WO2024059353A1 - Compositions de cannabinoïdes et d'acides gras oméga et leurs méthodes d'utilisation - Google Patents

Compositions de cannabinoïdes et d'acides gras oméga et leurs méthodes d'utilisation Download PDF

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WO2024059353A1
WO2024059353A1 PCT/US2023/061944 US2023061944W WO2024059353A1 WO 2024059353 A1 WO2024059353 A1 WO 2024059353A1 US 2023061944 W US2023061944 W US 2023061944W WO 2024059353 A1 WO2024059353 A1 WO 2024059353A1
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cbda
cbd
omega
cannabinoid
pharmaceutical composition
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PCT/US2023/061944
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English (en)
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Elliot Altman
Matthew Fuller
Gheda ALSAIF
Shannon Smith
Karen MAYNARD
Anthony FARONE
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Greenway Herbal Products, Llc
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Priority claimed from US17/931,249 external-priority patent/US20230015268A1/en
Application filed by Greenway Herbal Products, Llc filed Critical Greenway Herbal Products, Llc
Priority to CA3237737A priority Critical patent/CA3237737A1/fr
Priority claimed from US18/164,044 external-priority patent/US20230248747A1/en
Publication of WO2024059353A1 publication Critical patent/WO2024059353A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the immune system is a complex network of cells, effector proteins, and compounds that defends the body against invading agents. Usually the immune system responds to foreign antigens, such as bacteria, fungi, and viruses, or to tissue damage caused by contusions or abrasions. These responses are typically referred to as inflammatory since they induce or turn on the immune system. Unfortunately, the immune system can also respond to antigens produced by the body as well, the result of which is the development of autoimmune diseases.
  • autoimmune diseases The prevalence of autoimmune diseases is rapidly increasing with Addison’s disease, autoimmune hepatitis, Celiac disease, Crohn’s disease, Grave’s disease, idiopathic thrombocytopenic purpura, multiple sclerosis, primary biliary cirrhosis, psoriatic disease, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, systemic lupus erythematosus, type I diabetes, and ulcerative colitis all being recognized as autoimmune diseases.
  • Therapeutics used to treat inflammatory conditions or autoimmune diseases include nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid, ibuprofen, naproxen, and celecoxib; conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and gold salts; corticosteroids, such as cortisone, dexamethasone, hydrocortisone, and prednisone; nonantibody tumor necrosis factor alpha (TNFa or TNF) inhibitors such as the xanthine derivatives pentoxifylline and bupropion; and monoclonal antibody TNF inhibitors, such as adalimumab, etanercept, and infliximab.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs conventional synthetic disease-modifying antirheumatic drugs
  • NSAIDs are tried first to alleviate inflammatory conditions or symptoms of autoimmune diseases before progressing to conventional synthetic DMARDs, then corticosteroids, and ultimately TNF inhibitors.
  • the endocannabinoid system which functions due to the interaction of endocannabinoid compounds with G protein-coupled endocannabinoid receptors and is a key regulator of the brain and central nervous system, is also involved in the regulation of the immune system (Pandey et al., 2009; Barrie and Manolios, 2017).
  • the A 9 -tetrahydrocannibinol (A 9 -THC or THC) is a cannabinoid that can be derived by the decarboxylation of the natural plant phytocannabinoid THCA produced by Cannabis varieties.
  • CBD cannabinoid that can be derived by the decarboxylation of the natural plant phytocannabinoid cannabidiolic acid (CBD A).
  • Cannabis varieties It is produced by Cannabis varieties, and has gained attention as a potential anti-inflammatory or immunosuppressant therapeutic (Nagarkatti et al., 2009; Lodzki et al., 2003; Costa et al., 2004; Rajan et al., 2016; Petrosino et al., 2018). While it is unclear how CBD affects the endocannabinoid system, a number of studies have postulated potential mechanisms by which this might occur (Di Marzo and Piscitelli, 2015; McPartland et al., 2015).
  • Cannabis varieties produce eight major cannabinoids.
  • the metabolic pathway by which these cannabinoids are synthesized is shown in FIG. 1.
  • Cannabigerovarinic acid (CBGVA) is produced from geranyl pyrophosphate by geranyl transferase with the addition of divarinic acid
  • cannabigerolic acid (CBGA) is produced from geranyl pyrophosphate by geranyl transferase with the addition of olivetolic acid.
  • Cannabichromevarinic acid (CBCVA), A 9 - tetrahydrocannabivarinic acid (A 9 -THCVA or THCVA) and cannabidivarinic acid (CBDVA) is produced from CBGVA by cannabichromenic acid (CBCA) synthase, A 9 -tetrahydrocannabinolic acid A (A 9 -THCA or THCA) synthase and cannabidiolic acid (CBDA) synthase, respectively.
  • CBCA, A 9 -THCA and CBDA is produced from CBGA by CBCA synthase, A9-THCA synthase and CBDA synthase, respectively.
  • the natural CBGVA, CBGA, CBCVA, A 9 -THCVA, CBDVA, CBCA, A 9 -THCA and CBDA cannabinoids that are produced via the cannabinoid metabolic pathway can be decarboxylated with heat to yield cannabigerivarin (CBGV), cannabigerol (CBG), cannabichromevarin (CBCV), tetrahydrocannabivarin (A 9 -THCV or THCV), cannabidivarin (CBDV), cannabichromene (CBC), A 9 -tetrahydrocannabinol (A 9 -THC or THC) and cannabidiol (CBD), respectively.
  • CBDGV cannabigerivarin
  • CBDVA cannabigerol
  • CBCV cannabichromevarin
  • CBCV tetrahydrocannabivarin
  • a 9 -THCV or THCV cannabidivarin
  • a number of the natural cannabinoids and their decarboxylated derivatives can be converted to other cannabinoids.
  • CBCA and CBC can be converted to cannabicyclolic acid (CBLA) and cannabicyclol (CBL) by UV photo-irradiation
  • A9-THCA and A9-THC can be converted to cannabinolic acid (CBNA) and cannabinol (CBN) by oxidative degradation.
  • CBDA non-psychotropic cannabinoid
  • numerous hemp plants have been demonstrated to produce buds that contain upwards of 25% CBDA by mass.
