[0219] In embodiments, the disclosed primary and secondary bioactive molecules may be obtained via biosynthesis. Biosynthesis includes the production of molecules within a cell or a cell-free system. In embodiments, primary and / or secondary bioactive molecules are produced via biosynthesis. Methods for biosynthesis are known in the art (.g., PCT Pub. Nos. WO2021 / 052989, WO2019 / 173797, W02021 / 086513, and WO2019 / 180309, each incorporated by reference herein). Examples of known biosynthetic pathways in the art include those for cannabinoids, flavonoids, carotenoids, psilocybin, psilocin, other indole alkaloids (such as found in fungi), amino acids, and peptides (including monopeptides, dipeptides, tripeptides, and proteins).

[0241]

[0220] In embodiments, a bioactive molecule from a fungus is produced by biosynthesis. In embodiments, a bioactive molecule from a plant is produced by biosynthesis. In embodiments, a bioactive molecule from algae is produced by biosynthesis. Any such bioactive molecules may be used in the disclosed combinations.

[0242] C. Isolation, Fractionation, and Purification

[0243]

[0221] In embodiments, the primary and / or secondary bioactive molecules may be obtained via isolation, fractionation, or purification. Fractionation refers to a separation process wherein a certain quantity of a mixture is divided during a phase transition into a number of smaller quantities termed fractions, the composition of which varying according to a gradient. In embodiments, fractions containing target primary and / or secondary bioactive molecules may be obtained via fractional distillation, column chromatography, fractional crystallization, fractional freezing, and bioassay-guided fractionation. In embodiments, isolation of primary and / or secondary bioactive molecules from extracts containing the primary and / or secondary bioactive molecules may be completed. Numerous means of isolating compounds from extracts are known to those of skill in the art. However, exemplary means include thin layer chromatography, column chromatography, flash chromatography, sephadex chromatography, and HPLC (Sasidharan et al. AJTCAM. 2011;8(1):1— 10). In embodiments, extracts may be further purified to isolate a bioactive molecule. Such purification techniques will be those known to those of skill, and include HPLC and centrifugal partition chromatography (CPC). D. Compounds

[0244]

[0222] In embodiments, the disclosed primary and / or secondary bioactive molecules are pure or substantially pure. The terms “pure” or “substantially pure,” as used herein, refer to material that is substantially or essentially free from 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 accordingly defined as a preparation having a chromatographic purity (of the desired bioactive molecule) of greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, and greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method. Preferably, a pure or substantially pure bioactive molecule is substantially free of other active compounds which are not intended to be administered to a subject. In this context, “substantially free” means no active compound(s), other than intended to be administered, are detectable by HPLC or other detection method or are below a desired threshold of detection.

[0245]

[0223] The disclosed bioactive molecules may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Reference to a molecule herein includes all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Methods are known in the art for preparing optically active forms and determining activity.

[0246]

[0224] Reference to a bioactive molecule also includes those with at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., isotopically enriched or an “isotopolog.” Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. By way of example, isotopes of hydrogen including deuterium (2H) and tritium (3H) may be used anywhere in described structures that achieves the desired result. Alternatively or in addition, isotopes of carbon, e.g.,13C and14C, may be used. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In embodiments, the isotope is at least 60%, 70%, 80%, 90%, 95%, or 99% or more enriched in an isotope at any location. In an embodiment, deuterium is 90%, 95%, or 99% enriched.

[0247]

[0225] Reference to a bioactive molecule also includes pharmaceutically acceptable salts of such molecules. The term “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. For therapeutic use, salts of the compounds are those wherein the counter-ion is pharmaceutically acceptable. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc and the like (see Berge et al. J Pharm Sei. 1977;66(1 ): 1-19).

[0248]

[0226] Reference to a bioactive molecule also includes prodrugs thereof. A “prodrug” refers to a precursor of the molecule, which undergoes a chemical or metabolic conversion to become the molecule, such as the conversion of the prodrug psilocybin to its active metabolite psilocin.

[0249]

[0227] Disclosed bioactive molecules may exist in different forms. Reference to a bioactive molecule also includes such different forms. For example, the bioactive molecules may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms and nano-particulate forms, all of which are within the scope of the disclosure. Solid forms include stable crystalline forms, such as polymorphs.

[0250]

[0228] Reference to a bioactive molecule also includes its ion, free base, salt form, polymorph, hydrate or solvate form, co-crystal, an isotopolog, or an isomer or enantiomerically enriched mixture (in any proportions), each of which may provide merely an alternative embodiment within the scope hereof (with modifications to the formulation and dosage amounts made according to the disclosure and ordinary skill, if necessary or desired).

[0251]

[0229] Compositions within the scope of the disclosure should be understood to be open-ended and may include additional primary and / or secondary bioactive molecules, active or inactive agents, and ingredients.

[0252]

[0230] In embodiments, bioactive molecules are produced and tested in compliance with Good Laboratory Practice (GLP) or Good Manufacturing Practice (GMP) requirements, or equivalent and related practices, e.g., in Canada, when referring to Cannabis, the Good Production Practices (GPP) of the Cannabis Regulations. IV. Exemplary Therapeutic Combinations

[0253]

[0231] Although many therapeutic combinations will be appreciated by those of skill in view of the disclosure, certain exemplary combinations are now described, from which numerous others also will be readily known. The suffix “-P” is used to mean portion, i.e., “plant-P” and “fungal-P” means “plant portion” and “fungal portion.”

[0254]

[0232] In exemplary embodiments of a therapeutic combination, the combination comprises:

[0255]

[0233] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0256]

[0234] (a) a fungal extract; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0257]

[0235] (a) a fungal extract from a psilocybin-producing fungus; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0258]

[0236] (a) a fungal extract from a species in the Psilocybe genus; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0259]

[0237] (a) a P. cubensis extract; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0260]

[0238] (a) a bioactive molecule from a fungus; (b) a first plant-P; (c) a second plant-P; and (d) an algal-P.

[0261]

[0239] (a) psilocybin; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0262]

[0240] (a) psilocin; (b) a first plant portion; (c) a second plant portion; and (d) an algal portion.

[0263]

[0241] (a) psilocybin; (b) psilocin; (c) a first plant portion; (d) a second plant portion; and (e) an algal portion.

[0264]

[0242] (a) a fungal portion; (b) a plant extract; (c) a second plant portion; and (d) an algal portion.

[0265]

[0243] (a) a fungal-P; (b) a plant extract from the genus Cannabis,' (c) a second plant-P; and (d) an algal-P.

[0266]

[0244] (a) a fungal portion; (b) a bioactive molecule from a plant; (c) a second plant-P; and (d) an algal-P.

[0267]

[0245] (a) a fungal portion; (b) a C. sativa extract; (c) a second plant portion; and (d) an algal portion.

[0268]

[0246] (a) a fungal portion; (b) a bioactive molecule from Cannabis,' (c) a second plant-P; and (d) an algal-P.

[0269]

[0247] (a) a fungal portion; (b) a cannabinoid; (c) a second plant portion; and (d) an algal portion.

[0270]

[0248] (a) a fungal portion; (b) THC; (c) a second plant portion; and (d) an algal portion.

[0271]

[0249] (a) a fungal portion; (b) CBD; (c) a second plant portion; and (d) an algal portion.

[0272]

[0250] (a) a fungal portion; (b) a Dipteryx extract; (c) a second plant portion; and (d) an algal portion.

[0273]

[0251] (a) a fungal portion; (b) a D. odorata extract; (c) a second plant portion; and (d) an algal portion.

[0274]

[0252] (a) a fungal portion; (b) a bioactive molecule from Dipteryx,' (c) a second plant-P; and (d) an algal-P.

[0275]

[0253] (a) a fungal portion; (b) a bioactive molecule from D. odorata,' (c) a second plant-P; and (d) an algal-P.

[0276]

[0254] (a) a fungal-P; (b) a bioactive molecule from tonka beans; (c) a second plant-P; and (d) an algal-P.

[0277]

[0255] (a) a fungal portion; (b) coumarin; (c) a second plant portion; and (d) an algal portion.

[0278]

[0256] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) an algal extract.

[0279]

[0257] (a) a fungal-P; (b) a first plant-P; (c) a second plant-P; and (d) a bioactive molecule from an algae.

[0280]

[0258] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from a red algae (Rhodophyta).

[0281]

[0259] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from a genus in the family Bangiaceae.

[0282]

[0260] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a Pyropia extract.

[0283]

[0261] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a P. yezoensis extract.

[0284]

[0262] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from the genus Pyropia.

[0285]

[0263] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from P. yezoensis.

[0286]

[0264] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from Pyropia perforata.

[0287]

[0265] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from the genus Porphyra.

[0288]

[0266] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) a bioactive molecule from Porphyra umbilicalis.

[0289]

[0267] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) porphyran.

[0290]

[0268] (a) a fungal portion; (b) a first plant portion; (c) a second plant portion; and (d) taurine.

[0291]

[0269] (a) a fungal extract; (b) a first plant extract; (c) a second plant extract; and (d) an algal extract.

[0292]

[0270] (a) a Psilocybe extract; (b) a Cannabis extract; (c) a Dipteryx extract; and (d) a Pyropia extract.

[0293]

[0271] (a) a Psilocybe extract; (b) a Cannabis extract; (c) a Dipteryx extract; and (d) a Porphyra extract.

[0294]

[0272] (a) a P. cubensis extract; (b) a C. sativa extract; (c) a D. odorata extract; and (d) a P. yezoensis extract.

[0295]

[0273] (a) a bioactive molecule from a fungus; (b) a bioactive molecule from a first plant; (c) a bioactive molecule from a second plant; and (d) a bioactive molecule from an algae.

[0296]

[0274] (a) a bioactive molecule from P. cubensis,- (b) a bioactive molecule from C. sativa; (c) a bioactive molecule from D. odorata; and (d) a bioactive molecule from P. yezoensis.

[0297]

[0275] (a) a Psilocybe extract; (b) THC; (c) CBD; (d) coumarin; and (e) a Pyropia extract.

[0298]

[0276] (a) psilocybin; (b) THC; (c) coumarin; and (d) a Pyropia extract.

[0299]

[0277] (a) psilocin; (b) THC; (c) coumarin; and (d) taurine.

[0300]

[0278] (a) psilocybin; (b) CBD; (c) coumarin; and (d) a Pyropia extract.

[0301]

[0279] (a) psilocin; (b) CBD; (c) coumarin; and (d) a Pyropia extract.

[0302]

[0280] (a) psilocybin; (b) THC; (c) coumarin; and (d) taurine.

[0303]

[0281] (a) psilocybin; (b) THC; (c) coumarin; and (d) porphyran.

[0304]

[0282] Additional combinations include any of the foregoing embodiments, but wherein any other fungal portion, fungal extract, or bioactive molecule from a fungus, disclosed herein is substituted for any fungal portion, fungal extract, or bioactive molecule from a fungus comprising a combination. Additional combinations include any of the foregoing embodiments, but wherein any other plant portion, plant extract, or bioactive molecule from a plant, disclosed herein is substituted for any plant portion, plant extract, or bioactive molecule from a plant comprising a combination. Additional combinations include any of the foregoing embodiments, but wherein any other algal portion, algal extract, or bioactive molecule from an algae, disclosed herein is substituted for any algal portion, algal extract, or bioactive molecule from an algae comprising a combination.

[0305]

[0283] Additional combinations include any of the foregoing embodiments, but wherein the combination does not comprise a second plant portion, a second plant extract, or a bioactive molecule from a second plant. Further combinations include any of the foregoing embodiments, but wherein the combination does not comprise an algal portion, an algal extract, or a bioactive molecule from an algae. Yet further combinations include any of the foregoing embodiments, but wherein the combination does not comprise a second plant portion, a second plant extract, or a bioactive molecule from a second plant, and does not comprise an algal portion, an algal extract, or a bioactive molecule from an algae. In embodiments, such combinations may comprise, e.g., only: (1) a fungal portion, a first plant portion, and an algal portion; or (2) a fungal portion, a first plant portion, and a second plant portion. In embodiments, such combinations may comprise, e.g., only: (1) a fungal portion and a first plant portion; (2) a fungal portion and an algal portion; or (3) a first plant portion and an algal portion. It will be appreciated that the fungal portion, first plant portion, second plant portion, and algal portion in such embodiments may be any fungal, plant, or algal extract or bioactive molecule disclosed herein.

[0306]

[0284] In embodiments, the combination comprises a fungal portion, a fungal extract (e.g., a P. cubensis extract), or a bioactive molecule from a fungus (e.g., from P. cubensis). In embodiments, the fungal portion, the fungal extract, or the bioactive molecule from a fungus constitutes a percentage from less than 1 % to greater than 99% by volume of the combination. ‘A percentage from less than 1 % to greater than 99% by volume of the combination” refers to any percentage including less than 1 %, and about or at least each of 1 %, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, and 99%, including ranges in between these values, by volume of the combination.

[0307]

[0285] In embodiments, the fungal portion, the fungal extract, or the bioactive molecule from a fungus constitutes from about 10% to about 70%, about 20% to about 60%, about 30% to about 50%, or about 40% to about 50% by volume of the combination. In embodiments, the fungal portion, the fungal extract, or the bioactive molecule from a fungus constitutes about 45% by volume of the combination.

[0308]

[0286] In embodiments, the combination comprises a first plant portion, a first plant extract (e.g., a C. sativa extract), or a bioactive molecule from a first plant (e.g., from C. sativa). In embodiments, the first plant portion, the first plant extract, or the bioactive molecule from a first plant constitutes a percentage from less than 1 % to greater than 99% by volume of the combination. In embodiments, the first plant portion, the first plant extract, or the bioactive molecule from a first plant constitutes from about 1% to about 50%, about 5% to about 30%, or about 10% to about 20% by volume of the combination. In embodiments, the first plant portion, the first plant extract, or the bioactive molecule from a first plant constitutes about 15% by volume of the combination.

[0309]

[0287] In embodiments, the combination comprises a second plant portion, a second plant extract (e.g., a D. odorata extract), or a bioactive molecule from a second plant (e.g., from D. odorata). In embodiments, the second plant portion, the second plant extract, or the bioactive molecule from a second plant constitutes a percentage from less than 1 % to greater than 99% by volume of the combination. In embodiments, the second plant portion, the second plant extract, or the bioactive molecule from a second plant constitutes from about 1 % to about 20%, about 1 % to about 10%, or about 1 % to about 3% by volume of the combination. In embodiments, the second plant portion, the second plant extract, or the bioactive molecule from a second plant constitutes about 2% by volume of the combination.

[0310]

[0288] In embodiments, the combination comprises an algal portion, an algal extract (e.g., a P. yezoensis extract), or a bioactive molecule from an algae (e.g., from P. yezoensis). In embodiments, the algal portion, the algal extract, or the bioactive molecule from an algae constitutes a percentage from less than 1% to greater than 99% by volume of the combination. In embodiments, the algal portion, the algal extract, or the bioactive molecule from an algae constitutes from about 1 % to about 50%, about 5% to about 30%, or about 10% to about 20% by volume of the combination. In embodiments, the algal portion, the algal extract, or the bioactive molecule from an algae constitutes about 15% by volume of the combination.

[0311]

[0289] In embodiments, the first plant portion (as shorthand, “plant-P”) and the second plant-P are from different plant genera. In embodiments, the first plant-P and the second plant-P are from different plant species. In embodiments, the first plant-P and the second plant-P are from different plant extracts. In embodiments, the first plant-P and the second plant-P comprise different primary bioactive molecules. In embodiments, the first plant-P and the second plant-P comprise different secondary bioactive molecules. In embodiments, the first plant-P and the second plant-P are from the same plant genus. In embodiments, the first plant-P and the second plant-P are from the same plant species. In embodiments, the first plant-P and the second plant-P are from the same plant extract. In embodiments, the first plant-P and the second plant-P comprise the same primary bioactive molecules. In embodiments, the first plant-P and the second plant-P comprise the same secondary bioactive molecules.

[0312]

[0290] In embodiments, the single composition further comprises any of a flavorant, colorant, and diluent. In embodiments, the flavorant or colorant comprises ginger or bay laurel. In embodiments, the flavorant or colorant is ethanol infused with ginger and bay leaf. In embodiments, the flavorant or colorant constitutes from about 1 % to about 50%, about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, about 5% to about 20%, about 10% to about 30%, or about 10% to about 20% by volume of the single composition. In embodiments, the flavorant or colorant constitutes about 15% by volume of the single composition.