  • CBDA is more difficult to isolate than CBD because of decarboxylation that occurs during purification, a number of processes have been developed that can generate CBDA extracts that contain upwards of 80% CBDA.
  • CBD cannabinoid compositions having enhanced biologic activity, such as anti-inflammatory and/or immunosuppressant activity.
  • compositions including a cannabinoid including, for example, a phytocannabinoid (that is, a cannabinoid derived from or produced by a plant), and methods of using those compositions.
  • the composition may be useful for treating an inflammatory condition and/or an autoimmune disease.
  • the composition may be useful as an anti-cancer therapeutic.
  • this disclosure describes a pharmaceutical composition comprising a cannabinoid.
  • the cannabinoid may be chosen from: i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • Combinations thereof may include, for example, two cannabinoids, three cannabinoids, four cannabinoids, five cannabinoids, or more.
  • Exemplary combinations include CBC and CBCA; CBG and CBGA; CBL and CBLA; CBD and CBDA; CBC and CBDV; CBG, CBGA, and CBDA; CBD, CBDV, and CBGA; etc.
  • this disclosure describes a composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA further comprises an additional cannabinoid comprising CBC, CBCA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, or THCVA, or a combination thereof.
  • the composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA is free of or substantially free of other cannabinoids.
  • this disclosure describes a composition comprising a cannabinoid, an approximately 1 : 1 equimolar mixture of CBD: CBDA, and an omega unsaturated fatty acid (referred to herein as an “omega fatty acid”).
  • the disclosure describes a composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA and an omega fatty acid.
  • the composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA and an omega fatty acid is free of or substantially free of other cannabinoids.
  • the pharmaceutical composition is formulated for use as an anti-inflammatory agent or an immunosuppressant.
  • this disclosure describes a method for treating or preventing inflammation or autoimmunity in a subject.
  • the method includes administering to the subject a composition including an effective amount of a cannabinoid.
  • the cannabinoid is chosen from: i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the cannabinoid is chosen from i) CBL, CBLA, THCVA, and any combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • this disclosure describes a method for treating or preventing inflammation or autoimmunity in a subject. The method includes administering to the subject a composition including an effective amount of a cannabinoid.
  • the cannabinoid is chosen from: i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, ii) an approximately 1 :1 equimolar mixture of CBD:CBDA, and iii) an omega fatty acid.
  • the cannabinoid is chosen from i) CBL, CBLA, THCVA, and any combination thereof, ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA, and iii) an omega fatty acid.
  • “approximately” is defined as being within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%.
  • the term “free of’ or “substantially free of’ indicates that any elements listed after the phrase are not included or, if they are included, those elements do not substantially interfere with or contribute to the activity or action specified in the disclosure for the other elements in the composition. Those skilled in the art will readily appreciate that elements listed after the term “free of’ or “substantially free of’ may, in some circumstances, be present as the result of impurities from process such as extraction of cannabinoids from Cannabis. In some embodiments, when a composition is substantially free of other cannabinoids, the composition contains 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, or 0.1% or less of the other cannabinoids.
  • FIG. 1A - FIG IB show an exemplary Cannabis metabolic pathway for the synthesis of the major cannabinoids.
  • the synthesis of CBCA, CBDA, CBCVA, CBDVA, CBGA, CBGVA, A9-THCA and A9-THCVA from geranyl pyrophosphate (GPP) are shown along with the key enzymes that are involved.
  • FIG. 1A shows the synthesis of CBGA and CBGVA from GPP.
  • FIG IB shows the synthesis of CBCVA, CBDVA and THCVA from CBGVA and the synthesis of CBCA, CBDA and THCA and from CBGA.
  • FIG. 2A - FIG. 2G show structures of the cannabinoids used in Example 1.
  • FIG. 2A shows the structures of cannabichromene (CBC) and cannabichromenic acid (CBCA).
  • FIG. 2B shows the structures of cannabidiol (CBD) and cannabidiolic acid (CBDA).
  • FIG. 2C shows the structures of cannabidivarin (CBDV) and cannabidivarinic acid (CBDVA).
  • FIG. 2D shows the structures of cannabigerol (CBG) and cannabigerolic acid (CBGA).
  • FIG. 2E shows the structures of cannabicyclol (CBL) and cannabicyclolic acid (CBLA).
  • FIG. 2F shows the structures of cannabinol (CBN) and cannabinolic acid (CBNA).
  • FIG. 2G shows the structures of tetrahydrocannabivarin (THCV) and tetrahydrocannabivarinic acid (THCVA).
  • FIG. 3A - FIG. 3H show structures of omega fatty acids used in the studies of Examples 6A-C.
  • FIG. 3 A shows the structures of a-linolenic acid (ALA) omega-3 fatty acid.
  • FIG. 3B shows the structures of docosahexaenoic acid (DHA) omega-3 fatty acid.
  • FIG. 3C shows the structures of eicosapentaenoic acid (EP A) omega-3 fatty acid.
  • FIG. 3D shows the structures of octadecatetraenoic acid omega-3 fatty acid.
  • FIG. 3E shows the structures of palmitoleic acid omega-7 fatty acid.
  • FIG. 3F shows the structures of vaccenic acid omega-7 fatty acid.
  • FIG. 3G shows the structures of gondoic acid omega-9 fatty acid.
  • FIG. 3H shows the structures of oleic acid omega-9 fatty acid.
  • FIG. 4 depicts a graph of anti-inflammatory omega fatty acids dosed per mouse versus the percent suppression of cytokines as observed in Example 6B.
  • compositions comprising cannabinoids and methods of using those compositions including, for example, to treat or prevent inflammation, as an immunosuppressant, and/or as an anti-cancer therapeutic.
  • this disclosure describes a pharmaceutical composition including a cannabinoid.
  • the cannabinoid is chosen from: i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, and ii) an approximately 1:1 equimolar mixture of CBD: CBDA.
  • the IUPAC names of each of these cannabinoids are listed below in Table 1, and their structures are shown in FIG. 2. Table 1: Listing of Exemplary Cannabinoids
  • the cannabinoid is chosen from: i) the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, THCVA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the cannabinoid is chosen from cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • the cannabinoid is chosen from is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • the cannabinoid is chosen from: i) the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the cannabinoid is chosen from the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof. In other embodiments, the cannabinoid is chosen from the CBDV, CBL, CBLA, CBN, CBNA and any combination thereof. [0036] In other embodiments, the cannabinoid is chosen from the cannabinoid is chosen from i) the CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBL, CBLA, CBN, CBNA, THCV, and THCV A, and ii) the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the cannabinoid is chosen from i) the CBCA, CBDA, CBDV, CBDVA, CBL, CBLA, CBN, CBNA, and THCVA, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • a composition includes the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • the composition may be substantially free of other cannabinoids.
  • the cannabinoid consists essentially of the approximately 1 :1 equimolar mixture of CBD:CBDA.
  • the cannabinoid consists essentially of a 1: 1 equimolar mixture of CBD: CBDA.
  • the composition may further include an additional cannabinoid chosen from CBC, CBCA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • the cannabinoid is chosen from i) the CBD, CBDA, CBDV, CBDVA, CBG, and THCV and ii) the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the cannabinoid is chosen from chosen from: i) CBL, CBLA, and THCVA, and any mixture thereof; and ii) an approximately 1 :1 equimolar mixture of CBD:CBDA.
  • the composition may include a cannabinoid extract including, for example, from hemp flowers or buds. Extracts from hemp flowers or buds that contain high concentrations of a cannabinoid can be easily prepared by a variety of methods, which include but are not limited to supercritical fluid extraction using carbon dioxide, butane or water, or ethanol solvent extraction.
  • the individual cannabinoids CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, and THCVA, and a 1 : 1 equimolar mixture of CBD: CBDA each showed potential as antioxidant, antiinflammatory agents and/or immunosuppressants.
  • the cannabinoid may be at least half as effective as dexamethasone at reducing elevated cytokine levels in differentiated THP-1 cells that had been treated with LPS, indicating anti-inflammatory and/or immunosuppressant activity.
  • the individual cannabinoids CBCA, CBD, CBDA, CBDVA, CBDV, CBG, CBGA, CBLA, CBL, CBNA, CBN, THCVA, THCV, and a 1 : 1 equimolar mixture of CBD:CBDA were very effective at reducing elevated cytokine levels in differentiated THP-1 cells that had been treated with LPS.
  • the cannabinoid induces radical scavenging activity by at least two-fold compared to an untreated control.
  • the individual cannabinoids CBD, CBDA, CBDV, CBDVA, CBG, THCV and a 1 : 1 equimolar mixture of CBD:CBDA had significant antioxidant activity in a DPPH assay.
  • CBDA cannabinoids CBL, CBLA, THC VA, and a 1 : 1 equimolar mixture of CBD: CBDA proved to be particularly effective at inducing autophagy in differentiated U937 cells.
  • the immune system is stringently regulated via a counterbalance between inflammatory (proinflammatory) and anti-inflammatory cytokines.
  • Inflammatory cytokines induce the immune system while anti-inflammatory cytokines repress the immune system. Normally this counterbalance keeps the immune system in check and ready to act when necessary.
  • the levels of inflammatory cytokines drastically increase.
  • There are a number of extensive reviews that describe the regulation of the immune system by inflammatory and anti-inflammatory cytokines (Pripp and Stanisic M, 2014; Wang et al., 2015; Musolino et al., 2017; Nalbant and Birlik, 2017).
  • cytokine storm is generally used to describe the increase in inflammatory cytokine levels that occur in people suffering from inflammatory conditions or autoimmune diseases.
  • the inflammatory cytokines that are involved in cytokine storms and how their repression by pharmaceutical agents as treatment regimens has been extensively reviewed (Tisoncik et al. 2012; Gerlach, 2016; Behrens and Koretzky, 2017).
  • cytokines are inflammatory or antiinflammatory, however, IFNy, IL-1 , IL-2, IL-6, IL-12, IL-15, IL-16, IL-17, IL-18, IL-23 and TNFcr are widely recognized as being inflammatory cytokines while IL-IRA, IL-4, IL-10, IL-11, IL-13 and TGF0 are widely recognized as being anti-inflammatory cytokines (Pripp and Stanisic M, 2014; Wang et al., 2015; Musolino et al., 2017; Nalbant and Birlik, 2017). Over 100 cytokines have been identified to date and many have not yet been thoroughly characterized.
  • compositions are capable of suppressing or preventing the release of proinflammatory cytokines in the course of an inflammatory or autoimmune event, thereby reducing or preventing the cytokine storm.
  • a composition including a particular cannabinoid may consist essentially of that cannabinoid.
  • a composition including CBC may consist essentially of CBC.
  • a composition including a 1 : 1 equimolar mixture of CBD:CBDA may consist essentially of CBD and CBDA.
  • compositions comprising a cannabinoid may also likely contain other cannabinoids in lesser amounts.
  • a cannabinoid including, for example, a cannabinoid extract
  • the present examples demonstrate surprising synergistic activity of a 1 : 1 equimolar mixture of CBD:CBDA.
  • this synergistic activity is still present.
  • a composition including a particular cannabinoid may preferably be free of other cannabinoids.
  • a composition including CBC may be free of CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, and THCVA.
  • a composition comprising CBL, CBLA, CBD, and CBDA may be free of other cannabinoids.
  • a composition comprising a 1 :1 equimolar mixture of CBD:CBDA may be free of CBC, CBCA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, and THCVA.
  • the cannabinoid comprises i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, or THCVA, or a combination thereof, or ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • the cannabinoid comprises the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, or THCVA, or a combination thereof.
  • the cannabinoid comprises the CBD, CBDA, CBDV, CBDVA, CBG, and THCV, or any combination thereof.
  • the composition comprises an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • the cannabinoid comprises the CBD, CBDA, CBDV, CBDVA, CBG, or THCV, or any combination thereof.