[0313]

[0291] In embodiments, the diluent is water. In embodiments, the diluent (e.g., water) constitutes from about 1 % to about 30%, about 5% to about 30%, about 5% to about 20%, or about 5% to about 15% by volume of the single composition. In embodiments, the water constitutes about 8% by volume of the single composition

[0314] A. Exemplary Therapeutic Mechanisms

[0315]

[0292] Within a pathological system, energy may be spent on survival rather than cell differentiation, leading to rigid, self-perpetuating patterns, while central nervous system (CNS) dysfunction causes and exacerbates further dysfunction through signal failures, non-generative energy consumption, and excessive artifacts and oxidative stress, with age and other pathological factors further amplifying these effects. In embodiments, the bioactivity of a combination may result from redundant, promiscuous effects on CNS signaling capabilities, improving the integrity and density of neuronal cell structures, enhancing neurotransmitter synthesis and regulation, as well as neuroprotection, and / or positively exploiting plasticity mechanisms (e.g., BDNF, serotonergic muscle control, and glial networks). Failures within one or more of these neurological systems may contribute to the pathophysiology of a medical condition, and in embodiments each component of a disclosed combination may affect these neurological circuits in multiple, differing, and synergistic ways, such as supported by the privileged access and broad activity afforded to exogenous inputs from natural sources.

[0316]

[0293] Certain exemplary therapeutic mechanisms, with further appreciated by those of skill, are provided.

[0317]

[0294] Fungi. In embodiments, a combination comprising one or more bioactive molecules from fungi interacts with signaling pathways in the nervous and immune systems. Psilocin, like serotonin, has strong affinity to serotonin receptors 5-HT2Alocated in blood vessels, the Gl tract, platelets, central and peripheral nervous system, and smooth muscle (Madsen et al. Neuropsychopharmacol. 2019;44(7): 1328- 1334). Psilocin binding to S-HT^ activates dopamine-induced functions on cognitive and reward systems (striatum), behavioral control (premotor cortex), and visual functions (the occipital area) (Melse et al. J Parkinson’s Disease. 2014;4(2). Psilocin binds, with less affinity, to 5-HT1Areceptors mainly in the prefrontal cortex (Halberstadt & Geyer. Neuropharmacol. 2011 ;61 (3):364). In embodiments, a combination comprising one or more bioactive molecules from fungi, such as psilocin increases extracellular dopamine and serotonin; increases synaptic density, as measured by synaptic vesicle glycoprotein 2A (SV2A) or postsynaptic density protein 95 (PSD95, also known as synapse-associated protein 90 (SAP-90); and / or promotes structural and functional plasticity by way of 5-HT, mTOR, and other pathways. Psilocin binding to 5-HT^ receptors triggers activation of different pathways leading to restored mood and visual capacity (Lopez-Gimenez & Gonzalez-Maeso. Curr Top Behav Neurosci. 2018; 36: 45-73). In embodiments, a combination comprising one or more bioactive molecules from fungi may, by one mechanism of action, improve a disclosed disorder by interacting with 5-HT receptors (e.g., 5HT-1 receptors, 5-HT2 receptors) on cells (e.g., cortical neuronal cells) to change the course of the disease In embodiments, a combination comprising one or more bioactive molecules from fungi restores mood and visual capacity in a subject with a medical condition. In embodiments, a combination comprising one or more bioactive molecules from fungi promotes neuroplasticity.

[0318]

[0295] A 5-HT receptor-mediated pathway has recently been implicated in mitochondrial biogenesis and function in different cell types, such as cortical neuronal cells (Fanibunda et al. Proc Natl Acad Sci USA. 2019; 116(22): 11028-11037). In embodiments, a combination comprising one or more bioactive molecules from fungi improves mitochondrial biogenesis and function. In embodiments, for example, neurodegenerative disorders, may be characterized by the inhibition of neuronal regeneration, which can be caused by hyper-reactive microglia cells, essential in preserving tissue homeostasis. Microglia function to sense foreign and harmful pathogens and initiate an adequate immune response (Nayak et al. Ann Rev of Immunol. 2014;32:367). Pathogens trigger microglia’s own activation, and hyper-reactive microglia resulting from stressed neurons triggers neuronal damage and phagocytosis (Xu et al. Neural Regeneration Research. 2021 ; 16(2):270). In embodiments, psilocin secures neuronal survival by attenuating the phagocytic function of microglia. In embodiments, psilocin activation of 5-HT2Areceptors influences microglial functions by reducing biomarkers of an autoimmune disorder (e.g., TLR4, p65, and CD80 proteins) and upregulating neuroprotective receptors (TREM2). In embodiments, a combination comprising one or more bioactive molecules from fungi reduces concentrations of ROS, TNF-a, IL-6, and IL-10. In embodiments, a combination comprising one or more bioactive molecules from fungi enhances microglial function in a subject. In embodiments, a combination comprising one or more bioactive molecules from fungi upregulates neuroprotective receptors in a subject.

[0319]

[0296] Psilocin binding to 5-HT1Areceptors triggers the decrease in intracellular signaling molecule cAMP, opening ion channels to improve cell-to-cell communication related to executive functions of the brain’s prefrontal cortex (e.g., improved cognition) (Nichols. Pharmacol Rev. 2016;68(2):264). In embodiments, a combination comprising one or more bioactive molecules from fungi induces anti-nociceptive, analgesic, anti-depressive, or anxiolytic effects. A lack of cell-cell communication due to excess cAMP ultimately results in impaired working memory (planning and attention), short-term memory, personality expression, moderating social behavior, impulse control, and controlling certain aspects of speech and language (Foltynie et al. Movement Disorders: Official J Movement Disorder Soc’y. 2004; 19(8), 885-891; Aarsland et al. J Neurology, Neurosurgery, Psych. 2009;80(8), 928-930; Aarsland et al. Nature Rev Neurol. 2011 ;8(1), 35-47; Weintraub. Curr Neurol Neurosci Reports. 2006;6(4): 302-306). In embodiments, a combination comprising one or more bioactive molecules from fungi improves memory, personality expression, moderates social behavior, impulse control, and controls certain aspects of speech and language.

[0320]

[0297] Cannabis. In embodiments, a combination comprising one or more bioactive molecules from Cannabis, such as a cannabinoid, increases the activity and expression of tyrosine hydroxylase (see Bonnin et al. J Mol Neurosci. 1996;7:291-308; Hernandez et al. J Mol Neurosci. 1997;8:83-91). In embodiments, a combination comprising THC increases the synthesis and inhibits the uptake of dopamine (see Bloom & Dewey. Psychopharmacol (Berl). 1978;57:243-248; Maitre et al. Acta Psychiatr Scand Suppl. 1980;280:97-110; Banerjee et al. Pharmacol Exp Ther. 1975;194:74-81). In embodiments, wherein a combination comprises one or more bioactive molecules from Cannabis, CB1 receptor activation inhibits GABAergic neurotransmission in the ventral tegmental area (VTA) by a presynaptic mechanism (see Szabo et al. Eur J Neurosci. 2002;15:2057-2061); and / or depression of the GABAergic inhibitory effect on dopaminergic neurons increases their firing rate in vivo, increasing dopamine in the nucleus accumbens (NAc). In embodiments, THC and CBD decrease IL-10 and IL-6. In embodiments, CBD increases NRF2 expression, leading to decreased ROS, and reduces NF-KB levels. In embodiments, CBD increases NRF2 expression, while actively suppressing NF-kB by way of promoters p65 and p52. In embodiments, CBD activates PPAR-y networks and directly represses NF-KB transduction through CB1 and CB2 receptors. In embodiments, a combination comprising one or more bioactive molecules from Cannabis induces anti-nociceptive effects. Endocannabinoids (e.g., anandamide, AEA and 2-arachidonoglycerol, 2AG) and its receptors, CB! and CB2, play an important role in signaling anti-nociceptive responses (Guindon, J, Hohmann, AG. CNS & Neurological Disorders Drug Targets. 2009;8(6):403). Its deficiency is known to be related to depression, migraine, fibromyalgia, IBS, and related conditions (Russo, EB. Cannabis & Cannabinoid Research. 2016;1 (1):154). In embodiments, activation of CBi receptors inhibits neuronal voltage-activated calcium currents, increases potassium currents, and inhibits neurotransmitter release in central and peripheral neurons, signaling for regulation of nociception (pain control); increases the amount of sleep a subject receives; exhibits neuroprotective effects; reduces stress response; improves emotion; regulates behavior; and / or increases reward signaling in a subject.

[0321]

[0298] Dipteryx. In embodiments, a combination comprising one or more bioactive molecules from Dipteryx, such as a coumarin analog or derivative, modulates serotonin, dopamine, and adrenergic receptors, and induces neuroprotective effects; inhibits MAO-B, responsible for the oxidative deamination of exogenous and endogenous amines, including neurotransmitters such as dopamine, which translates into more dopamine availability to be used by the brain; activates macrophages and other immune cells through mediation of cell-adhesion molecules; upregulates synthesis and release of dopamine; decreases the production of nitric oxide (NO), TNF-a, and IL-10; inhibits the LPS-induced protein and mRNA expression levels of nitric oxide synthase (iNOS); reduces the LPS-stimulated phosphorylation of IKKa / p, p-IxBa and IKBQ degradation as well as the nuclear translocation of the p65 subunit of NF-KB; activates transcription factors NRf2, further modulating NF-kB activity and exerting useful cytoprotective mechanisms; induces antioxidant activity via modulation of Nrf2; induces antioxidant, anticancer, antiviral, and neuroprotective effects; and / or suppresses oxidative stress by moderating excessive ROS generation and enhancing antioxidants by inhibiting neutrophil-dependent superoxide anion generation and lipid peroxidation.

[0322]

[0299] Algae. In embodiments, a combination comprising one or more bioactive molecules from an algae, such as an oligosaccharide from Pyropia, inhibits the loss of tyrosine hydroxylase, thereby increasing synthesis of dopamine; protects dopaminergic neurons and elevates dopamine levels. In embodiments, a combination comprising one or more bioactive molecules from an algae, induces antioxidant, anti-aging, anti-atrophic, immunomodulatory, anticancer, and neuroprotective properties and high bioactivity; down-regulates NF-KB and activates Nrf2 signaling cascades; reduces concentrations of IL-6; stabilizes biomembranes, encourages redox homeostasis, and scavenges oxidative factors; enhances mitochondrial functionality by modulating the expression of numerous protective factors and enzymes, improves metabolic syndrome, and decreases oxidative stress, which plays a role in the onset and development of mental health disorders like depression;increases levels of vitamin B12 in a subject, where a vitamin B12 deficiency can cause several neurological symptoms and cognitive defects; suppresses LPS-induced immune activation; and / or lowers cholesterol levels in a subject.

[0300] In embodiments, chronic stress across immune, neurological, and mitochondrial systems systematically reduces overall system competence. In embodiments, symptoms of a medical condition may be caused by the dysregulation of various interconnected pathways. In embodiments, a combination promotes simultaneous modulation of these pathways to disrupt patterns of pathological activity, helping to dislodge the foundation of the disease and restore physiological activity. In embodiments, a combination enhances neuroplasticity in a subject via improved monoaminergic neurotransmission. In embodiments, the combination creates synergistic effects, resulting in effective neuroplasticity, further with additional antioxidant and metabolic support, that is useful in treating a disclosed disorder in a subject.

[0323]

[0301] In embodiments, a combination modulates, regulates, or enhances, monoaminergic neurotransmission in a subject. “Monoaminergic neurotransmission” includes processes where monoaminergic neurotransmitters such as dopamine (DA), serotonin (5-HT), and norepinephrine (NE) are released by a presynaptic cell upon excitation and cross the synapse to stimulate or inhibit a postsynaptic cell. In embodiments, a combination increases endogenous DA, 5-HT, and NE via any of the activation and mediation of the 5-HT system, activation of NPR19, CB^ CB2, TRPV1, PPAR-y, rebalancing AchE and AchE activities, increasing DA release via PKA and CaMK II, upregulating cAMP and Ca2+, upregulating tyrosine hydroxylase, activating DA transport, or increasing monoamine oxidase (MAO) inhibition. In embodiments, a combination inhibits MAO enzymes, responsible for oxidative deamination of exogenous and endogenous amines, like DA. In embodiments, inhibiting MAO enzymes translates into more DA availability to be used by the brain.

[0324]

[0302] In embodiments, a combination enhances neuroplasticity in a subject. In embodiments, a combination improves neuroplasticity in a subject. “Neuroplasticity” refers to the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections after an injury, for example, and includes neural plasticity or brain plasticity. Clinical studies suggest that some psychedelic substances, such as psilocybin, induce cognitive, antidepressant, anxiolytic, and anti-addictive effects suggested to arise by inducing neuroplasticity (de Vos et al. Front Psychiatry. 2021; 12:724606). The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity (id.). In addition, the endocannabinoid system plays a role in homeostasis and neuroplasticity, including neurogenesis and refinement of neuronal connections (Haney Am J of Psychiatry. 2022; 179(1 ):21 -25).

[0325]

[0303] In embodiments, a combination achieves a disruptive effect on deeply entrenched patterns of pathological activity; modulates the immune system in a subject; regulates the nervous system in a subject; halts or slows disease progression and promotes tissue repair through a complex and synergistic array of cellular activity involving signal transduction pathways, second messenger and retrograde signaling, and adaptive responses; supports management of symptoms of a neurodegenerative disorder, acting as a multi-target disease modifier; enhances neurochemical signaling fidelity in a subject; activates dopamine and serotonin receptors, both of which are implicated in modulating pathways underlying certain medical conditions; enhances dopaminergic signaling functioning in a subject; enhances serotonin signaling functioning in a subject; enhances norepinephrine signaling functioning in a subject; modulates mitochondrial signaling in a subject; improves monoaminergic neurotransmission in a subject with a medical condition; and / or increases presynaptic and postsynaptic protein density, which improves monoaminergic neurotransmission in a subject.

[0326]

[0304] In embodiments, improving monoaminergic neurotransmission in a subject reduces bioamine dysmediation; reduces neuroplasticity degradation; reduces defective neuron-neuroglia coupling; reduces symptoms of a medical condition; .reduces oxidative stress perturbation; and / or reduces bioenergetic imbalance and improves bioenergetic reactivity.

[0327]

[0305] In embodiments, neuroprotective effects of combinations result from synergistic and overlapping effects of the fungal, plant, and algal portions, said synergy being defined in embodiments as a neuroprotective effect that is greater than the additive neuroprotective effects or neuroprotective properties of the portions when administered alone. In embodiments, the synergy is a synergistic effect in, e.g., neuroprotective capacity, potency, bioactivity, bioaccessibility, bioavailability, therapeutic effect, or a combination thereof.

[0328]

[0306] In embodiments, a combination enhances immunoplasticity; restores mitochondrial functionality, increases biogenesis, and enhances mitochondrial plasticity; enhances cellular plasticity; modulates the bioenergetic apparatus in a subject (e.g., the conversion of energy for use in various biological processes within cells); and / or modifies membrane potentiation and modulates ionic gradients.

[0329]

[0307] In embodiments, a combination decreases concentrations of co-repressors, NF-kp and / or AP-1 , at NURR1. NF-kp and AP-1 are transcription factors that orchestrate expression of many genes involved in proliferation, cell death, development, as well as innate and adaptive immune responses. In embodiments, genetic deletion of NURR1 inhibits the development of midbrain dopamine producing neurons. In embodiments, decreasing concentrations of co-repressors, NF-kp and / or AP-1, at NURR1 , improves monoaminergic neurotransmission in a subject, as repression of NF-kp and / or AP-1 at NURR1 re-enables basal microglial down regulation and creates an environment conducive to dopaminergic restoration.

[0330]

[0308] In embodiments, a combination reduces concentrations of TNF-a and IL-1 p through direct and indirect amplification and / or interference with NF-kp and AP-1 transduction mechanisms. Exposure to TNF-a and IL-1 p reduces mitochondrial function, such as cellular respiration, and thus, ATP production (see Doll et al. J Neurochem. 2015;132(4):443-51 ; Zhang et al. J Cell Physiol. 2021 ;236(11 ):7504-7515). In embodiments, a combination reduces TNF-a and IL-1 p concentrations by lowering oxidative ROS, nitric oxide (NO), and / or myeloperoxidase (MPO). NO and its toxic metabolite, peroxynitrite, can inhibit mitochondrial respiration, causing energy failure and cell death (Stewart & Heales, Free Radio Biol Med. 2003;34(3):287-303), and also contribute to persistent pain states (Koch et al. Inflamm Res. 2007;56(1):32-7), while MPO, an immune enzyme, promotes oxidative stress through biomolecule oxidation (Lin et al. Antioxidants. 2024; 13(1): 132). In embodiments, a combination reduces IL-6 concentration, treating chronic pain and autoimmune disorders.

[0331]

[0309] In embodiments, a combination inhibits the NF-KB signaling pathway. In embodiments, a combination increases NRF2 expression, leading to decreased ROS, which may reduce NF-KB levels (e.g., by way of promoters p65 and p52). In embodiments, a combination represses NF-kB transduction through activation of CB! and CB2receptors. In embodiments, a combination activates peroxisome proliferator-activated receptor-? (PPAR?) networks. PPAR activation is involved in the regulation of metabolism, in relation to insulin sensitivity, mitochondrial biogenesis, and glucose and lipid homeostasis (Corona & Duchen, Free Radio Biol Med. 2016;100:153-63). In embodiments, a combination downregulates cytokine and chemokine production and upregulates the production of T-regulatory cells (TREGs), which, for example, maintain immune homeostasis.

[0332]

[0310] Mitochondrial respiration is the primary source of reactive oxidative species (ROS), including free radicals, which drive oxidative stress (Kowalcyzk et al. Int J Mol Sci. 2021 ;22(24): 13384). Excessive ROS can damage DNA, leading to mutagenesis and disease progression, while oxidative stress occurs when ROS production overwhelms cellular antioxidant defenses (Bell et al. Circulation. 2013; 128(11 Suppl 1); Hou et al. Redox Biology. 2018; 14). Mitochondrial dysfunction exacerbates ROS generation, creating a negative cycle, and protein misfolding in the endoplasmic reticulum (ER), a key site for protein folding, further contributes to ROS production (Cao & Kaufman, Antioxidants & Redox Signaling. 2014;21 (3):396); ROS compromises biomolecular integrity through lipid peroxidation, protein oxidation, and DNA damage, while damaged neurons may activate toxic microglial responses, amplifying neuronal injury. In embodiments, a combination reduces apoptosis, enhances antioxidant activity, and improves behavioral, learning, and memory deficits in a subject.

[0333]

[0311] In embodiments, oxidative stress is mitigated by restoring cellular redox balance through increased antioxidant levels. A combination enhances antioxidant levels while reducing oxidant levels in cells, tissues, and organs affected by a medical condition. In embodiments, a combination helps achieve or preserve cellular redox homeostasis, exerting antioxidant effects beneficial to treat or prevent a disclosed medical condition.

[0334]

[0312] In embodiments, a combination reduces cholesterol levels. Cholesterol accumulation may lead to mitochondrial dysfunction, an autoimmune disorder, or a pain disorder, among other disorders. Accumulation of cholesterol in mitochondria above physiological levels has a negative impact on mitochondrial function by limiting antioxidant defenses, increasing ROS and oxidation (Goicoechea et al. Redox Biol. 2023;61 : 102643).

[0335] B. Synergistic Effects

[0336]

[0313] In embodiments, a combination comprising two bioactive molecules, which may be from different fungi, plants, and / or algae, or which may be from the same fungus, plant, or algae, will be synergistic (equivalently, will have or will demonstrate “synergy” or “synergistic effects,” or will exhibit or demonstrate “synergism”).

[0337]

[0314] In embodiments, a combination comprising a bioactive molecule from a fungus and a bioactive molecule from a plant will be synergistic. In embodiments, a combination comprising a bioactive molecule from a fungus, and a bioactive molecule from a plant will be synergistic. In embodiments, a combination comprising a bioactive molecule from a fungus and a bioactive molecule from an algae will be synergistic. In embodiments, a combination comprising a bioactive molecule from a plant and a bioactive molecule from an algae will be synergistic. In embodiments, a combination comprising a bioactive molecule from a fungus, a bioactive molecule from a plant, and a bioactive molecule from an algae will be synergistic.

[0338]

[0315] The synergistic effects of a combination may be based on or associated with any of the exemplary therapeutic mechanisms described above. For example, in some embodiments a combination provides synergistic antioxidant effects, such synergy including for example an antioxidant effect greater than the additive antioxidant effects or antioxidant properties of the individual fungal, plant, and / or algal portions.

[0339]

[0316] In embodiments, a combination will be “synergistic” if one or more effects are greater than the additive effects of the individual components. A synergy, for example, permits the effective treatment and / or prevention of a disorder using lower amounts (doses) of the individual components. This includes lower doses of a first bioactive molecule or a second bioactive molecule (“apparent one-way synergy”), or lower doses of both bioactive molecules (“two-way synergy”), than would normally be required when either bioactive molecule is used alone to treat and / or prevent the disorder. Lower doses, for example, may result in increased safety and / or lower toxicity without reduced efficacy. A synergistic effect may additionally result in improved efficacy, including an improved avoidance or reduction of disease as compared to any single therapy.

[0340]

[0317] Numerous methods known to those of skill exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1 +1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang et al. Front Pharmacol. 2019;10:1222), or the equation of Loewe additivity (Loewe & Muischnek. Archivf. experiment. Pathol, u. Pharmakoi. 1926;114:313-326). A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner. Clin Pharmacokinet. 1981 ;6(6):429-453) and the median-effect equation (Chou & Talalay. Adv Enzyme Regul. 1984;22:27-55). The corresponding graphs associated with the equations above are the concentration-effect curve and combination index curve, respectively. The equations referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing effects of a combination.

[0341]

[0318] Synergistic effects include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including additional therapeutic effects), greater than the additive contributions of the individual components alone, and / or are greater than the contribution of the isolated bioactive molecules alone.

[0342]

[0319] In embodiments, a composition is prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase adherence or ease-of-use, increase a desired property, such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as PK or PD), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0343]

[0320] “Therapeutic effects” that may be increased or added in embodiments include antioxidant, antiinflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, anticholinergic, anti-ischemic, antihistamine, anti-craving, antibiotic, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, serotonergic, neuroactive, entactogenic, nootropic, euphoric, empathogenic, entheogenic, psychedelic, sedative, adaptogenic, actoprotectant, antihypoxant, opoidergic, and stimulant effects, and such effects known to ameliorate symptoms caused by a mitochondrial or other disclosed disorder.

[0344]

[0321] Exemplary combinations, which may provide synergy, include the following embodiments, which comprise one or more primary and / or secondary bioactive molecules from each of the numbered sources:

[0345]

[0322] (1) a psilocybin-producing fungus; and (2) Cannabis.

[0346]

[0323] (1) a psilocybin-producing fungus; and (2) Dipteryx.

[0347]

[0324] (1) a psilocybin-producing fungus; and (2) Pyropia or Porphyra.

[0348]

[0325] (1) Cannabis,' and (2) Dipteryx.

[0349]

[0326] (1) Cannabis; and (2) Pyropia or Porphyra.

[0350]

[0327] (1) Dipteryx; and (2) Pyropia or Porphyra.

[0351]

[0328] (1) a psilocybin-producing fungus; (2) Cannabis; and (3) Dipteryx.

[0352]

[0329] (1) a psilocybin-producing fungus; (2)Cannabis; and (3) Pyropia or Porphyra.

[0353]

[0330] (1) a psilocybin-producing fungus; (2) Dipteryx; and (3) Pyropia or Porphyra.

[0354]

[0331] (1) Cannabis; (2) Pyropia or Porphyra; and (3) Dipteryx.

[0355]

[0332] (1) a psilocybin-producing fungus; (2) Cannabis; (3) Dipteryx; and (4) Pyropia or Porphyra.

[0356]

[0333] (1) one or more species of Copelandia, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe; and (2) one or more species of Cannabis.

[0357]

[0334] (1) one or more species of Copelandia, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe; and (2) one or more species of cumaru.

[0358]

[0335] (1) one or more species of Copelandia, Gymnopilus, Inocybe, Panaeolus, Pholiotina, Pluteus, and Psilocybe; and (2) one or more species of Pyropia or Porphyra.

[0359]

[0336] In embodiments of each of the above, the combination will be synergistic.

[0360]

[0337] In embodiments, a combination is a botanical formulation comprising minimal or low doses of whole extracts of C. sativa plant, P. cubensis fungi, P. yesoensis algae, and D. odorata bean, relative to those that would otherwise be understood or expected in the art, and a synergy is an ability to provide an effect at the given dose amounts. Because the disclosed combinations, compositions, and methods synergistically permit the effective use of surprisingly low doses of one or more of the bioactive molecules, in some embodiments these low doses will avoid receptor exhaustion, avoid the activation of self-regulating compensatory measures, or avoid induced compensatory neurological or immunological effects.

[0361]

[0338] The goal of increasing an existing therapeutic effect, providing an additional therapeutic effect, increasing adherence or ease-of-use, increasing a desired property, such as stability or shelf-life, decreasing an unwanted effect or property, altering a property in a desirable way, such as pharmacokinetics (PK) or pharmacodynamics (PD), modulating a desired system or pathway (e.g., a neurotransmitter system), or otherwise inducing synergy, in embodiments, is achieved by the inclusion of an additional active agent. C. Additional Active Agents

[0362]

[0339] A combination may be used together with an additional active agent, which may contribute to or provide an additional therapeutic effect, or contribute to or provide a synergistic effect. “Agent” refers to an agent that affects or modulates the activity of a target, such as a receptor. In embodiments, an agent is a ligand for a receptor and modulates the activity of the receptor. In embodiments, an agent binds to, blocks, activates, inhibits, or otherwise influences (e.g., via an allosteric reaction) activity at a given receptor system.

[0363]

[0340] An additional active agent may be an ion, free base, salt form, polymorph, hydrate or solvate form, co-crystal, an isotopolog, or an isomer or enantiomerically enriched (non-racemic) mixture (in any proportions).

[0364]

[0341] In embodiments, the additional active agent is a metabolic cofactor. A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme’s role as a catalyst; that is, it increases the rate of a chemical reaction. Metabolic cofactors include those classified as inorganic ions and as complex organic molecules, which also may be referred to as metabolic coenzymes. Broadly, and without being bound by theory, metabolic coenzymes are generally derived from vitamins and other organic essential nutrients.

[0365]

[0342] In embodiments, the additional active agent is a metabolic coenzyme. In embodiments, the metabolic coenzyme is nicotinamide adenine dinucleotide, including as NAD, NAD+, NADH, or a combination thereof. In embodiments, the metabolic coenzyme is a nicotinamide adenine dinucleotide precursor, such as tryptophan (Trp), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinamide (NAM), nicotinic acid (NA), nicotinic acid adenine dinucleotide (NAAD), nicotinic acid mononucleotide (NaMN), and nicotinic acid riboside (NaR). In embodiments, the additional active agent is a methyl donor supplement, such as tri-methyl glycine (e.g., betaine); a NAMPT-activating agent, such as berberine or resveratrol; and an agent that inhibits NAD+ degradation, including a cyclic ADP ribose hydrolase (CD38) inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, or a sterile-a and toll / interleukin 1 receptor motif-containing protein 1 (SARM1) inhibitor. CD38 inhibitors include darzalex and isatuximab. PARP inhibitors include olaparib, rucaparib, niraparib, and talazoparib. SARM1 inhibitors include berberine chloride and zinc chloride. In embodiments, the additional active agent is a coenzyme, such as flavin adenine dinucleotide (FAD) or pyrroloquinoline (PQQ).

[0366]

[0343] In embodiments, the additional active agent is a metabolic energy enhancer, such as a B-complex vitamin, including thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12). In embodiments, the additional active agent is a mineral, such as iodine, sulfur (e.g., dimethyl sulfoxide or methylsulfonylmethane), or magnesium (e.g., as oxide, citrate, or chloride).

[0367]

[0344] In embodiments, the additional active agent is an antioxidant. In embodiments, the antioxidant is any of lutein, glutathione, selenium, a flavonoid (e.g., tangeretin, sudachitin, nobiletin, rutin), an isoflavonoid (e.g., genistein), alpha lipoic acid (ALA), beta-carotene, ubiquinone, lycopene, CoQ10, ellagic acid, retinol, masoprocol, nitric oxide, phenolic compounds, such as catechins, resveratrol, p-coumaric acid, pramipexole, pentoxifylline, anthocyanins (e.g., cyanidin, delphinidin, malvidin, cyanidin-3-glucoside (Cy3g)), allopurinol, dimethylglycine (DMG), dimethyl sulfoxide, probucol, EPI-743, cysteine donors, 3-4-dihydroxinnamic acid, 3-hydroxyanthranilic acid, dihydrolipoic acid, AEOL-10150, melatonin, N-acetylcysteine (NAC), ALC, curcumin, transcrocetinate, L-methylfolate, ascorbic acid, vitamin A, vitamin E, lipoic acid, apigenin, resveratrol, quercetin, nicaraven, isorhamnetin, lodoxamide, ferulic acid, uric acid, idebenone, chromic chloride, thiosulfuric acid, mequinol, hydroquinone, selenic acid, ocopherol, rebamipide, allicin, anisodamine, bucillamine, edaravone, tempol, propyl gallate, apocynin, tocotrienol, hydroxytyrosol, acteoside, tirilazad, chromanol, alpha-tocopherol succinate, alpha-tocopherol acetate, sodium bisulfate, tocopherylquinone, N-N'-diphenyl-1 ,4- phenylenediamine, 4-(lsoproylamino)diphenylamine, turmeric, calcium ascorbate, kojic acid, ebselen, dexpramipexole, gamma-Tocopherol, carvedilol, 2,5-di-tert-butylhydroquinone, cyclo(his-pro), tricetin, t-butylhydroquinone, droloxifene, maritime pine extract, garlic oil, baicalein, silibinin, vitis vinifera seed, d- alpha-tocopherol acetate, sodium ascorbate, magnesium ascorbate, ferrous ascorbate, bisphenol A, acetylcysteine zinc, avasopasem manganese, morin, tyrosol, butyated hydroxytoluene, rosmarinic acid, disufenton, omaveloxolone, sonlicronmanol, and ergothioneine.

[0368]

[0345] In embodiments, the additional active agent is an amino acid, or a derivative thereof. In embodiments, the amino acid, or a derivative thereof, is any of thiamine, arginine, leucine, creatine, and citrulline. In embodiments, the additional active agent is a phenoxyacetic acid derivative, such as bezafibrate. In embodiments, the additional active agent is a cyclohexanone, such as omaveloxolone.

[0369]

[0346] In embodiments, the additional active agent is any of an amino acid, antioxidant, anti-inflammatory agent, anti-hyperglycemic agent, antineuropathic agent, antimigraine agent, analgesic, antinociceptive agent, anxiolytic, antidepressant (e.g., SSRIs, SNRIs, TCAs, MAOIs, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, lithium, bupropion, sertraline, amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, venlafaxine), antipsychotic, anti-PTSD agent, NMDA antagonist, dissociative agent, immunostimulant, anti-cancer agent, antiemetic, orexigenic, antiulcer agent, anticholinergic agent, anti-ischemic agent, antihistamine, anti-craving agent, antibiotic, antihypertensive agent, anticonvulsant (e.g., carbamazepine, oxcarbazepine, lamotrigine, valproic acid, topiramate, levetiracetam, brivaracetam, seletracetam), antiepileptic, bronchodilator, mood stabilizer, cognitive enhancer, neuroprotectant, nootropic, serotonergic agent, neuroactive agent, neurotropic agent, adaptogen, actoprotector, antihypoxant, entheogen, entactogen, empathogen, psychedelic, monoamine oxidase inhibitor (e.g., RIMA), tryptamine, terpene, phenethylamine, sedative, stimulant, opioid modulator, opioid (e.g., fentanyl, methadone, morphine, buprenorphine), phosphodiesterase inhibitor, metabolic or glucose modulator (e.g., metformin), peptide (e.g., elamipretide), enzyme, coenzyme, calcium channel blocker, immunomodulator, immunosuppressant (e.g., macrolides like rapamycin), proton-pump inhibitor, acetate (e.g., dichloroacetate), biguanide, central nervous system agent (e.g., sodium phenylbutyrate / taurursodiol), or antiviral, including protease inhibitors (e.g., Mpro inhibitors, ritonavir, nirmatrelvir, amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir, asunaprevir, boceprevir, grazoprevir, glecaprevir, paritaprevir, simeprevir, telaprevir, GC376, ensitrelvir, simnotrelvir), nucleoside analogues (e.g., remdesivir, ganciclovir, ribavirin, valganciclovir, cidofovir, deuremidevir, obeldesivir, acyclovir), polymerase inhibitors (e.g., RdRp inhibitors, molnupiravir, favilavir, bemnifosbuvir, sofosbuvir), and other antiviral classes, such as uncoating inhibitors, entry inhibitors, integrase inhibitors, neuraminidase inhibitors (e.g., zanamivir, oseltamivir), interferons (e.g., interferon alpha, beta, gamma), integrase strand transfer inhibitors (e.g., dolutegravir), and nucleoside reverse transcriptase inhibitors (e.g., abacavir, lamivudine, zidovudine).