  • the composition when the cannabinoid comprises the CBD, and CBDA, the composition includes an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • the cannabinoid comprises CBL, CBLA, THCVA, or any combination thereof, comprises the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • a cannabinoid composition comprises an approximately 1 :1 equimolar mixture of CBD:CBDA. In some embodiments, a cannabinoid composition comprises a 1 : 1 equimolar mixture of CBD:CBDA.
  • a 1 : 1 equimolar mixture of CBD:CBDA was surprisingly found to be more effective at reducing elevated cytokine levels in THP-1 cells treated with LPS than CBD or CBDA alone, to demonstrate a significant antioxidant activity in a DPPH assay, and to induce autophagy in differentiated U937 cells - each indicating its potential as an anti-inflammatory agent or an immunosuppressant.
  • the 1 : 1 equimolar mixture of CBD: CBDA demonstrated a significant effect of all three of these activities in the present Examples.
  • CBD and CBDA act as potent anti-inflammatory agents was also surprising and somewhat counterintuitive. Numerous studies on THCA and its decarboxylated derivative, THC, have made it abundantly clear that while THC is a potent psychoactive compound, THCA is not. Based on this fact, most studies on other phytocannabinoids have presumed that the decarboxylated derivative and not the precursor is biologically active. Thus, it was surprising to find that the precursor CBDA is actually more potent than CBD as an anti-inflammatory agent.
  • this disclosure describes a pharmaceutical composition including a cannabinoid and an omega fatty acid.
  • the cannabinoid is chosen from: i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, and ii) an approximately 1 :1 equimolar mixture of CBD:CBDA.
  • the IUPAC names of each of these cannabinoids are listed above in Table 1, and their structures are shown in FIG. 2.
  • the pharmaceutical composition may include i) an approximately 1 :1 equimolar mixture of CBD:CBDA, and ii) an omega fatty acid.
  • the IUPAC names of possible omega fatty acids are listed below in Table 2, and their structures are shown in FIGS. 3A-3H.
  • Table 2 Listing of Exemplary Omega Fatty Acids
  • the omega fatty acid may include an anti-inflammatory omega unsaturated fatty acid.
  • the omega fatty acid may include an omega-3 fatty acid.
  • An omega-3 fatty acid may include a-linolenic acid (ALA) (FIG. 3 A), docosahexaenoic acid (DHA) (FIG. 3B), eicosapentaenoic acid (EP A) (FIG. 3C), or octadecatetraenoic acid (FIG. 3D).
  • the omega-3 fatty acid may include some other type of omega-3 fatty acid.
  • the omega fatty acid may include an omega-7 fatty acid.
  • An omega-7 fatty acid may include palmitoleic acid (FIG. 3E) or vaccenic acid (FIG. 3F).
  • An omega-7 fatty acid may include some other type of omega-7 fatty acid.
  • the omega fatty acid may include an omega-9 fatty acid.
  • An omega-9 fatty acid may include gondoic acid (FIG. 3G) or oleic acid (FIG. 3H).
  • An omega-9 fatty acid may include some other type of omega-9 fatty acid.
  • an omega fatty acid may include some other type of unsaturated fatty acid.
  • Omega unsaturated fatty acids have anti-inflammatory properties and can reduce inflammation and suppress immune responses. Like other anti-inflammatory agents, omega fatty acids may lower the levels of cytokines (Simopoulos, 2002; Fritsche; Calder, 2017).
  • ALA may be extracted from plant seeds, such as flax seeds or hemp seeds.
  • DHA or EPA may be extracted from fish, such as salmon or pollock.
  • omega-7 or omega-9 fatty acids may be extracted from fish. Table 3, below, shows the percentage of the major unsaturated fatty acids that are found in various fish oils. Table 4, below, shows the percentage of the omega-3, omega-7, and omega-9 fatty acids that are found in various fish oils.
  • ALA In nature ALA, DHA and EPA can exist as triacylglycerols or triglycerides where three fatty acids are combined with glycerol. Single or mono ethyl ester forms of the fatty acids may be isolated by esterifying the triglyceride form with ethanol. This process allows an entity to readily concentrate and purify fatty acids.
  • the present disclosure provides a pharmaceutical composition that comprises a cannabinoid and a pharmaceutically acceptable carrier.
  • the cannabinoid is chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • the present disclosure provides a pharmaceutical composition that comprises a cannabinoid, an omega fatty acid, and a pharmaceutically acceptable carrier.
  • the cannabinoid is chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • the omega fatty acid of the pharmaceutical composition may include multiple types of omega fatty acids.
  • the pharmaceutical composition may include a mixture of different types of fatty acids.
  • a majority (e.g., by weight, volume, or some other measurement) of the omega fatty acids in the mixture may include DHA.
  • a majority of the omega fatty acids in the mixture may include EPA.
  • a majority of the omega fatty acids in the mixture may include DHA and EPA.
  • a majority of the plurality of omega fatty acids may include a mixture of DHA and EPA.
  • the active agent may be formulated in a pharmaceutical composition to be administered to a subject in a formulation adapted to the chosen route of administration.
  • the formulation may include one suitable for oral, rectal, vaginal, topical, nasal, ophthalmic, or parenteral (including subcutaneous, intramuscular, intraperitoneal, and intravenous) administration.
  • the pharmaceutically acceptable carrier may include, for example, an excipient, a diluent, a solvent, an accessory ingredient, a stabilizer, a protein carrier, or a biological compound.
  • solvents include propanediol, propylene glycol, and polysorbate 80.
  • an oil may be used as a solvent.
  • Non-limiting examples of an oil include a vegetable oil such as corn oil, peanut oil, or coconut oil.
  • Non-limiting examples of a protein carrier includes keyhole limpet hemocyanin (KLH), bovine serum albumin (BSA), ovalbumin, or the like.
  • Non-limiting examples of a biological compound which may serve as a carrier include a glycosaminoglycan, a proteoglycan, and albumin.
  • the carrier may be a synthetic compound, such as dimethyl sulfoxide or a synthetic polymer, such as a polyalkyleneglycol. Ovalbumin, human serum albumin, other proteins, polyethylene glycol, or the like may be employed as the carrier.
  • the pharmaceutically acceptable carrier includes at least one compound that is not naturally occurring or a product of nature.