[0370]

[0347] In embodiments, the additional active agent is a serotonergic agent. In embodiments, a “serotonergic agent” refers to any compound that binds to, blocks, or influences (e.g., via an allosteric reaction) activity at a serotonin receptor (5-HT-R), including any 5-HT-R subtype. In embodiments, the serotonergic agent is any of: an agent that binds to a 5-HT-R; an agent that indirectly affects a 5-HT-R, e.g., via interactions affecting the reactivity of other molecules at the 5-HT-R; an agonist, e.g., a compound activating a 5-HT-R; an antagonist, e.g., a compound binding but not activating a 5-HT-R, e.g., blocking a 5-HT-R; an effector molecule, e.g., a compound binding to an enzyme for allosteric regulation; a 5-HT uptake or reuptake inhibitor; or an antidepressant or anxiolytic, such as an SSRI, serotonin-norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MAOI), or atypical antidepressant. In embodiments, the serotonergic agent acts (directly or indirectly) at more than one type of receptor, including receptors other than 5-HT or other monoaminergic receptors. In embodiments, the serotonergic agent blocks the 5-HT transporter (SERT), elevates the synaptic concentration of 5-HT, and increases neurotransmission. In embodiments, the serotonergic agent is a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of 5-HT from the synapse into the presynaptic neuron, leading to an increase in extracellular concentrations of 5-HT and an increase in neurotransmission. In embodiments, the serotonergic agent inhibits the activity of one or both MAO enzymes, increasing concentrations of 5-HT and increasing neurotransmission. In embodiments, the serotonergic agent is selected from any of: (1) serotonin transport inhibitors; (2) serotonin receptor modulators; (3) serotonin reuptake inhibitors; (4) serotonin and norepinephrine reuptake inhibitors; (5) serotonin dopamine antagonists; (6) monoamine reuptake inhibitors; (7) pyridazinone aldose reductase inhibitors; (8) stimulants of serotonin receptors; (9) stimulants of serotonin synthesis; (10) serotonin receptor agonists; (11) serotonin receptor antagonists; and (12) serotonin metabolites.

[0371]

[0348] In embodiments, the additional active agent is any of a phenolic compound, a terpene, a polysaccharide, a polyphenol, a lipid, an organic acid, a polyunsaturated fatty acid (PUFA), an imminosugar, and a tocopherol extracted from fungi, algae, and / or plants. In embodiments, the additional active agent is extracted from genera including any of Cheirolophus, Rhaponticoides, Volutaria, Zingiber, Rosmarinus, Salvia, Thymus, Origanum, Ocimum, Melissa, Mentha, Origanum, Satureja, Hyssopus, Laurus, Bacopa, Bupleurum, Camellia, Berberis, and Lathyrus. In embodiments, the additional active agent is extracted from the genus Zingiber, such as from Zingiber officinale. In embodiments, the additional active agent is extracted from Zingiber officinale rhizomes. In embodiments, the additional active agent is extracted from the genus Lauros, e.g., from Laurus nobilis. In embodiments, the additional active agent is extracted from Laurus nobilis leaves. In embodiments, a disclosed composition comprises an additional active agent from Zingiber, e.g., from Zingiber officinale rhizomes, and an additional active agent from Laurus, e.g., from L. nobilis leaves.

[0372]

[0349] For any disclosed class of agents, additional agents in such class will be known to those in the art, or can be found according to skill in the art, for example, on DrugBank (https: / / go.drugbank.com / ).

[0373]

[0350] In embodiments, the one or more additional active agents may be administered in separate dosage forms or as a single dosage form comprising one or more primary and / or secondary bioactive molecules according to the disclosure in combination with one or more additional active agents.

[0374] V. Pharmaceutical Compositions

[0375]

[0351] In some aspects are disclosed pharmaceutical compositions comprising one or more portion of a combination, or comprising a combination. “Pharmaceutical compositions” (also “compositions” as shorthand, unless context indicates otherwise) comprise one or more portions (including all portions, i.e., a combination) together in an amount (for example, in a unit dosage form) with a pharmaceutically acceptable carrier, diluent, or excipient. Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and / or excipients. Compositions can be prepared by standard pharmaceutical formulation techniques such as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Acad Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; & Poznansky et al. Drug Delivery Sys. (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253-315). “Formulation” as used herein is equivalent to “composition” and “pharmaceutical composition” unless context clearly indicates otherwise.

[0376]

[0352] In embodiments, a composition comprises a non-naturally occurring carrier, diluent, or excipient, examples of which will be known to those in the art. In embodiments, “non-naturally occurring” refers to a carrier, diluent, or excipient that does not naturally occur in a fungus, a plant, and / or an algae, or in any of the same fungi, plants, and / or algae from which any of the portions in the composition are or can be derived.

[0377]

[0353] “Pharmaceutically acceptable” used in connection with an excipient, carrier, diluent, agent, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[0378]

[0354] Compositions 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, lyophilised formulations, tablets, capsules, pills, powders, patches, inhalable formulations, formulations used in nebulizers, pulsatile release formulations, multi-particulate formulations, immediate release formulations, and modified release formulations.

[0379]

[0355] Modified release formulations include controlled release, sustained release, extended release, and mixed immediate release and controlled release formulations. In embodiments, the plasma half-life of a modified release compared to an immediate release formulation is greater 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 in between. In embodiments of modified release formulations, the formulations are designed to result in a comparable area under the curve, or AUCO-24, and a similar safety and efficacy profile, but having 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 in between. In embodiments, a formulation is designed to be a product with a specific time course based on an optimum therapeutic window, such as 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 times in between.

[0380]

[0356] In embodiments, a composition is formulated in a unit dosage form. “Unit dosage form” refers to a physically discrete unit suited as unitary dosages for the subject to be treated, each unit containing a quantity of bioactive molecule to produce desired therapeutic effect(s), and a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms may be used for ease of administration and uniformity of dosage. Unit dosage forms can contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof. Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, which may include a composition in a freeze-dried or lyophilised state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Unit dosage forms include ampules and vials with liquid compositions disposed therein. Unit dosage forms include compounds for transdermal administration, e.g., “patches” that contact the epidermis (including the mucosa) of a subject for an extended or brief period of time.

[0381]

[0357] In embodiments, a composition is formulated in a pharmaceutically acceptable oral dosage form.

[0382]

[0358] In embodiments, a composition is formulated as an oral solid dosage form. Oral solid dosage forms may include but are not limited to, lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. In embodiments, disclosed oral solid dosage forms may be in the form of a tablet (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder), a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In embodiments, a disclosed composition is in the form of a tablet, including a fast-melt tablet. A disclosed composition may be administered as a single capsule or in multiple capsule dosage form. In embodiments, a disclosed composition is administered in two, three, four, or more capsules or tablets.

[0359] Oral solid dosage forms may comprise excipients such as fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, viscosity-increasing agents, film-forming agents, granulation aid, flavoring agents, sweetener, coating agents, solubilizing agents, and combinations thereof; may comprise additives such as a compatible carrier, complexing agent, ionic dispersion modulator, disintegrating agent, surfactant, lubricant, colorant, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, alone or in combination; and may comprise preservatives, antioxidants, and antimicrobial agents, including antibacterial, antiviral, and antifungal agents.

[0383]

[0360] In some embodiments where a solid dosage form comprises multiple portions or bioactive molecules, the dosage form may be formulated to provide different release profiles for each portion or molecule. For example, a tablet may comprise an inner component covered by an outer component. Tablets, pills, and other oral solid dosage forms may be coated or compounded for site specific drug delivery, such as to provide prolonged action. For example, two components can be separated by an enteric layer that serves to resist disintegration and permits the inner component to pass through the stomach intactly or to be delayed in release.

[0384]

[0361] In embodiments, the compositions are formulated as a pharmaceutically acceptable oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. These oral liquid dosage forms may be formulated with any pharmaceutically acceptable excipient known to those of skill in the art for the preparation of liquid dosage forms, and with solvents, diluents, carriers, excipients, and the like chosen as appropriate to the solubility and other properties of the active agents and other ingredients. Solvents include water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof. Oral liquid dosage forms may be monophasic or biphasic. Monophasic liquid forms include syrups, linctuses, spirits / essences, elixirs, and fluid extracts. Biphasic liquid forms include oral suspensions, oral emulsions, and mixtures. Oral liquid dosage forms may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, combinations of pharmaceutically suitable surfactants, suspending agents, and emulsifying agents. In embodiments, liquid formulations also may be prepared as single dose or multi-dose beverages. In embodiments, suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil, as well as carrier oils, such as MCT and long chain triglyceride (LCT) oils. A suspension preparation may comprise esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides; may comprise alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol; glycerol, and propylene glycol; may comprise ethers, such as polyethylene glycol; petroleum hydrocarbons, such as mineral oil and petrolatum; and water; and may be an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.

[0385]

[0362] Oral liquid dosage forms may comprise additives, such as disintegrating agents, dispersing agents, wetting agents, preservatives, viscosity-enhancing agents, sweetening agents, and / or flavoring agents; may comprise inert diluents such as water or other solvents, solubilizing agents, emulsifiers, flavoring agents, and / or sweeteners; and may comprise co-solvents or adjuvants.

[0386]

[0363] In embodiments, a composition is formulated to be absorbed at a specific site within an organism. For example, in some embodiments a tincture is provided to be absorbed by epithelial tissue prior to digestion.

[0387]

[0364] In embodiments, a composition is formulated as an inhaled formulation, such as a soft mist inhaler formulation, a dry powder aerosol formulation, or a vaporizer formulation. In embodiments, the inhaled formulation is a soft mist inhaler formulation or “soft mist” formulation. Soft mist formulations may be produced by combining liquids comprising bioactive molecules in a cartridge or syringe. The cartridge or syringe is placed within a soft mist inhaler device, such as described in W02020 / 167893 and US9108011, both incorporated by reference herein. A solubilizer may be used to assist in homogenizing a formulation (e.g., polysorbate 80 or TWEEN-80). In embodiments, a liquid comprising disclosed bioactive molecules is a liquid extract obtained via any method disclosed herein, and may be with or without a solubilizing agent. In embodiments, the inhaled formulation is a dry powder aerosol formulation, where bioactive molecules are provided as a powder and are aerosolized by an inhaler device, such as a metered dose inhaler (MDI). In embodiments, the inhaled formulation is a vaporizer formulation, such as any of vape juice, e-liquid, e-juice, and the like. In embodiments, the vaporizer formulation is a liquid (including an oil) and / or a solid (including wax and dry powder). In embodiments, the vaporizer formulation is produced by combining a bioactive molecule in a suitable base liquid, the formulation capable of being vaporized by a heating element in or on a vape pen, e-cig, e-pipe, or other such e-smoking device. Examples of suitable liquids include propylene glycol (PG), vegetable glycerin (VG), polyethylene glycol (PEG), and mixtures thereof, in any proportions. In embodiments, the base liquid may contain a liquid of lower viscosity to act as a thinning agent, including water and / or ethanol (including where ethanol is an alcoholic spirit, e.g., vodka). In embodiments, the vaporizer formulation contains a flavorant, which may be any flavor or flavor concentrate.

[0388]

[0365] In embodiments, a composition is formulated as an effervescent powder.

[0389]

[0366] In embodiments, a composition is formulated for transdermal application, including as an ointment, cream, suspension, lotion, paste, gel, spray, foam, oil, and the like, and any combination thereof.

[0390]

[0367] In embodiments, a composition is an injectable formulation, and is formulated for subcutaneous, intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, or intracerebroventricular injection. In embodiments, injectable formulations may be prepared by dissolving, suspending, or emulsifying the primary and / or secondary bioactive molecules in an aqueous or nonaqueous solvent, non-limiting examples of which include oils, such as vegetable oil, synthetic aliphatic acid glycerides, and esters of higher aliphatic acids or propylene glycol; and may also comprise additives such as solubilizers, stabilizers, and suspending, preserving, wetting, emulsifying, dispensing, and isotonic agents. Injectable formulations may comprise additives such as preserving, wetting, emulsifying, and dispensing agents; antibacterial and antifungal agents, such as parabens, benzoic acid, benzyl alcohol, chlorobutanol, phenol, and sorbic acid; and isotonic agents, such as sugars and sodium chloride. Prolonged drug absorption of the injectable form can be provided by using an agent delaying absorption, such as aluminum monostearate or gelatin. Injectable formulations for extended-release via SC or IM injection can avoid first-pass metabolism and lower dosages of the bioactive molecules necessary to maintain desired plasma levels. In such formulations, as in other formulations (e.g., oral), the particle size and range of the particle sizes of the bioactive molecules can be used to control the release of the bioactive molecules by controlling the rate of dissolution, e.g., in fat or muscle.

[0391]

[0368] In embodiments, a composition is formulated for a specific tissue or for a specific route of administration, other than for oral gastrointestinal administration, such as mucosal (e.g., sublingual, buccal, rectal, vaginal, nasal), IV, intramuscular (IM), subcutaneous (SC), cutaneous, intranasal, inhaled, and the like. Such administration, in some embodiments, may result in a reduction of side effects, reduced toxicity, increased efficacy, improved selectivity, enhanced bioavailability, and minimized drug-drug interactions.

[0392]

[0369] In embodiments, a composition is a nanostructured formulation, e.g., a nanoemulsion, nanocapsule, nanoparticle conjugate, or nano-encapsulated oral, sublingual, buccal, or nasal spray. A nanostructured formulation may be prepared according to ordinary skill (see, e.g., Jaiswal et al. 3 Biotech. 2015;5(2): 123-127).

[0393]

[0370] In embodiments, where a composition comprises natural compounds or compounds found in nature, at least one of the carrier(s), diluent(s), and / or excipient(s) used in the combination, composition, or formulation are non-natural or non-naturally-occurring, or other agent(s), such as additional active agent(s), in the disclosed combination, composition, or formulation are non-natural or non-naturally-occurring, i.e., the natural compound(s) are combined with non-natural ingredient(s), so that the combination, composition, or formulation comprises at least one non-natural ingredient, and additionally, in embodiments, provides surprising synergistic effects. Where each of the compounds in a combination, composition, or formulation are natural or are found in nature, the combination, composition, or formulation, and / or the compound(s) therein, in embodiments, will demonstrate markedly different characteristics than than the natural products themselves.

[0394]

[0371] In embodiments, a combination comprises two or more compositions, such as provided in a single kit. In embodiments, a combination comprises more than two compositions. In embodiments, a combination comprises more than three, more than four, more than five, or more than six separate compositions.

[0395]

[0372] Each such composition may be formulated in any suitable dosage form, such as a dosage form disclosed herein. In exemplary embodiments, one or more portions of a combination are provided as an inhalable formulation, such as for a soft mist inhaler, and the other portions of the combination are provided as a tincture. In embodiments, one or more portions of a combination are provided as an inhalable formulation, and the other portions of the combination are provided as an oral dissolving strip. In embodiments, one or more portions of a combination are provided as a tincture, and the other portions of the combination are provided as an oral dissolving strip. In embodiments, one or more portions of a combination are provided as an inhalable formulation, and the other portions of the combination are provided as an oral spray, such as an oral mucosal spray. In embodiments, one or more portions of a combination are provided as a tincture, and the other portions of the combination are provided as an oral spray.

[0373] By way of non-limiting and merely suggestive example, certain formulations may be prepared as described herein, and may be used in the disclosed methods. Other formulations will be readily appreciated.

[0396]

[0374] In all disclosed exemplary formulation embodiments, the formulation may solely comprise a bioactive molecule from a fungus and a bioactive molecule from a plant (where “solely comprise” refers to no additional disclosed bioactive molecules, although a 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 solely comprise a bioactive molecule from a single genus of fungus and a bioactive molecule from a single genus of plant (where the molecule(s) are extracted, isolated, derived, or otherwise obtained from a single genus, not necessarily only found in one genus). In embodiments, the formulation may solely comprise a bioactive molecule from a single species of fungus and a bioactive molecule from a single species of plant (where the molecule(s) are extracted, isolated, derived, or otherwise obtained from a single species, not necessarily only found in one species). In embodiments, the formulation may solely comprise one bioactive molecule from a fungus and one bioactive molecule from a plant.

[0397]

[0375] In embodiments, a formulation may solely comprise a bioactive molecule from a psilocybin-producing species, and a bioactive molecule from a Cannabis plant (as shorthand, “from Cannabis"). In embodiments, a formulation may solely comprise a bioactive molecule from P. azurescens, P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. cubensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrill- osa, or P. liniformans, and a bioactive molecule from Cannabis. In embodiments, a formulation may solely comprise one bioactive molecule from a psilocybin-producing species, and one bioactive molecule from Cannabis. In embodiments, a formulation may solely comprise one bioactive molecule 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, and one bioactive molecule from Cannabis. In embodiments, a formulation may solely comprise a bioactive molecule from a Psilocybe fungus (i.e., a Psilocybe spp. fungus), and a bioactive molecule from Cannabis. In embodiments, a formulation may solely comprise one bioactive molecule from a Psilocybe fungus, and one bioactive molecule from Cannabis.

[0398]

[0376] For example, each of the below embodiments may be made with psilocybin (or psilocin) only, or both; with CBD (or THC) only, or both; and with each of coumarin, whole Pyropia extract, and ethanol and ginger (and any other disclosed active or inactive ingredients) optional, i.e., in some embodiments any one or more of coumarin, whole Pyropia extract, and ethanol and a flavorant and / or colorant such as ginger (and any other disclosed active or inactive ingredients) may not be included. Accordingly, in embodiments, the exemplary formulation solely comprises psilocybin and CBD. In embodiments, the exemplary formulation solely comprises psilocin and CBD. In embodiments, the exemplary formulation solely comprises psilocybin, psilocin, and CBD. In embodiments, the exemplary formulation solely comprises psilocybin, THC, and CBD. In embodiments, the exemplary formulation solely comprises psilocin, THC, and CBD. In embodiments, the exemplary formulation solely comprises psilocybin, psilocin, and THC. In embodiments, the exemplary formulation solely comprises psilocybin and THC. In embodiments, the exemplary formulation solely comprises psilocin and THC. As above, “solely comprises” refers to no additional disclosed bioactive molecules, although a formulation may further comprise one or more carriers, diluents, or excipients, other inactive ingredients, and / or in embodiments, additional active agents as disclosed, or as otherwise appropriate to the formulation, such as known in the art.

[0377] In embodiments, any one or more of psilocybin, psilocin, THC, and CBD may be replaced with another bioactive molecule, such as another bioactive molecule from the same fungus or same plant. In embodiments, a flavorant and / or colorant (equivalently and as shorthand “flavorant / colorant”) is optional. Accordingly, any of the below examples without a flavorant / colorant is an additional embodiment. In embodiments, the “flavorant / colorant” in an example is ethanol and ginger. In embodiments, a formulation comprises an additional active agent. Where an active and / or inactive ingredient from a disclosed exemplary formulation is not present, the formulation will be prepared as described, together with general skill and knowledge in the art, and with such modifications as will be appreciated by ordinary artisans. Where an ingredient may be provided as a solid or as a liquid, one of skill will appreciate how to convert between mass amounts and volume amounts, including for ingredients, whether as a solid or a liquid, of an alternate or variable concentration.

[0399] EXAMPLE 1: Tincture formulation

[0400]

[0378] A tincture is prepared with proportions provided in Table 1 below, Tincture Preparation Proportions:

[0401]

[0379] The solution is prepared by combining the isolated bioactive molecules from a fungus, a plant, and an algae, and / or extracts comprising them (“bioactive molecules and / or extracts comprising them”) with a flavoring agent and a solvent. In embodiments, an amount or a proportion of an ingredient, such as when expressed as a mass or as a percentage, includes the term “about.” In embodiments, “about” a mass or “about” a percentage, including where the term “about” is implied by the context, refers to a range of ± 2%. Thus for example, in embodiments where psilocybin (or a psilocybin-containing fungal extract) is 45% of a formulation, it will be understood that the amount in embodiments refers to psilocybin or a psilocybin-containing extract of “about” 45%, and in some such embodiments, an amount of “about” 45% refers to an amount of 45% ± 2%, i.e., between 43% and 47% of psilocybin or a psilocybin-containing extract, inclusive. In some other embodiments, an amount, such as expressed as a mass or a percentage, will also refer to “about” that amount, with “about” having the meaning as elsewhere described.

[0402]

[0380] In embodiments, a fungal extract comprises about 45% of each dose, and contains about 400 pg of combined psilocybin and psilocin per dose; a Cannabis extract comprises about 15% of each dose, and contains about 1 mg CBD and about 1 mg THC per dose; a cumaru extract comprises about 2% of each dose, and contains about 1 mg of coumarin per dose; and an algal extract, which in embodiments is a Pyropia extract, comprises about 15% of each dose; the flavorant and / or colorant, which in some embodiments is ethanol infused with ginger and bay leaf, 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 constitutes about 8% of each dose. In embodiments, a tincture or other liquid formulation further comprises a solubilizing agent, such as a cyclodextrin, lecithin, propylene glycol, xanthan gum, or a combination thereof.

[0403]

[0381] Tinctures may be prepared by exposing fungal, plant, and / or algal matter to a solvent capable of extracting the desired primary and / or secondary bioactive molecules, combining the extracts, and then optionally adding a flavorant and / or coloring agent.

[0404]

[0382] In embodiments, the solvent is an alcohol. In embodiments, the alcohol may be, e.g., 40% to 60% ethanol, or may be 80% to 90% ethanol, and then diluted to between 40% and 60% ethanol. In embodiments, the solvent is water. In embodiments, the solvent may be an acid, for example, acetic acid.

[0405]

[0383] As an example, food coloring may be added to the tincture in order to provide a certain appearance to the solution and may contain additional compounds sufficient to improve the taste of the tincture. In embodiments, the food coloring may comprise a compound which improves the biological activity of the primary and / or secondary bioactive molecules. Examples of suitable food coloring for use with disclosed extracts, compositions and tinctures include turmeric extracts, cinnamon extracts, beetroot extracts, carrot extracts, caramel, blueberry extracts, blackberry extracts, and ginger extracts.

[0406]

[0384] In embodiments, a subject will be administered, on a daily basis, one dose of a tincture having ingredients in the amounts as formulated above, two doses of a tincture in the amounts as formulated above, three such doses, four such doses, five such doses, or greater than five such doses daily. In some embodiments, a daily dosage amount is four such doses.

[0407] EXAMPLE 2: Oral spray and oral mucosal spray formulation

[0408]

[0385] An oral spray is prepared comprising the same ingredients, quantities (units) of ingredients, and overall proportions as in EXAMPLE 1 (Table 1). Where an oral spray is formulated for oral mucosal (e.g., sublingual or buccal) administration, it may further comprise a penetration enhancer and / or a mucoadhesive polymer, such as in proportions as will be known in view of the disclosure and the general knowledge in the art.

[0409] EXAMPLE 3: Soft mist inhaler formulation

[0410]

[0386] A soft mist inhaler formulation is prepared as follows, comprising the same ingredients, quantities (units) of ingredients, and overall proportions as in EXAMPLE 1 (Table 1) above: The solution is prepared by combining the bioactive molecules from a fungus, a plant, and an algae, and / or extracts comprising them with the flavorant / colorant and the solvent. The bioactive molecules and / or extracts comprising them are mixed and combined, and then may be further combined with ethanol and / or water, and an optional added preservative, for example, benzalkonium chloride, to a suitable volume, for example, 15 mL. Reference may be made to Anderson. Int J Chron Obstruct Pulmon Dis. 2006;1 (3):251-259 and Dalby et al. Med Devices (Auckl). 2011 ;4:145-155, both of which are incorporated by reference herein in their entirety.

[0411] EXAMPLE 4: Vaporizer formulation

[0412]

[0387] A vaporizer formulation, comprising 500 pg psilocybin, 300 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 16 mg whole Pyropia extract, 16 mg flavorant / colorant, and 10 mL 50:50 base liquid (50% PG, 50% VG), is prepared as follows: The bioactive molecules and / or extracts comprising them are mixed and combined (in solid form, and / or as part of one or more liquid extracts) with the 50:50 base liquid prepared for use with any liquid vaporization device or appliance, such as e-liquid vaporizers, e-cigs, mods, vape pens, and the like. A flavorant / colorant (e.g., comprising ginger and / or bay laurel) optionally may be added. The formulation also can be prepared for any oil, thin oil, e-juice, or e-liquid vaporizer, according to ordinary skill.

[0413] EXAMPLE 5: Tablet and scorable double-strength tablet formulation

[0414]

[0388] Tablets comprising 500 pg psilocybin, 300 pg psilocin, 1 mg CBD, 1 mg THC, 1 mg coumarin, 16 mg whole Pyropia extract, 170 mg microcrystalline cellulose, 10 mg colloidal silicon dioxide, and 7.5 mg stearic acid are prepared by blending the bioactive molecules and / or extracts comprising them together with the other ingredients, and compressing it to form tablets. Scorable double strength tablets comprising 1000 pg psilocybin, 600 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 32 mg whole Pyropia extract, 35 mg microcrystalline cellulose, 45 mg starch, 4.5 mg sodium carboxymethyl starch, 0.5 mg magnesium (Mg2+) stearate, 1 mg talc, and 4 mg polyvinylpyrrolidone (PVP) (as 10% solution in water), 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 solution of PVP is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules are dried at 50-60° C and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, Mg2+stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are added to the granules which, after mixing, are compressed on a tablet machine to yield tablets. Tablets are scored to provide an ability to create equal half doses.

[0415] EXAMPLE 6: Capsule formulation

[0416]

[0389] Capsules, each comprising 500 pg psilocybin, 300 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 16 mg whole Pyropia extract, 119 mg cellulose and / or starch, and 1 mg magnesium stearate are made by blending the bioactive molecules and / or extracts comprising them, together with the 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. EXAMPLE 7: Alternate capsule formulation, optionally with additional active agent(s)

[0417]

[0390] Capsules, each comprising 1000 pg psilocybin, 600 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 16 mg whole Pyropia extract, 50 mg serotonergic agent, 100 mg cellulose and / or starch, and 1 mg magnesium stearate are made as follows: The bioactive molecules and / or extracts comprising them, cellulose and / or starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard or soft gelatin capsules. Optionally, an additional active agent may be added during blending. In embodiments, the additional active agent is a serotonergic agent, such as an antidepressant or an anxiolytic. In embodiments, the additional active agent is an antioxidant, as disclosed herein or generally known in the art.

[0418] EXAMPLE 8: Suspension formulation

[0419]

[0391] A suspension, comprising 250 pg psilocybin, 150 pg psilocin, 1 mg CBD, 1 mg THC, 1 mg coumarin, and 8 mg whole Pyropia extract is made as follows: The bioactive molecules and / or extracts comprising them are blended together with 1.75 g sucrose and 4 mg xanthan gum, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of 50 mg sodium carboxymethyl cellulose (11 %) and 50 mg microcrystalline cellulose (89%) in water. 10 mg sodium benzoate and optional flavorant / colorant q.s. to taste, are diluted with a volume of water and added with stirring. Sufficient water is then added to make 5 mL.

[0420] EXAMPLE 9: Intravenous solution formulation

[0421]

[0392] An intravenous formulation, comprising 250 pg psilocybin, 150 pg psilocin, 1 mg CBD, 1 mg THC, 1 mg coumarin, 8 mg whole Pyropia extract, and 1 ,000 mL isotonic saline, may be prepared as follows: The bioactive molecules and / or extracts comprising them are dissolved in appropriate solvent, such as isotonic saline or another suitable solvent; additional active or inactive ingredients such as solubilizers and preservatives may be added, as otherwise described above, and within the general knowledge of the art. It will be understood that the amount of each bioactive molecule and / or extract can be adjusted accordingly to reach the desired mg / mL.

[0422] EXAMPLE 10: Injectable solution formulation

[0423]

[0393] An injectable formulation, comprising 250 pg psilocybin, 150 pg psilocin, 1 mg CBD, 1 mg THC, 1 mg coumarin, 8 mg whole Pyropia extract, and 5 mL isotonic saline, may be prepared as follows: The bioactive molecules and / or extracts comprising them are dissolved in appropriate solvent, such as isotonic saline or another suitable solvent; additional active or inactive ingredients such as preservatives may be added, as otherwise described above, and within the knowledge in the art. It will be understood that the amount of each bioactive molecule and / or extract can be adjusted accordingly to reach the desired mg / mL.

[0424] EXAMPLE 11: Topical formulation for transdermal administration

[0425]

[0394] A topical formulation, comprising 400 pg psilocybin, 250 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 8 mg whole Pyropia extract, 30 mg emulsifying wax, 20 mg liquid paraffin, in an amount of white soft paraffin to equal 100 g total, may be prepared as follows: White soft paraffin is heated until molten. Liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. Bioactive molecules and / or extracts comprising them are added and stirring is continued until dispersed. The mixture is then cooled until solid. To aid solubility and penetration, penetration enhancers, solubilizes, and other excipients such as DMSO, oleic acid, PEG, and the like may be used, as also described herein and as known to those of skill in view hereof.

[0426] EXAMPLE 12: Cut matrix sublingual or buccal tablet formulation

[0427]

[0395] Sublingual or buccal tablets, comprising 500 pg psilocybin, 300 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 8 mg whole Pyropia extract, 210.5 mg glycerol, 143 mg water, 4.5 mg sodium citrate, 26.5 mg polyvinyl alcohol, and 15.5 mg polyvinylpyrrolidone (PVP), are made as follows: The glycerol, water, sodium citrate, polyvinyl alcohol, and PVP are admixed by continuous stirring while maintaining a temperature of about 90 °C. When the polymers have gone into solution, the solution is cooled to about 50-55 °C and the bioactive molecules and / or extracts comprising them are slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. The diffusion matrix is then cut to form individual tablets of the appropriate size.

[0428] EXAMPLE 13: Individually formed sublingual or buccal lozenge formulation

[0429]

[0396] Sublingual or buccal lozenges, comprising 500 pg psilocybin, 300 pg psilocin, 2 mg CBD, 2 mg THC, 2 mg coumarin, 8 mg whole Pyropia extract, 350 mg silica gel powder, 400 mg citric acid powder, 600 mg acacia powder, 1 g polyethylene glycol (PEG), and optionally 100 mg flavorant / colorant, are made as follows: The silica gel powder, citric acid powder, acacia powder, optional flavorant / colorant, and PEG are mixed by continuous stirring at a temperature of about 90 °C. When the PEG has melted and the other ingredients have gone into solution, the solution is cooled to about 50-55 °C and the bioactive molecules and / or extracts comprising them are slowly admixed. The homogenous mixture is poured into separate molds and allowed to cool. Reference may also be made to the incorporated U.S. Patent No. 10,034,832 and the Examples therein.

[0430] EXAMPLE 14: Intranasal delivery formulation

[0431]

[0397] A nasal spray formulation for intranasal delivery, comprising 250 pg psilocybin, 150 pg psilocin, 1 mg CBD, 1 mg THC, 1 mg coumarin, 8 mg whole Pyropia extract, 50 pL DMSO, 5 mL MCT, in saline (1 % cremophor) to a total formulation of 10 mL, may be prepared as follows: The solution at approximately 1 mg / mL of bioactive molecules and / or extracts comprising them in 49.5% MCT, 49.5% saline, 0.5% DMSO, and .5% cremophor is prepared for use in nasal spray device. In other embodiments, a nasal formulation can be prepared as a dry powder for inhalation, e.g., by combining the bioactive molecules and / or extracts comprising them with lactose and mixing for use with a dry powder inhaling appliance, or as in U.S. Pub. No. US2015 / 0367091 A1 and references cited therein.

[0432]

[0398] In some exemplary embodiments, a combination or composition comprises the primary bioactive molecules in the tables below (Tables 3-5), from each listed component of the combination or composition, and such combination or composition may be formulated according to any of the disclosed Examples, or as another exemplary formulation according to the disclosure and general knowledge in the art:

[0433] TABLE 3: Primary Bioactive Molecules in a Therapeutic Combination from C. sativa

[0434] TABLE 4: Primary Bioactive Molecules in a Therapeutic Combination from P. cubensis

[0435] TABLE 5: Primary Bioactive Molecules in a Combination from D. odorata and P. yezoensis

[0436]

[0399] While certain primary and / or secondary bioactive molecules, and certain extracts comprising them, are disclosed, this should not be construed as limiting the disclosure, nor should it be construed as limiting the formulation of EXAMPLE 1 (Table 1) to the primary and / or secondary bioactive molecules disclosed above. Thus, in embodiments, the formulation of EXAMPLE 1 (or any other Example herein) contains additional, or fewer, primary and / or secondary bioactive molecules than are disclosed; including any of the primary and / or secondary bioactive molecules disclosed herein for each of the fungal, Cannabis, cumaru, and algal extracts.