  • the composition including the pharmaceutically acceptable carrier is a composition that is not naturally occurring or a product of nature.
  • the pharmaceutical composition is formulated in combination with one or more additional (for example, “second”) active agent(s).
  • the pharmaceutical composition may be formulated in combination with a nonsteroidal antiinflammatory drug (NSAIDs), such as acetylsalicylic acid, ibuprofen, naproxen, or celecoxib; a conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, or gold salts; a corticosteroid, such as cortisone, dexamethasone, hydrocortisone, or prednisone; a non-antibody tumor necrosis factor alpha (TNFa or TNF) inhibitor such as a xanthine derivative (pentoxifylline or bupropion); or a monoclonal antibody TNF inhibitor, such as adalimumab, etanercept, or
  • NSAIDs nonsteroidal
  • composition may be conveniently presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a pharmaceutical carrier. In some embodiments, the composition may be prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulations.
  • a composition suitable for oral administration may be presented as discrete units such as tablets, troches, capsules, lozenges, wafers, or cachets, each containing a predetermined amount of the active agent as a powder or granules, as liposomes, or as a solution or suspension in an aqueous liquor or non-aqueous liquid such as a syrup, an elixir, an emulsion, or a draught.
  • the tablets, troches, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose, or aspartame; and a natural or artificial flavoring agent.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid, and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, fructose, lactose, or aspartame
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like.
  • a syrup or elixir may contain one or more of a sweetening agent, a preservative such as methyl- or propylparaben, an agent to retard crystallization of the sugar, an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, a dye, and flavoring agent.
  • the material used in preparing any unit dosage form is substantially nontoxic in the amounts employed.
  • the active agent may be incorporated into preparations and devices in formulations that may, or may not, be designed for sustained release or controlled release.
  • a formulation suitable for parenteral administration may include a sterile aqueous preparation of the active agent, or a dispersion of a sterile powder of the active agent, which is preferably isotonic with the blood of the subject.
  • Parenteral administration of a pharmaceutical composition is one form of administration.
  • An isotonic agent may be included in the liquid preparation including, for example, a sugar; a buffer; and/or a salt including, for example, sodium chloride.
  • a solution of the active agent may be prepared in water, optionally mixed with a nontoxic surfactant.
  • a dispersion of the active agent may be prepared in water, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycols, and the like), a vegetable oil, or a glycerol ester, or a mixture thereof.
  • the ultimate dosage form may be sterile, fluid, and stable under the conditions of manufacture and storage.
  • the necessary fluidity may be achieved, for example, by using liposomes, by employing the appropriate particle size in the case of dispersions, or by using surfactants.
  • Sterilization of a liquid preparation may be achieved by any convenient method that preserves the bioactivity of the active agent, preferably by filter sterilization. Methods for preparing a powder include vacuum drying and freeze drying of the sterile injectable solutions.
  • antimicrobial agents for example, antibacterial, antiviral and antifungal agents including parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Absorption of the active agents over a prolonged period may be achieved by including agents for delaying, for example, aluminum monostearate and gelatin.
  • Nasal spray formulations include purified aqueous solutions of the active agent with a preservative agent and/or an isotonic agents. Such formulations may be adjusted to a pH and isotonic state compatible with the nasal mucous membranes. Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats, or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye. Topical formulations include the active agent dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations. Topical formulations may be provided in the form of a bandage, wherein the formulation is incorporated into a gauze or other structure and brought into contact with the skin.
  • a CBD product may be prepared in a neutral medium chain triglyceride (MCT) oil.
  • MCT neutral medium chain triglyceride
  • An example of such an MCT may include MCT coconut oil.
  • CBD is soluble in a variety of oils.
  • certain CBD products may be prepared in an oil that may include an unsaturated fatty acid, such as an omega fatty acid.
  • preprating a CBD product in an unsaturated fatty acid may enhance the anti-inflammatory capability of the CBD product.
  • this disclosure describes administration of a cannabinoid (including, for example, a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and a combination thereof, and ii) an approximately 1: 1 equimolar mixture of CBD: CBDA), as the active agent, to a subject.
  • a cannabinoid including, for example, a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and a combination thereof, and ii) an approximately 1: 1 equimolar mixture of CBD: CBDA), as the active agent, to a subject.
  • this disclosure describes administration of a composition including a cannabinoid (including, for example, a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and a combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA) and an omega fatty acid, as the active agent, to a subject.
  • a cannabinoid including, for example, a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and a combination thereof, and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA) and an omega fatty acid, as the active agent, to a subject.
  • the active agent may be administered alone or in a pharmaceutical composition that includes the active agent and a pharmaceutically acceptable carrier.
  • administered encompasses administration of a prophylactically and/or therapeutically effective dose or amount of the active agent to a subject.
  • the active agent may be administered to a subject in an effective amount to produce the desired effect.
  • an “effective amount” of an agent is an amount that results in a reduction of at least one pathological parameter.
  • an effective amount is an amount that is effective to achieve a reduction of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%, compared to the expected reduction in the parameter in an individual not treated with the agent.
  • a “therapeutically effective amount” is meant a sufficient amount of the compound to treat the subject at a reasonable benefit/risk ratio applicable to obtain a desired therapeutic response. It will be understood, however, that the total daily usage of the compounds and compositions will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including, for example, the disorder being treated and the severity of the disorder, activity of the specific compound employed, the specific composition employed, the age, body weight, general health, sex and diet of the patient, the time of administration, route of administration, and rate of excretion of the specific compound employed, the duration of the treatment, drugs used in combination or coincidentally with the specific compound employed, and like factors well known in the medical arts.
  • a composition (either a cannabinoid composition or a cannabinoid-omega fatty acid composition) as an active agent may be introduced into the subject systemically or locally.
  • a composition may be introduced at a site of inflammation or the site of a tumor.
  • the active agent may be administered to the subject in an amount effective to produce the desired effect.
  • a composition may be administered in a variety of routes, including orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • Local administration may include topical administration, administration by injection, or perfusion or bathing of an organ or tissue, for example.
  • a formulation may be administered as a single dose or in multiple doses.
  • a formulation may be administered once per day or more than once per day including, for example, twice per day, three times per day, or four times per day.
  • Useful dosages of the active agent may be determined by comparing their in vitro activity and the in vivo activity in animal models. Methods for extrapolation of effective dosages in mice, and other animals, to humans are known in the art.
  • examples of anti-inflammatory therapies which may form the basis for determining dosages and dosing regiments for a cannabinoid may be found in online at, cbdoilreview.org/cbd-cannabidiol/cbd-dosage/medium.com/cbd-origin/whats-the-best- cbd-dosage-81ec4f95503b; www.projectcbd.org/how-to/cbd-dosage; or www.marijuanabreak.com/cbd-oil-dosage.
  • Dosage levels of the active agent in the pharmaceutical compositions may be varied to obtain an amount of the active agent which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the composition, the age, sex, weight, condition, general health, and prior medical history of the subject being treated, and like factors well known in the medical arts.
  • a composition may be administered to a subject in an amount of at least 5 mg, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, or at least 5 g.
  • a composition may be administered to a subject in an amount of up to 40 mg, up to 50 mg, up to 60 mg, up to 70 mg, up to 80 mg, up to 90 mg, up to 100 mg, up to 1000 mg, up to 5 g, or up to 10 g.
  • a composition may be administered orally at least once per day including, for example, as a medication, nutritional supplement, or food additive.
  • a composition may be administered to a subject intravenously or intramuscularly.
  • a composition may be administered to a subject in an amount effect to provide a daily dosage of at least 0.01 mg/kg body weight, at least 0.03 mg/kg body weight, at least 0.1 mg/kg body weight, at least 0. 3 mg/kg body weight, or at least 1 mg/kg body weight.
  • a composition may be administered to a subject in an amount effect to provide a daily dosage of up to 1 mg/kg body weight, up to 5 mg/kg body weight, up to 10 mg/kg body weight, or up to 20 mg/kg body weight.
  • a physician or veterinarian having ordinary skill in the art may determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician could start doses of the composition employed at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • this disclosure describes methods that include using a cannabinoid to treat or prevent inflammation and/or as an immunosuppressant. In another aspect, this disclosure describes methods that include using a cannabinoid-omega fatty acid composition to treat or prevent inflammation and/or as an immunosuppressant.
  • the individual cannabinoids CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV and THCVA, and a 1 : 1 equimolar mixture of CBD:CBDA each showed potential as anti-inflammatory agents, immunosuppressants and/or antioxidants (see Tables 7 and 8). Accordingly, the present disclosure provides in some embodiments methods of treating or preventing inflammation and/or autoimmunity in a subject in need thereof using the cannabinoid compositions described herein.
  • the individual cannabinoids CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, and THCVA and an omega fatty acid each showed potential as anti-inflammatory agents, immunosuppressants and/or antioxidants (see Tables 15-20, below).
  • the present disclosure provides in some embodiments methods of treating or preventing inflammation and/or autoimmunity in a subject in need thereof using the cannabinoid-omega fatty acid compositions described herein.
  • the present disclosure provides methods for inducing autophagy in a subject in need thereof comprising administering an effective amount of a composition comprising a cannabinoid chosen from: i) CBL, CBLA, THCVA, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBD A.
  • a composition comprising a cannabinoid chosen from: i) CBL, CBLA, THCVA, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBD A.
  • the present disclosure provides methods for inducing autophagy in a subject in need thereof comprising administering an effective amount of a composition comprising a cannabinoid chosen from: i) CBL, CBLA, THCVA, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA; and iii) an omega fatty acid.
  • a composition comprising a cannabinoid chosen from: i) CBL, CBLA, THCVA, and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA; and iii) an omega fatty acid.
  • the induction of the autophagy may treat or prevent cancer.
  • the induction of the autophagy may reduce inflammation in the subject.
  • TNF inhibitors cause a number of side effects that may be fatal, and many patients are nonresponsive to them (Jain and Singh, 2013; Hadam et al., 2014) - one or more compositions (either cannabinoid compositions or cannabinoid-omega fatty acid compositions) identified herein as anti-inflammatory agents or immunosuppressants could be used as a replacement for one or more of a more toxic anti-inflammatory drugs that is currently in use. Additionally or alternatively, as further described herein, a composition may be used in combination with another antiinflammation drug or drug cocktail.
  • a composition is administered in an amount effective to treat or prevent inflammation.
  • Administration of the composition may be performed before, during, or after a subject develops inflammation and/or or manifests symptoms of inflammation.
  • Therapeutic treatment is initiated after the development of inflammation.
  • Treatment initiated after the development of inflammation, or after manifestation of a symptom of inflammation may result in decreasing the severity of a symptom, or completely removing a symptom.
  • a composition may be administered before, during, or after a subject develops symptoms of an autoimmune disease.
  • Exemplary symptoms of an autoimmune disease or inflammation include fatigue, joint pain and/or swelling, skin problems, abdominal pain and/or digestive issues, recurring fever, swollen glands, etc.
  • a composition may be administered prophylactically in an amount effective to prevent or delay the development of inflammation in a subject.
  • Treatment that is prophylactic may be initiated before a subject develops inflammation, or manifests symptoms of inflammation.
  • An example of a subject who is at particular risk of developing inflammation is a person with an autoimmune disease including, for example, rheumatoid arthritis Crohn’s disease, lupus erythematosus (SLE), Sjogren syndrome, immune thrombocytopenic purpura (ITP), myasthenia gravis, sarcoidosis, Addison’s disease, autoimmune hepatitis, Celiac disease, Grave’s disease, idiopathic thrombocytopenic purpura, multiple sclerosis, primary biliary cirrhosis, psoriatic disease, scleroderma, systemic lupus, etc.
  • Administration of a composition may occur before, during, and/or after other treatments including, for example, additional active agent(s).
  • combination therapy may involve the administration of a composition before, during and/or after the use of other therapeutics used to treat inflammatory conditions or autoimmune diseases including, for example, nonsteroidal anti-inflammatory drugs (NSAIDs), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), corticosteroids, non-antibody tumor necrosis factor alpha (TNFa or TNF) inhibitors, and monoclonal antibody TNF inhibitors.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs conventional synthetic disease-modifying antirheumatic drugs
  • corticosteroids corticosteroids
  • TNFa or TNF non-antibody tumor necrosis factor alpha
  • monoclonal antibody TNF inhibitors monoclonal antibody TNF inhibitors.