[0437]

[0400] In some alternative embodiments of this Example, the formulation comprises at least one bioactive molecule from a fungus, and at least one bioactive molecule from a plant, the bioactive molecule(s) from fungi comprising those from a psilocybin-producing species, such as from the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, and Pluteus, and the bioactive molecule(s) from plant(s) comprising those from a cannabinoid-producing species, such as from the genus Cannabis. In some such alternative embodiments, the formulation comprises no further bioactive molecule(s) from fungi and bioactive molecule(s) from plant(s) except for those from a psilocybin-comprising species and from a cannabinoid- producing species. In some such alternative embodiments, the formulation comprises no further bioactive molecule(s) from fungi and bioactive molecule(s) from plant(s) except for those from the genera Copelandia, Galerina, Gymnopilus, Inocybe, Panaeolus, Pholiotina, and Pluteus, and from the genus Cannabis. In some such alternative embodiments, the formulation comprises no bioactive molecules from the genus Dipteryx. In some such alternative embodiments, the formulation comprises no bioactive molecules from algae, a marine algae, the family Bangiaceae, 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.

[0438]

[0401] It will be appreciated that the above formulation examples are illustrative only. Any of the disclosed primary and / or secondary bioactive molecules may be used in the formulation examples, in a dosage range applicable for said primary and / or secondary bioactive molecules. It will be understood that reference to a particular primary and / or secondary bioactive molecule is merely illustrative, and bioactive molecules in any Example may be substituted by other primary and / or secondary bioactive molecules disclosed herein.

[0439]

[0402] It will be readily appreciated that compositions are not limited to combinations of a single primary and / or secondary bioactive molecule, or (when formulated as a composition) limited to a single carrier, diluent, and / or excipient, but may include multiple primary and / or secondary bioactive molecules (including additional bioactive molecules), and / or multiple carriers, diluents, and excipients. Compositions may comprise any disclosed primary and / or secondary bioactive molecules. In embodiments, a composition may comprise a primary and / or secondary bioactive molecule from a fungus, a plant, and an algae, optionally together with one or more other bioactive molecules (or a derivative or analog) in combination, together with one or more pharmaceutically acceptable carriers, diluents, and / or excipients, and with one or more other active agents.

[0440]

[0403] The type of formulation employed for the administration of the disclosed primary and / or secondary bioactive molecules employed in the methods generally may be dictated by the primary and / or secondary bioactive molecule(s) employed, the type of pharmacokinetic profile desired from the route of administration and the primary and / or secondary bioactive molecule(s), and the state of the subject. It will be appreciated that any of the above embodiments also be combined to form additional embodiments.

[0441] A. Routes of Administration

[0442]

[0404] 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, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, vaginal, ocular, nasal, cutaneous, topical, otic, ocular, transdermal, and subcutaneous administration.

[0443]

[0405] In embodiments, a composition is administered as an oral solid or liquid dosage form; sublingually or buccally; as an injection (e.g., IV, intra-arterial, IP, intraosseous, IM, intrathecal, and intracerebroventricular); rectally, vaginally, ocularly, nasally, cutaneously, topically, oticly, transdermally, and subcutaneously.

[0444]

[0406] In embodiments, in which administration is enteral, parenteral, or both, an effective amount of a primary and / or secondary bioactive molecule is systemically administered to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered orally, intravenously, nasally, via inhalation, via injection, topically (dermally), ophthalmically, or rectally to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is intravenously administered to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered by inhalation to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered by nasal administration to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered by injection to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered topically (dermally) to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered by ophthalmic administration to a subject. In embodiments, an effective amount of a primary and / or secondary bioactive molecule is administered rectally to a subject. In embodiments, the primary and / or secondary bioactive molecules disclosed herein and employed in the methods described herein are effectively administered to a subject via other means, and prepared as any acceptable composition known to those of skill. In embodiments, such compositions may be prepared in any manner known in the pharmaceutical arts that comprise at least one bioactive molecule (Sheth et al. Compressed tablets. In: Pharmaceutical Dosage Forms: Tablets Eds. H.A. Lieberman and L. Lachman. Vol. 1. 1980. 109. Marcel Dekker).

[0445]

[0407] In embodiments, the bioactive molecules disclosed herein are administered by multiple routes, which may differ between subjects, such as a patient, according to subject preferences, comorbidities, side effect profiles, pharmacokinetic and pharmacodynamic considerations, and other factors. In embodiments are the presence of other substances with the primary and / or secondary bioactive molecules, known to those skilled in the art, such as modifications in the preparation to facilitate absorption through various routes (e.g., gastrointestinal, transdermal, etc.), to extend the effect of the drugs, and / or attain higher or more stable serum levels or enhance the therapeutic effect of the primary and / or secondary bioactive molecules disclosed herein.

[0408] In embodiments, a composition is administered via enteral or parenteral routes. Enteral administration includes, but is not limited to, oral solid or liquid dosage forms, sublingual, buccal, and rectal administration. Parenteral administration, but is not limited to, includes bolus injection or continuous infusion via intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, vaginal, ocular, nasal, cutaneous, topical, otic, transdermal, and subcutaneous routes. In embodiments, parenteral administration includes injections, which comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, emulsions, liposomes, or sterile powders for reconstitution into injectable solutions or dispersions, in addition to other equivalent administration methods known to those of skill.

[0446]

[0409] In embodiments, a pharmaceutical composition is administered to a subject via injection. In embodiments, a pharmaceutical composition is administered to a subject via nasal systems or the mouth through, for example, an oral solid and / or oral liquid dosage forms; inhalation, via a nasal spray or oral inhaler; nebulization, from a nebulizer, such as a machine that turns liquid medicine into a mist; or buccally / sublingually. In embodiments, a pharmaceutical composition is administered to a subject via a combination of administration means. In embodiments, the pharmaceutical composition is administered to a subject via an enteral administration means. In embodiments, the pharmaceutical composition is administered to a subject via a parenteral administration means. In embodiments, the composition is administered to a subject via at least one enteral administration means, and at least one parenteral administration means. In embodiments, an equivalent route of administration known to one of skill is used.

[0447]

[0410] In embodiments, the portions in a combination are administered via multiple routes of administration. For example, in embodiments, the fungal portion of a combination is administered via one route of administration, and the plant portion(s) and algal portion are administered via a different route of administration. In embodiments, the plant portion(s) of a combination is / are administered via one route of administration, and the fungal and algal portions are administered via a different route of administration. In embodiments, the algal portion of a combination is administered via one route of administration, and the plant portion(s) and fungal portion are administered via a different route of administration.

[0448]

[0411] Administration of different (fungal, plant, or algal) portions of a combination to different tissues may in embodiments maximize one or more therapeutic effects of the combination, result in reduction of side effects, reduction of patient discomfort, and / or increase in bioavailability. In an example, a combination comprising a plant portion comprising a cannabinoid (e.g., THC) or a Cannabis extract, which is administered to the oral mucosa via spray; while other portions (e.g., fungal, algal, and / or other plant portions) are delivered to epithelial cells in the lung via a soft-mist inhaler. In some such embodiments, administration results in reduced throat irritation (e.g., in individuals sensitive to inhaling Cannabis or cannabinoids), maximizes bioavailability for the other ingredients (e.g., fungal, algal, and / or other plant portions), and improves the pharmacokinetic profiles of the components of the combination; for example, by expediting the uptake of the longer-lasting plant portion (e.g., the THC or Cannabis extract) while moderating the uptake of shorter-lasting portions.

[0412] In another example, a combination comprises an algal portion comprising Pyropia or a Pyropia extract, which is administered to the oral mucosa via oral spray; while remaining ingredients (e.g., fungal, plant, and / or algal portions) are delivered to epithelial cells in the lungs via soft-mist inhaler. In embodiments, administration according to this exemplary procedure results in reduced throat irritation, maximizes bioavailability of ingredients (e.g., fungal, plant, and / or algal portions), and improves the pharmacokinetic profiles of the components of the combination; for example, by expediting the uptake of the long-lasting portions while moderating the uptake of the shorter-lasting algal portion (e.g., the Pyropia or Pyropia extract).

[0449] B. Methods of Administration

[0450]

[0413] In some aspects, provided are methods of administration or methods of administering a primary and / or secondary bioactive molecule disclosed herein. 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 one who has an indication for which a disclosed combination may be efficacious, or who otherwise may benefit thereby. In general, all of the disclosed combinations, compositions, and methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.

[0451]

[0414] Provided are methods for using therapeutically effective amounts of disclosed combinations with a mammal, preferably a human. Such methods include treating or preventing mitochondrial, metabolic, autoimmune, pain, mental health, endocrine, viral, and degenerative disorders, including in healthy individuals.

[0452]

[0415] Administration of a composition in an “effective” or “therapeutically effective” dose or amount refers to a dose or amount sufficient to provide a desired therapeutic effect, for example, relieving a symptom of a disorder being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease or disorder, or any other desired alteration of a biological system. A “therapeutically effective amount” includes, in some embodiments, a prophylactically effective amount. A “pharmacologically effective amount” refers to an amount sufficient to provide a biochemical or physiological response indicative of efficacy.

[0453]

[0416] An “effective amount,” such as of a bioactive molecule, refers to an amount sufficient to achieve a desired pharmacological or therapeutic effect, for example a meaningful therapeutic improvement, or a response after treatment judged to be desirable and beneficial. The effective amount may vary based on factors including the subject’s metabolism, age, weight, overall health, the condition being treated, the severity of the condition, the route of administration, pharmacogenomic factors, such as the subject’s genotype and its impact on pharmacokinetics, pharmacodynamics, or therapeutic efficacy. One skilled in the art can readily determine the appropriate effective amount based on these considerations and on clinical judgment.

[0454] 1. Dosing

[0455]

[0417] Dosages may vary depending upon whether a treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional, or local side effects, the presence of comorbid conditions, medical and familial history, and other factors appreciated by one in the art.

[0456]

[0418] In all embodiments that include dose amounts of less than about 1 mg, such amounts include further specific dose amounts 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.

[0457]

[0419] When referring to an amount of “a single dose,” the single dose may be in such an amount irrespective of whether or not the dose is present in a single unit dosage form, and may be in more than one dosage form.

[0458]

[0420] In all embodiments that include dose amounts of at least about 1 mg or more, up to and including about 75 mg, such amounts include further specific dose amounts of (with all such milligram dose amounts to be understood also 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, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg,

[0459] 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg,

[0460] 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, as well as amounts within these ranges.

[0461]

[0421] In all embodiments that include dose amounts of 75 mg, as well as greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg, such amounts include further specific dose amounts of 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, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg,

[0462] 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg,

[0463] 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg,

[0464] 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, and 200 mg. Such dose amounts additionally include amounts within these ranges, and in all such embodiments, a single dose moreover may be greater than 200 mg, including 225 mg, 250 mg, or greater than 250 mg.

[0465]

[0422] In some embodiments where a combination comprises a bioactive molecule from a fungus, it is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0466]

[0423] In some embodiments where a combination comprises a bioactive molecule from a fungus, it is present in an amount so that a single dose is about 100 pg or less, (including 95 pg, 90 pg, 85 pg, 80 pg, 75 pg, 70 pg, 65 pg, 60 pg, 55 pg, 50 pg, 45 pg, 40 pg, 35 pg, 30 pg, 25 pg, 20 pg, 15 pg, 10 pg, 5 pg, and 5 pg or less), or at least about 100 pg, or more, and greater than 1 ,000 pg, including 1 ,500 pg, 2,000 pg, up to and including 5,000 pg, and in embodiments, greater than 5,000 pg.

[0467]

[0424] In some embodiments where the bioactive molecule from a fungus is psilocybin, psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, or a p-carboline, it is present in an amount so that a single dose is about 100 pg or less, at least about 100 pg, or more, and greater than 1 ,000 pg, including 1 ,500 pg, 2,000 pg, up to and including 5,000 pg.

[0468]

[0425] In embodiments, the primary bioactive molecule from a fungus is psilocybin. In embodiments, the psilocybin is present in an amount so that a single dose is between about 10 and 1000 pg, 50 and 500 pg, 100 and 400 pg, or 200 and 300 pg. In embodiments, a single dose of psilocybin is about 250 pg.

[0469]

[0426] In embodiments, the primary bioactive molecule from a fungus is psilocin. In embodiments, the psilocin is present in an amount so that a single dose is between about 10 and 500 pg, 20 and 300 pg, 20 and 200 pg, or 100 and 200 pg. In embodiments, a single dose of psilocin is about 150 pg.

[0470]

[0427] In some embodiments where the 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, choline, or a lactone, it is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0471]

[0428] In all embodiments that include dose amounts of about 100 pg or less, such embodiments include further specific dose amounts including about 95 pg, 90 pg, 85 pg, 80 pg, 75 pg, 70 pg, 65 pg, 60 pg, 55 pg, 50 pg, 45 pg, 40 pg, 35 pg, 30 pg, 25 pg, 20 pg, 15 pg, 10 pg, 5 pg, and about 5 pg or less.

[0472]

[0429] In all embodiments that include dose amounts of at least about 100 pg, or more, and greater than

[0473] 1 ,000 pg, including 1 ,500 pg, 2,000 pg, up to and including 5,000 pg, such embodiments include further specific dose amounts including 110 pg, 120 pg, 130 pg, 140 pg, 150 pg, 160 pg, 170 pg, 180 pg, 190 pg, 200 pg, 210 pg, 220 pg, 230 pg, 240 pg, 250 pg, 260 pg, 270 pg, 280 pg, 290 pg, 300 pg, 310 pg, 320 pg,

[0474] 330 pg, 340 pg, 350 pg, 360 pg, 370 pg, 380 pg, 390 pg, 400 pg, 410 pg, 420 pg, 430 pg, 440 pg, 450 pg,

[0475] 460 pg, 470 pg, 480 pg, 490 pg, 500 pg, 510 pg, 520 pg, 530 pg, 540 pg, 550 pg, 560 pg, 570 pg, 580 pg,

[0476] 590 pg, 600 pg, 610 pg, 620 pg, 630 pg, 640 pg, 650 pg, 660 pg, 670 pg, 680 pg, 680 pg, 700 pg, 710 pg,

[0477] 720 pg, 730 pg, 740 pg, 750 pg, 760 pg, 770 pg, 780 pg, 790 pg, 800 pg, 810 pg, 820 pg, 830 pg, 840 pg,

[0478] 850 pg, 860 pg, 870 pg, 880 pg, 890 pg, 900 pg, 910 pg, 920 pg, 930 pg, 940 pg, 950 pg, 960 pg, 970 pg,

[0479] 980 pg, 990 pg, and 1000 pg, as well as in some embodiments, greater than 5,000 pg.

[0480]

[0430] In some embodiments where the combination comprises a bioactive molecule from a plant, it is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0481]

[0431] In embodiments, the bioactive molecule from a plant is a cannabinoid. In embodiments, the cannabinoid is THC. In embodiments, the THC is present in an amount so that a single dose is between about 0.1 and 5 mg, 0.5 and 2 mg, or between about 0.5 and 1.5 mg. In embodiments, the THC is present in an amount so that a single dose is about 1 mg. In embodiments, the cannabinoid is CBD. In embodiments, the CBD is present in an amount so that a single dose is between about 0.1 and 5 mg, 0.5 and 2 mg, or between about 0.5 and 1 .5 mg. In embodiments, the CBD is present in an amount so that a single dose is about 1 mg.

[0482]

[0432] In some embodiments where the bioactive molecule from a plant is a cannabinoid (e.g., THC, CBD), coumarin, or a coumarin derivative (e.g., a phenylpropanoid, coumarin, or coumarinoid), is is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg. In embodiments, the primary bioactive molecule from a plant is coumarin. In embodiments, the coumarin is present in an amount so that a single dose is between about 1 and 10 mg, 0.1 and 10 mg, 0.1 and 5 mg, 0.5 and 2 mg, or between about 0.5 and 1.5 mg. In embodiments, the coumarin is present in an amount so that a single dose is about 1 mg.

[0483]

[0433] In some embodiments where the bioactive molecule from a plant is a flavone or a flavonoid, a terpene or a terpenoid, a carbohydrate, a fatty acid or fatty acid ester (FAE), an amide, an amine, a phytosterol, a phenolic compound, cumaru, an isoflavone, a lupeol derivative, (±)-balanophonin, (-)-lariciresinol, 3'-hydroxy- retusin-8-methyl-ether, 5-methoxyxanthocercin A, 6,4'-dihydroxy-3'-methoxy- aurone, 7-hydroxychromone, 7,3'-dihydroxy-8,4'-dimethoxyisoflavone, betulin, butin, coumaric-acid-beta- glucoside, dipteryxin, dipteryxic acid, eriodictyol, ferulic-acid, isoliquiritigenin, lupeol, melilotoside, melilotoside- 1-p-coumaryl-beta-d-glucose, methyl-linolenate, methyl-oleate, O-coumaricacid, 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'-tri hydroxyflavone, luteolin, or umbelliferone, it is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0484]

[0434] In some embodiments where the combination comprises a bioactive molecule from an algae, the it is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0485]

[0435] In embodiments, the bioactive molecule from an algae is a primary bioactive molecule from a species in the genus Pyropia or Porphyra. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is porphyran or oligo-porphyran, a polysaccharide, an oligo-polysaccharide, a monosaccharide, a peptide, a phycobiliprotein, a mycosporine-like amino acid, an essential amino acid, a nonessential amino acid, a carotene or intermediate carotenoid, a glycoprotein, taurine, or an amino sulfonic acid, and is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose may be > 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is present in an amount so that a single dose is between about 1 and 20 mg. In embodiments, the primary bioactive molecule from Pyropia or Porphyra is present in an amount so that a single dose is about 8 mg.