  • compositions may be separated in time from the administration of another active agent by hours, days, or even weeks; alternatively, the other active agent(s) may be administered concurrently, either together in the same composition or in separate compositions. Additionally or alternatively, the administration of a composition may be combined with another active agent or modality such as, for example, non-drug therapies, such as, but not limited to, radiotherapy, heat therapy, cryotherapy, electrical therapy, massage, and acupuncture.
  • non-drug therapies such as, but not limited to, radiotherapy, heat therapy, cryotherapy, electrical therapy, massage, and acupuncture.
  • Example 4 The results described in Example 4 - that CBL, CBLA, and a 1 : 1 equimolar mixture of CBD:CBDA were effective at inducing autophagy - are noteworthy, given the increasing evidence that autophagy plays an important role in regulating the immune system (Kuballa et al., 2012) and suggest these compounds may serve as therapeutics for the treatment of inflammatory conditions and autoimmune diseases. Autophagy has been demonstrated to be downregulated in a number of autoimmune diseases (Wang and Muller, 2015; Wang et al., 2017) and agents that may induce autophagy have been proposed as potential new therapeutics for the treatment of inflammatory conditions and autoimmune diseases (Nguyen et al., 2013).
  • this disclosure describes methods that include using a cannabinoid or cannabinoid-omega fatty acid composition as an anti-cancer therapeutic.
  • CBD has been used as a nutritional supplement to treat cancer and recent scientific reports have validated its potential as an anticancer agent (Kenyon et al., 2018; Sule-Suso et al, 2019).
  • the results of Example 4 indicate for the first time that CBL, CBLA, THCVA, and a 1 :1 equimolar mixture of CBD:CBDA may be useful anticancer agents.
  • the cancer includes a lung cancer. (See Sule-Suso et al, 2019).
  • the cancer includes breast cancer (Kenyon et al., 2018).
  • the cancer includes glioma (Kenyon et al., 2018).
  • the cancer includes cervical cancer (Lukhele et al. BMC Complement Altern Med. 2016; 16:335).
  • the cancer includes colon cancer (Aviello et al. J Mol Med (Berl).2012;90:925- 934).
  • cancers to be treated include, but are not limited to, melanoma, basal cell carcinoma, colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer (including small-cell lung carcinoma and non-small-cell lung carcinoma), leukemia, lymphoma, sarcoma, ovarian cancer, Kaposi's sarcoma, Hodgkin's lymphoma, NonHodgkin's lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, head and neck cancers, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer
  • a composition is administered in an amount effective to treat or prevent a cancer.
  • Administration of the composition may be performed before, during, or after a subject develops cancer and/or or manifests symptoms of cancer.
  • Therapeutic treatment is initiated after the development of cancer.
  • Treatment initiated after the development of cancer, or after manifestation of a symptom of cancer may result in decreasing the severity of a symptom, or completely removing a symptom.
  • a composition may be administered before, during, or after a subject develops symptoms of a cancer.
  • Treatment of a cancer may include, for example, killing tumor cells, reducing the growth of tumor cells, reducing tumor size, inducing apoptosis in a tumor cell, and/or inducing tumor cells syncytial formation.
  • the efficacy of such methods for the treatment of cancer may be assessed by any of various parameters well known in the art.
  • Such methods include, but are not limited to, determinations of a reduction in tumor size, determinations of the inhibition of the growth, spread, invasiveness, vascularization, angiogenesis, and/or metastasis of a tumor, determinations of the inhibition of the growth, spread, invasiveness and/or vascularization of any metastatic lesions, determinations of tumor infiltrations by immune system cells, and/or determinations of an increased delayed type hypersensitivity reaction to tumor antigen.
  • the efficacy of treatment may also be assessed by the determination of a delay in relapse or a delay in tumor progression in the subject or by a determination of survival rate of the subject, for example, an increased survival rate at one or five years post treatment.
  • a relapse is the return of a tumor or neoplasm after its apparent cessation.
  • a composition may be administered prophylactically in an amount effective to prevent or delay the development of cancer in a subject.
  • Treatment that is prophylactic for instance, may be initiated before a subject develops cancer, or manifests symptoms of cancer.
  • An example of a subject who is at particular risk of developing cancer is a person who has been exposed to a carcinogen or who has tested positive for a genetic marker of cancer risk (for example, BRCA1 or BRCA2).
  • Administration of a composition may occur before, during, and/or after other treatments including, for example, additional active agent(s) or therapeutic agent(s).
  • such combination therapy may involve the administration of a composition before, during and/or after the use of other therapeutics used to treat cancer.
  • the administration of a composition may be separated in time from the administration of another active agent or therapeutic agent by hours, days, or even weeks; alternatively, the other active agent(s) or therapeutic agent(s) may be administered concurrently, either together in the same composition or in separate compositions.
  • the administration of a composition may be combined with another active agent or modality such as, for example, non-drug therapies, such as, but not limited to, radiotherapy, heat therapy, cryotherapy, electrical therapy, massage, and acupuncture.
  • the administration of a composition may allow for the effectiveness of a lower dosage of other therapeutic modalities when compared to the administration of the other therapeutic modalities alone, providing relief from the toxicity observed with the administration of higher doses of the other modalities.
  • an additional active agent or therapeutic agent may be an agent whose use for the treatment of cancer is known to the skilled artisan.