[0486]

[0436] In some embodiments where a combination comprises P. yezoensis extract, the extract is present in an amount so that a single dose is between about 1 and 20 mg, 1 and 10 mg, or between about 5 and 10 mg. In embodiments, the P. yezoensis extract is present in an amount so that a single dose is about 8 mg.

[0487]

[0437] In some embodiments where the bioactive molecule from an algae is a mineral, a vitamin, a lipid, a phenolic compound, or a phlorotannin, it is present in an amount so that a single dose is less than about 1 mg, about 1 mg, or more than about 1 mg, up to and including about 75 mg. In embodiments, a single dose is greater than 75 mg, including 100 mg, 150 mg, 200 mg, or greater than 200 mg.

[0488]

[0438] In embodiments, a combination (i.e., a combination comprising, inter alia, a bioactive molecule from a fungus and a bioactive molecule from a plant) is administered in a total daily dose of between about 50 mg and 1 g. In embodiments, the total daily dose is between 50 mg and 1 g, between 100 mg and 500 mg, or between 100 mg and 400 mg. In embodiments, each individual dose of a combination is between 5 mg and 500 mg, between 10 mg and 400 mg, or between 10 mg and 100 mg, including where each range is modified by about.

[0489]

[0439] In embodiments, for example where a combination is administered in a single composition, a single dose is between about 10 mg and 1 g, 10 mg and 200 mg, 20 mg and 200 mg, 10 mg and 100 mg, 20 mg and 100 mg, 20 mg and 80 mg, or 30 mg and 60 mg. In embodiments, a single dose is 50 mg or about 50 mg.

[0490]

[0440] In embodiments, a single composition is administered between 1 and 8 doses daily. In embodiments, the single composition is administered once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, 6 times per day, 7 times per day, or 8 times per day. In embodiments, the single dose is administered between 1 and 8 doses daily, for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or 3 months.

[0491]

[0441] In embodiments, a subject is administered a therapeutically effective dose of a combination (i.e., the composition(s)) on a regular basis, and is administered the combination daily, several times per day (at least one, two, three, four, or greater than four times per day); on a set, repeating schedule, such as administered a therapeutically effective dose of the combination every other day, every three days, every four days, every five days, every six days, every seven days, or more than every seven days; or, in embodiments, a varying schedule comprised of a plurality of days “on” (wherein the therapeutically effective dose of the combination administered), and a plurality of days “off’ (wherein no administration occurs), such as one day on two days off, two days on three days off, three days on four days off, or other such schedules as would be apparent to those of skill (see, e.g., what are known as the Paul Stamets or James Fadiman microdosing protocols).

[0492]

[0442] In embodiments, a physician may determine or adjust the administered dose based on factors such as delivery method, patient age, weight, comorbidities, concurrent medications, and any patient-specific aspects that could affect the way in which the primary and / or secondary bioactive molecules in a combination interact with the patient (e.g., metabolism, individual response), all taken together with the teachings hereof. Disclosed dosage ranges are not intended to be limiting. In some instances, lower doses may be sufficient, while in other instances, higher doses may be used without harmful effects, including through divided administration.

[0493]

[0443] Compositions may be administered and dosed in accordance with good medical practice. Dosage may differ from subject to subject, for a subject over time, and for different formulations, dosage forms, dosing regimens, routes of administration, and the like, but may be determined with ordinary skill in view hereof.

[0494]

[0444] Dose amount, frequency, or duration; and concentrations or ratios of concentrations of components of disclosed combinations and compositions may be altered as indicated by the clinical outcome desired, status of the pathology or symptom, any adverse side effects of the treatment or therapy, or concomitant medications. For example, in some embodiments, a disclosed combination comprises a tryptamine (such as, 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). In some such embodiments, a patient taking a MAOI medication may be administered a composition with a reduced concentration of the tryptamine, as the MAOI may reduce the metabolic excretion of the tryptamine, thus affecting the ratios and synergistic effects of bioactive molecules.

[0495]

[0445] In an example, the percentage of a portion of a combination may be increased or decreased according to individual tolerance. For example, an individual with appreciable tolerance for Cannabis or a cannabinoid (e.g., THC) may be administered a combination with greater THC to account for such tolerance. In an example, individuals with certain medical conditions may be particularly sensitive or tolerant to the effects of a disclosed composition. By way of example only, in some embodiments, an individual with Lewy Body Dementia (LBD) may be administered a disclosed composition comprising a reduced concentration of a cannabinoid (e.g., THC) or a Cannabis extract, for example, if it is reasonably suspected (e.g., per the discretion of a physician or another medical practitioner) that the cannabinoid or Cannabis extract could aggravate cognitive or psychiatric symptoms of LBD, and / or increase the patient’s sensitivity to the composition or any of its constituents. In an example, an individual with clinical depression may be administered a disclosed composition with an increased concentration of a tryptamine (such as, psilocin and / or psilocybin), which may provide clinical advantages, such as promoting serotonin regulation, neuroplasticity, and connectivity.

[0496]

[0446] A skilled artisan, with the benefit of this disclosure, will recognize factors influencing dosage, frequency, and timing to achieve a therapeutic effect while minimizing adverse effects. In other embodiments, appropriate dosages, including upper and lower bounds, may be determined by individuals, including non-clinicians, based on public information, knowledge, and subjective considerations of desired outcomes.

[0497]

[0447] In embodiments, the bioactive molecules or individual portions in a combination are administered to a patient as a single composition. In embodiments, the bioactive molecules or individual portions in a combination are administered to a patient separately, sequentially, or simultaneously. In embodiments, the bioactive molecules or individual portions in a combination are individually formulated as pharmaceutical compositions that are administered to a patient separately, sequentially, or simultaneously. In embodiments, the timing of administration depends on the primary and / or secondary bioactive molecules administered.

[0448] Sequential administration includes administration of one composition immediately following administration of another composition (e.g., within about 5 minutes of the administration of the first composition); simultaneous administration includes administration of each composition at substantially the same time; and separate administration includes administration with an amount of time elapsing between the administrations, such as an amount from about 5 to 30 minutes, 10 to 60 minutes, 30 to 180 minutes, 180 to 360 minutes, or more than 360 minutes, including intervals of 8, 12, 16, 20, or 24 hours, as well as 36 hours, 48 hours, 72 hours, 5 days, 7 days, 10 days, 14 days, 21 days, 30 days, or any duration in between.

[0498]

[0449] A composition may be administered, in embodiments, between about one and about eight times per day, including 1 , 2, 3, 4, 5, 6, 7, and 8 times per day. As an example, a composition is administered twice per day or 3 times per day, while another composition is administered once per day or twice per day, and any further composition(s) are administered on other appropriate administration schedules as applicable thereto.

[0499]

[0450] A dosing schedule may be the same over time, or be modified after a specific duration of time, such as 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; and the manner in which administration is completed (i.e., via separate, sequential, or simultaneous administration) may be adjusted as needed, such that the entire dosing schedule may only include sequential, simultaneous, or separate dosing; may include a combination of two of sequential, simultaneous, or separate dosing; or may include all of sequential, simultaneous, or separate dosing. In embodiments, the frequency of dosing and duration of time between dosing may depend on the bioactive molecules and the condition treated.

[0500]

[0451] In embodiments, administration may comprise separate, sequential, or simultaneous oral administrations, sublingual administrations, buccal administrations, intravenous injections, intra-arterial injections, intraperitoneal injections, intraosseous injections, intramuscular injections, intrathecal injections, intracerebroventricular injections, rectal administrations, vaginal administrations, ocular administrations, nasal administrations, cutaneous administrations, topical administrations, otic administrations, transdermal administrations, or a combination thereof, as would be apparent to one of skill depending on the desired therapeutic effect. As disclosed herein, such may be advantageous in situations wherein the primary and / or secondary bioactive molecules have varying durations of action and maximum plasma concentrations.

[0501] VI. Pharmaceutical Kits

[0502]

[0452] In embodiments, especially where a formulation is prepared in single unit dosage form, suggested dosage amounts shall be known by reference to the format of the preparation itself. In other embodiments, suggested dosage amounts may be known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to one of skill or the public. Also provided herein are pharmaceutical kits (“kits”) containing a combination, suggested administration guidelines or prescribing information therefore, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Compositions can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0503]

[0453] In an exemplary kit, capsules, tablets, caplets, or other unit dosage forms are packaged in blister packs. “Blister pack” refers to any of several types of pre-formed container, especially plastic packaging, that contains separate receptacles (e.g., cavities or pockets) for single unit doses, where such separate receptacles are individually sealed and can be opened individually. Blister packs include such pharmaceutical packs known to those of skill, including Aclar® Rx160, Rx20e, Su...

Claims

CLAIMSThe invention claimed is:1 . A method of treating or preventing a medical condition in a subject, comprising administering to the subject a therapeutic combination comprising: a. a fungal portion, which comprises a Psilocybe spp. extract; b. a first plant portion, which comprises a Cannabis spp. extract; c. a second plant portion, which comprises a Dipteryx spp. extract; and d. an algal portion, which comprises a Porphyra spp. or Pyropia spp. extract; wherein the medical condition is any of a mitochondrial disorder, a metabolic disorder, an autoimmune disorder, a pain disorder, a mental health disorder, an endocrine disorder, a viral disorder, or a degenerative disorder.

2. The method of claim 1 , wherein the Psilocybe spp. extract is from any of P. cubensis, P. azurescens,P. bohemica, P. semilanceata, P. baeocystis, P. cyanescens, P. tampanensis, P. weilii, P. hoogshagenii, P. stuntzii, P. cyanofibrillosa, and P. liniformans, and combinations thereof.

3. The method of claim 1 , wherein the Cannabis spp. extract is from any of Cannabis sativa, Cannabis indica, and Cannabis ruderalis, and combinations thereof.

4. The method of claim 1 , wherein the Dipteryx spp. extract is from Dipteryx odorata.

5. The method of claim 1 , wherein the Porphyra spp. or Pyropia spp. extract is from any of Pyropia yezoensis, Pyropia perforata, and Porphyra umbilicalis, and combinations thereof.

6. The method of claim 1 , wherein any of the fungal portion, first plant portion, second plant portion, and algal portion are administered in separate compositions.

7. The method of claim 1 , wherein any of the fungal portion, first plant portion, second plant portion, and algal portion are administered simultaneously.

8. The method of claim 7, wherein any of the fungal portion, first plant portion, second plant portion, and algal portion are administered in a single composition.

9. The method of claim 1 , wherein: a. the fungal portion comprises a Psilocybe cubensis extract; b. the first plant portion comprises a Cannabis sativa extract; c. the second plant portion comprises a Dipteryx odorata extract; and d. the algal portion comprises a Pyropia yezoensis extract.

10. The method of claim 9, wherein the Psilocybe cubensis extract is obtained by ultrasonic extraction or Soxhlet extraction.11 . The method of claim 10, wherein the Psilocybe cubensis extract comprises a mixture of a Psilocybe cubensis extract obtained by ultrasonic extraction and a Psilocybe cubensis extract obtained by Soxhlet extraction in a weight ratio from about 0.5:1 to about 5:1 .

12. The method of claim 11 , wherein the weight ratio of the Psilocybe cubensis extract obtained by ultrasonic extraction and the Psilocybe cubensis extract obtained by Soxhlet extraction is 2:1 .

13. The method of claim 12, wherein the Psilocybe cubensis extract comprises psilocybin and psilocin.

14. The method of claim 13, wherein the Psilocybe cubensis extract comprises psilocybin and psilocin in a weight ratio from about 1 :5 to about 5:1 .

15. The method of claim 14, wherein the Psilocybe cubensis extract comprises psilocybin and psilocin in a weight ratio of about 5:3.

16. The method of claim 13, wherein the Psilocybe cubensis extract comprises from about 50 pg to about 500 pg of psilocybin and from about 20 pg to about 200 pg of psilocin.

17. The method of claim 16, wherein the Psilocybe cubensis extract comprises about 250 pg of psilocybin and about 150 pg of psilocin.

18. The method of claim 9, wherein the Cannabis sativa extract is obtained by Soxhlet extraction.

19. The method of claim 9, wherein the Cannabis sativa extract comprises A9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

20. The method of claim 19, wherein the Cannabis sativa extract comprises THC and CBD in a weight ratio from about 1 :5 to about 5: 1 .21 . The method of claim 20, wherein the Cannabis sativa extract comprises THC and CBD in a weight ratio of about 1 :1.

22. The method of claim 19, wherein the Cannabis sativa extract comprises from about 0.1 mg to about 5 mg of THC and from about 0.1 to 5 mg of CBD.

23. The method of claim 22, wherein the Cannabis sativa extract comprises about 1 mg of THC and about 1 mg of CBD.

24. The method of claim 9, wherein the Dipteryx odorata extract is obtained by anhydrous ethanol percolation.

25. The method of claim 9, wherein the Dipteryx odorata extract comprises coumarin.

26. The method of claim 9, wherein the Dipteryx odorata extract comprises from about 1 mg to about 10 mg of coumarin.

27. The method of claim 28, wherein the Dipteryx odorata extract comprises about 1 mg of coumarin.

28. The method of claim 9, wherein the combination comprises from about 1 mg to about 20 mg of Pyropia yezoensis extract.

29. The method of claim 28, wherein the combination comprises about 8 mg of Pyropia yezoensis extract.

30. The method of claim 9, wherein the Pyropia yezoensis extract is obtained by ultrasonic extraction.31 . The method of claim 9, wherein the Pyropia yezoensis extract comprises porphyran.

32. The method of claim 9, wherein any of the Psilocybe cubensis extract, Cannabis sativa extract,Dipteryx odorata extract, and Pyropia yezoensis extract are administered in separate compositions.

33. The method of claim 9, wherein any of the Psilocybe cubensis extract, Cannabis sativa extract, Dipteryx odorata extract, and Pyropia yezoensis extract are administered simultaneously.

34. The method of claim 33, wherein any of the Psilocybe cubensis extract, Cannabis sativa extract, Dipteryx odorata extract, and Pyropia yezoensis extract are administered in a single composition.

35. The method of claim 34, wherein the Psilocybe cubensis extract constitutes from about 20% to about 60% by volume of the single composition.

36. The method of claim 35, wherein the Psilocybe cubensis extract constitutes about 45% by volume of the single composition.

37. The method of claim 34, wherein the Cannabis sativa extract constitutes from about 5% to about 30% by volume of the single composition.

38. The method of claim 37, wherein the Cannabis sativa extract constitutes about 15% by volume of the single composition.

39. The method of claim 34, wherein the Dipteryx odorata extract constitutes from about 1 % to about 5% by volume of the single composition.

40. The method of claim 39, wherein the Dipteryx odorata extract constitutes about 2% by volume of the single composition.41 . The method of claim 34, wherein the Pyropia yezoensis extract constitutes from about 5% to about 30% by volume of the single composition.

42. The method of claim 41 , wherein the Pyropia yezoensis extract constitutes about 15% by volume of the single composition.

43. The method of claim 34, wherein the single composition further comprises any of a flavorant, colorant, and diluent.

44. The method of claim 43, wherein the flavorant or colorant comprises ginger or bay laurel.

45. The method of claim 44, wherein the flavorant or colorant is ethanol infused with ginger and bay leaf.

46. The method of claim 44, wherein the flavorant or colorant constitutes from about 5% to about 30% by volume of the single composition.

47. The method of claim 46, wherein the flavorant or colorant constitutes about 15% by volume of the single composition.

48. The method of claim 43, wherein the diluent is water.

49. The method of claim 48, wherein the water constitutes from about 5% to about 15% by volume of the single composition.

50. The method of claim 49, wherein the water constitutes about 8% by volume of the single composition.51 . The method of claim 34, comprising administering between about 10 and 200 mg of the single composition per single dose.

52. The method of claim 51 , comprising administering between about 50 mg of the single composition persingle dose.

53. The method of claim 52, comprising administering between 1 and 8 doses of the single composition per day.

54. The method of claim 53, comprising administering between 1 and 8 doses of the single composition per day for at least one week, two weeks, three weeks, 1 month, 2 months, or 3 months.

55. The method of claim 1 , wherein administering the therapeutic combination to the subject reduces the severity of a symptom of the medical condition.

56. The method of claim 55, wherein the reduction in the severity of the symptom is durable for at least one week, two weeks, three weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or at least 12 months, when measured from baseline.

57. The method of claim 1 , wherein the mitochondrial disorder is any of a primary mitochondrial disorder, a secondary mitochondrial disorder, myopathy with exercise intolerance; eyelid ptosis; ophthalmoparesis; pigmentary retinopathy; sensorineural hearing loss; hypertrophic cardiomyopathy; migraine disorder; mitochondrial disease NOS; demyelination due to mitochondrial disease; mitochondrial cytopathy; a liver disease due to a mitochondrial disorder; a disorder of mitochondrial oxidative phosphorylation; a multiple mitochondrial DNA deletion syndrome; a mitochondrial protein translation defect; a mitochondrial myopathy; a glomerular disease associated with a mitochondrial disease; myoclonus due to a mitochondrial cytopathy; a disorder of mitochondrial membrane transport; epilepsy due to a mitochondrial disorder; an intestinal congenital motility disorder due to a mitochondrial disease; mitochondrial diabetes; mitochondrial ocular myopathy; congenital muscular dystrophy with mitochondrial structural abnormalities; a disorder of mitochondrial fatty acid oxidation; ataxia due to a mitochondrial mutation; mitochondrial isocitrate dehydrogenase deficiency; chorea due to mitochondriopathy; mitochondrial thiamine pyrophosphate carrier deficiency; dystonia due to a mitochondrial cytopathy; dilated cardiomyopathy due to a mitochondrial myopathy; mitochondrial disease with hypertrophic cardiomyopathy; mitochondrial myopathy with sideroblastic anemia; and mitochondrial 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, potassium-stimulated.

58. The method of claim 57, wherein the primary mitochondrial disorder is any of Barth syndrome; growth delay, amino aciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome); chronic progressive external ophthalmoplegia (CPEO); oculopharyngeal muscular dystrophy (OPMD); Amish lethal microcephaly; optic atrophy; Leber hereditary optic neuropathy (LHON); Kearns-Sayre syndrome (KSS); Leigh and Leigh-like syndrome; Sengers syndrome; maternally inherited deafness and diabetes (MIDD); a mitochondrial DNA depletion syndrome; encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); encephalopathy due to defective mitochondrial and peroxisomal fission; ethylmalonic encephalopathy; a mitochondrial myopathy; a mitochondrial complex deficiency; a mitochondrial DNA depletionsyndrome; progressive external ophthalmoplegia (PEO); HSD10 mitochondrial disease; neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS); fatal infantile cardioencephalomyopathy; a combined oxidative phosphorylation deficiency; a POLG-related disorder; a mitochondrial trifunctional protein deficiency; a mitochondrial phosphate carrier deficiency; a pyruvate dehydrogenase complex deficiency; mitochondrial short-chain enoyl-CoA hydratase 1 deficiency; and Pearson syndrome.

59. The method of claim 57, wherein the secondary mitochondrial disorder is any of Wolfram syndrome; muscular dystrophy; Alzheimer’s disease; Charcot-Marie-Tooth disease; 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL); myopathic carnitine deficiency; early infantile epileptic deficiency; sensorineural hearing loss or deafness; hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome); 3-methylglutaconic aciduria; a carnitine palmitoyltransferase deficiency; ophthalmoplegic neuromuscular disorder with abnormal mitochondria; pyruvate carboxylase deficiency; reticular dysgenesis; cardiomyopathy; infantile mitochondrial striatonigral degeneration; retinitis pigmentosa-deafness syndrome; infantile cerebellar-retinal degeneration; muscle atrophy; a deficiency in mitochondrial import-stimulating factor; cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome; and a mitochondrial HMG-CoA synthase-2 deficiency.

60. The method of claim 1 , wherein the metabolic disorder is any of hyperlipidemia; dyslipidemia; hypercholesterolemia; hypertriglyceridemia; metabolic syndrome; metabolic syndrome X; Fabry disease; Gaucher’s disease; phenylketonuria (PKU); hyperglycemia; insulin resistance; impaired glucose tolerance; hyperinsulinism; hypertension; Hunter syndrome; Hurler syndrome; Krabbe disease; maple syrup urine disease; metachromatic leukodystrophy; Niemann-Pick disease; galactosemia; Tay-Sachs disease; a glycogen storage disease; a peroxisomal disorder; a metal metabolism disorder; an organic acidemia; a urea cycle disorder; an inborn error of metabolism; a disorder of metabolite absorption or transport; a disorder of lipoprotein metabolism or certain specified lipidemias; and a metabolic or transporter liver disease .61 . The method of claim 1 , wherein the autoimmune disorder is any of achalasia; Addison’s disease; adult Still’s disease; agammaglobulinemia; alopecia areata; amyloidosis; Ankylosing spondylitis; anti-GBM / anti-TBM nephritis; antiphospholipid syndrome; autoimmune angioedema; autoimmune dysautonomia; autoimmune encephalitis; autoimmune inner ear disease (AIED); autoimmune myocarditis; autoimmune oophoritis; autoimmune orchitis; autoimmune pancreatitis; autoimmune retinopathy; autoimmune urticaria; axonal and neuronal neuropathy (AMAN); Balo disease; Behcet’s disease; benign mucosal pemphigoid (mucous membrane pemphigoid); bullous pemphigoid; Castleman disease (CD); Chagas disease; chronic inflammatory demyelinating polyneuropathy(Cl DP); chronic recurrent multifocal osteomyelitis (CRMO); Churg-Strauss syndrome (CSS) oreosinophilic granulomatosis (EGPA); cicatricial pemphigoid; Cogan’s syndrome; cold agglutinin disease; complex regional pain syndrome (formerly known as reflex sympathetic dystrophy); congenital heart block; Coxsackie myocarditis; dermatitis herpetiformis; dermatomyositis; Devic’s disease (neuromyelitis optica); Dressier’s syndrome; eosinophilic esophagitis (EoE); eosinophilic fasciitis; erythema nodosum; essential mixed cryoglobulinemia; Evans syndrome; fibrosing alveolitis; giant cell arteritis (temporal arteritis); giant cell myocarditis; glomerulonephritis; Goodpasture’s syndrome; granulomatosis with polyangiitis; Graves’ disease; hemolytic anemia; Henoch-Schonlein purpura (HSP); herpes gestationis or pemphigoid gestationis (PG); Hidradenitis suppurativa (HS) (acne inversa); IgA nephropathy; I gG4-related sclerosing disease; immune thrombocytopenic purpura (ITP); inclusion body myositis (IBM); interstitial cystitis (IC); juvenile myositis (JM); Lambert-Eaton syndrome; lichen planus; lichen sclerosus; ligneous conjunctivitis; linear IgA disease (LAD); Meniere’s disease; microscopic polyangiitis (MPA); mixed connective tissue disease (MCTD); Mucha-Habermann disease; multifocal motor neuropathy (MMN) or MMNCB; MS; myasthenia gravis; myelin oligodendrocyte glycoprotein antibody disorder; myositis; narcolepsy; neuromyelitis optica / devic disease; neutropenia; ocular cicatricial pemphigoid; optic neuritis; palindromic rheumatism (PR);PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections); paraneoplastic cerebellar degeneration (PCD); paroxysmal nocturnal hemoglobinuria (PNH); Parsonage-Turner syndrome; pemphigus; perivenous encephalomyelitis; pernicious anemia (PA); disease affecting many nerves, organomegaly, abnormal enlargement of an organ, endocrinopathy, disease affecting certain hormone-producing glands that help to regulate sexual function, and certain metabolic functions, monoclonal gammopathy or M proteins, and skin abnormalities (POEMS syndrome); polyarteritis nodosa; polyglandular syndromes type I, II, III; polymyalgia rheumatica; polymyositis; postmyocardial infarction syndrome; postpericardiotomy syndrome; primary biliary cholangitis; primary sclerosing cholangitis; progesterone dermatitis; progressive hemifacial atrophy (PHA) (also known as Parry Romberg syndrome); pulmonary alveolar proteinosis (PAP); pure red cell aplasia (PRCA); Pyoderma gangrenosum; Raynaud’s phenomenon; relapsing polychondritis; retroperitoneal fibrosis; rheumatic fever; sarcoidosis; Schmidt syndrome or autoimmune polyendocrine syndrome type II; scleritis; stiff person syndrome (SPS); Susac’s syndrome; sympathetic ophthalmia (SO); Takayasu’s arteritis; temporal arteritis / giant cell arteritis; thrombocytopenic purpura (TTP); thrombotic thrombocytopenic purpura (Ttp); thyroid eye disease (TED); Tolosa-Hunt syndrome (THS); transverse myelitis; undifferentiated connective tissue disease (UCTD); vitiligo; Vogt-Koyanagi-Harada disease; and warm autoimmune hemolytic anemia.

2. The method of claim 1 , wherein the pain disorder is any of acute pain; episodic pain; phantom pain; soft tissue pain; nociceptive pain; functional pain; idiopathic pain; radicular pain; referred pain; breakthrough pain; herniated disc pain; perioperative pain; pre-operative pain; post-operative pain;neuropathic pain; post-herpetic neuralgia; trigeminal neuralgia; back pain; neck pain; phantom limb pain; chronic pelvic pain; vulvodynia; nerve pain; complex regional pain syndrome or a related neuralgia; pain associated with HIV; nerve injury; root avulsion; erythromelalgia; paroxysmal extreme pain disorder; burning mouth syndrome; a central pain syndrome; a post-surgical pain syndrome; bone and / or joint pain; repetitive motion pain; dental pain; polymyositis / myofascial pain; a muscular injury; chronic pain; dysmenorrhea; pain associated with angina; pain due to inflammation; pain due to a rheumatic disease; pain due to teno-synovitis; bursitis; polymyalgia rheumatica; primary hyperalgesia; secondary hyperalgesia; primary allodynia; secondary allodynia; pain caused by central sensitization; chronic arthritic pain or a related neuralgia; migraine disorder; headache pain; a cluster headache; a non-vascular headache; traumatic nerve injury; nerve compression or entrapment; neuroma pain; testicular pain (orchialgia); lasting pain in scar tissue; herpes zoster or shingles; frozen shoulder; pain due to a bone fracture; pain due to sickle cell disease; pain due to kidney stones; pain due to appendicitis; complex regional pain syndrome (CRPS); pain due to gout; pain due to acute pancreatitis; pain due to a stomach or peptic ulcer; pain due to a heart attack; Munchausen syndrome; pain due to another injury or medical condition; an arthritis; a sexual pain disorder; dysmenorrhea disorder; painful periods disorder; abdominal pain disorder; emporomandibular joint disorder; chronic temporomandibular disorder pain; cold impediment disorder; painful impediment disorder; chronic primary headache or orofacial pain; chronic primary temporomandibular disorder pain; puerperal abdominal pain disorder; chest impediment disorder; heart pain disorder; true heart pain disorder; Lumbago disorder; low back pain disorder; wind impediment disorder; migrating painful movement disorder; growth pain disorder; hypochondrium pain disorder; an abdominal pain-related functional Gl disorder in a child; chronic headache or orofacial pain associated with non-vascular intracranial disorder; acute whiplash associated disorder with complaint of neck pain with neurological signs; chronic headache or orofacial pain associated with disorders of homoeostasis; headache or orofacial pain associated with chronic secondary temporomandibular disorders; chronic headache or orofacial pain associated with cranial or cervical vascular disorder; acute whiplash associated disorder with complaint of neck pain with musculoskeletal signs; and acute whiplash associated disorder with complaint of neck pain, stiffness or tenderness only.

3. The method of claim 1 , wherein the mental health disorder is any of a neurodevelopmental disorder; schizophrenia or another primary psychotic disorder; catatonia; a mood disorder; an anxiety or fear-related disorder; an obsessive-compulsive or related disorder; a disorder specifically associated with stress; a dissociative disorder; a feeding or eating disorder; an elimination disorder; a disorder of bodily distress or bodily experience; a disorder due to substance use or addictive behaviors; an impulse control disorder; a disruptive behavior or dissocial disorder; a personality disorder or related trait; a paraphilic disorder; a factitious disorder; a neurocognitive disorder; a mental or behavioraldisorder associated with pregnancy, childbirth, or the puerperium; a sleep-wake disorder; a sexual dysfunction; gender incongruence; a bipolar or related disorder; a depressive disorder; a trauma- or stressor-related disorder; a somatic symptom or related disorder; gender dysphoria; and a substance-related or addictive disorder.

64. The method of claim 1 , wherein the endocrine disorder is any of PMDD; PMS; a complication or symptom arising from perimenopause; acromegaly; Addison's disease; adrenal cancer; adrenoleukodystrophy; benign adrenal tumors; cancer; carcinoid tumors; chronic kidney disease; congenital adrenal hyperplasia; Cushing syndrome; cystic fibrosis; diabetic nephropathy (kidney disease); end-stage renal disease; erectile dysfunction; galactorrhea; gender dysphoria; gestational diabetes; goiter; Graves' disease; high cholesterol; high potassium (hyperkalemia); hirsutism; Hurthle cell cancer; hypercalcemia; hypereosinophilic syndrome; hyperparathyroidism; hyperthyroidism (overactive thyroid); hypoglycemia; hypoparathyroidism; hypopituitarism; hypothyroidism (underactive thyroid); infertility; an inherited metabolic disorder; insulinoma; Klinefelter syndrome; low potassium (hypokalemia); male hypogonadism; male infertility; metabolic bone disease; multiple endocrine neoplasia, type 1 (MEN 1); multiple endocrine neoplasia, type 2 (MEN 2); neuroblastoma; neuroendocrine tumors; osteomalacia; osteopenia; osteopetrosis; osteoporosis; Paget's disease of bone; Paget's disease of the breast; pheochromocytoma; a pituitary tumor; POEMS syndrome; polycystic ovary syndrome (PCOS); primary aldosteronism; prolactinoma; Sheehan's syndrome; thyroid cancer; thyroid disease; thyroid eye disease; thyroid nodules; Turner syndrome; varicocele; and Whipple's disease.

65. The method of claim 1 , wherein the viral disorder is any of SARS; COVID; Lyme disease; the common cold (rhinovirus); the flu (influenza); avian influenza (H5N1); respiratory syncytial virus (RSV); human metapneumovirus (hMPV); parainfluenza; norovirus, rotavirus, astrovirus, a hepatitis virus; human immunodeficiency virus (HIV); genital herpes (HSV); Fifth disease; Mpox; viral myocarditis; acute viral myocarditis; chronic viral myocarditis; cytomegaloviral disease; lentivirus; filovirus; Lassa fever; arenavirus; orthopoxvirus; arbovirus; viral keratitis; and flavivirus.

66. The method of claim 1 , wherein the degenerative disorder is any of muscle degeneration; lung degeneration; vascular degeneration; artery degeneration; aortic degeneration; Monckeberg's degeneration; degeneration of sinus; cortex degeneration; kidney degeneration; corneal degeneration; degeneration of the uterus; fatty degeneration; brain degeneration; vitreous degeneration; conjunctival or subconjunctival degenerations or deposits; breast degeneration; lenticular degenerative disease; cerebromacular degeneration; multidegenerative joint disease; ovarian degeneration; placental degeneration; degeneration of turbinate; degeneration of penis; degeneration of iris or ciliary body; a degenerative condition of the spine; degenerative knee disease; follicular degeneration syndrome; degenerative rupture of tendon; hyaloid degeneration; lens degeneration; pulp degeneration; adegenerative disorder of the spleen; degeneration of meniscus; hereditary retinal degeneration; peripheral retinal degeneration; cystic degeneration of ovary; neovascular late-stage age-related macular degeneration; a degenerative spinal instability; a degenerative myelopathic disorder; corticobasal degeneration; pituitary gland degeneration; polypoid sinus degeneration; fatty degeneration of aorta; dystonia associated with heredodegenerative disorders; thyroid degeneration; cochlea degeneration; degenerative or vascular disorders of the ear; degeneration of cervix uteri; another specified degeneration of macula or posterior pole; degenerative mitral valve prolapse; pineal gland degeneration; degenerative dementia; cardiovascular degeneration; suprarenal gland degeneration; lymph gland degeneration; juvenile macular degeneration-hypotrichosis; colloid degeneration of the skin; and choroidal degeneration.

7. A method of preventing or treating a medical condition in a subject, comprising administering to the subject a therapeutic combination comprising: a. a fungal portion; b. a first plant portion; c. optionally, a second plant portion; and d. optionally, an algal portion; wherein the medical condition is any of a mitochondrial disorder, a metabolic disorder, an autoimmune disorder, a pain disorder, a mental health disorder, an endocrine disorder, a viral disorder, or a degenerative disorder.

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