  • treatments include, but are not limited to, surgical resection, radiation therapy, hormone therapy, vaccines, antibody based therapies, whole body irradiation, bone marrow transplantation, peripheral blood stem cell transplantation, the administration of a chemotherapeutic agent, cytokines, antiviral agents, immune enhancers, tyrosine kinase inhibitors, protein kinase C (PKC) modulator (such as, for example, the PKC activator ingenol 3-angelate (PEP005) or the PKC inhibitor bisindolylmaleimid (enzastaurin), signal transduction inhibitors, antibiotics, antimicrobial agents, a TLR agonist (such as for example, bacterial lipopolysaccharides (LPS) or a CpG oligonucleotide (ODN)), an inhibitor of IDO, such as, for example
  • a chemotherapeutic agent may be, for example, a cytotoxic chemotherapy agent, such as, for example, epidophyllotoxin, mitoxantrone, platinum coordination complexes such as cisplatin and carboplatin, leucovorin, tegafur, paclitaxel, docetaxol, vincristine, vinblastine, methotrexate, cyclophosphamide, gemcitabine, estramustine, carmustine, adriamycin (doxorubicin), etoposide, arsenic trioxide, irinotecan, epothilone derivatives, navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, ifosamide, and droloxafine.
  • a cytotoxic chemotherapy agent such as, for example, epidophyllotoxin, mitoxantrone, platinum coordination complexes such as cisplatin and
  • a chemotherapeutic agent may be, for example, an alkylating agent, such as, for example, irofulven, nitrogen mustards (such as chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, and uracil mustard), aziridines (such as thiotepa), methanesulphonate esters (such as busulfan), nitroso ureas (such as carmustine, lomustine, and streptozocin), platinum complexes (such as cisplatin and carboplatin), and bioreductive alkylators (such as mitomycin, procarbazine, dacarbazine and altretamine), ethylenimine derivatives, alkyl sulfonates, triazenes, pipobroman, temozolomide, triethylene-melamine, and tri ethylenethiophosphoramine.
  • an alkylating agent such as, for example,
  • a chemotherapeutic agent may be an antimetabolite, such as, for example, a folate antagonist (such as methotrexate and trimetrexate), a pyrimidine antagonist (such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, gemcitabine, and floxuridine), a purine antagonist (such as mercaptopurine, 6-thioguanine, fludarabine, and pentostatin), a ribonucleotide reductase inhibitor (such as hydroxyurea), and an adenosine deaminase inhibitor.
  • a folate antagonist such as methotrexate and trimetrexate
  • a pyrimidine antagonist such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, gemcitabine, and floxuridine
  • a purine antagonist such as mercaptopurine, 6-thi
  • a chemotherapeutic agent may be a DNA strand-breakage agent (such as, for example, bleomycin), a topoisomerase II inhibitor (such as, for example, amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide), a DNA minor groove binding agent (such as, for example, plicamydin), a tubulin interactive agent (such as, for example, vincristine, vinblastine, and paclitaxel), a hormonal agent (such as, for example, estrogens, conjugated estrogens, ethinyl estradiol, diethylstilbesterol, chlortrianisen, idenestrol, progestins (such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol), and androgens (such as testosterone, testosterone propionate, fluoxy
  • At least one additional therapeutic agent includes radiation therapy.
  • radiation therapy includes localized radiation therapy delivered to the tumor.
  • radiation therapy includes total body irradiation.
  • Cytokines include, but are not limited to, IL-la, IL-ip, IL-2, IL-3, IL-4, IL-6, IL- 8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-18, IL-19, IL-20, IFN-a, IFN-p, IFN-y, tumor necrosis factor (TNF), transforming growth factor-P (TGF-P), granulocyte colony stimulating factor (G- CSF), macrophage colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), and or Fit- 3 ligand.
  • TGF-P tumor necrosis factor
  • TGF-P tumor necrosis factor
  • G- CSF granulocyte colony stimulating factor
  • M-CSF macrophage colony stimulating factor
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • Fit- 3 ligand Fit- 3 ligand.
  • Antibody therapeutics include, for example, trastuzumab (Herceptin) and antibodies to cytokines, such as IL-10 and TGF-p.
  • a measurement of response to treatment observed after administering both a composition and an additional active agent or therapeutic agent is improved over the same measurement of response to treatment observed after administering either the composition alone or the additional agent alone.
  • the administration of a composition as described herein and the at least one additional therapeutic agent demonstrate therapeutic synergy.
  • a combination may demonstrate therapeutic synergy if it is therapeutically superior to one or other of the constituents used at its optimum dose (Corbett et al., 1982, Cancer Treatment Reports; 66: 1187.
  • a combination demonstrates therapeutic synergy if the efficacy of a combination is characterized as more than additive actions of each constituent.
  • kits that contains at least one cannabinoid or composition described herein, together with instructions for use.
  • This disclosure also further describes a kit that contains at least one cannabindoid, an omega fatty acid, or composition described herein, together with instructions for use.
  • the instructions for use provide instructions for use in the treatment or prevention of inflammation and/or autoimmunity.
  • the kit includes a pharmaceutically acceptable carrier.
  • the carrier may be separately provided, or it may be present in a composition that includes the compound.
  • the kit may further include one or more additional active agents which may be co-administered with the composition.
  • the one or more active agent(s) may have cumulative or complementary activities, as described in more detail elsewhere herein.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i)
  • composition of embodiment 1, wherein the cannabinoid is chosen from: i) the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, THCVA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • composition of embodiment 1, wherein the cannabinoid is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 1, wherein the cannabinoid is chosen from: i) the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1:1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 5, wherein the cannabinoid is chosen from the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof.
  • composition of embodiment 6, wherein the cannabinoid is chosen from the CBDV, CBL, CBLA, CBN, CBNA and any combination thereof.
  • the cannabinoid is chosen from i) the CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBL, CBLA, CBN, CBNA, THCV, and THCVA, and ii) the approximately 1:1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 1, wherein the cannabinoid is chosen from i) the CBCA, CBDA, CBDV, CBDVA, CBL, CBLA, CBN, CBNA, and THCVA, and ii) the approximately 1:1 equimolar mixture of CBD:CBDA.
  • composition of embodiment 10 or 11, wherein the cannabinoid consists essentially of the approximately 1:1 equimolar mixture of CBD:CBDA.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i)
  • the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • composition of embodiment 15, wherein the cannabinoid is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 15, wherein the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, and THCVA.
  • the pharmaceutical composition of embodiment 15, wherein the cannabinoid is chosen from the CBDV, CBL, CBLA, CBN, CBNA, and any combination thereof. [00135] 20. The pharmaceutical composition of embodiment 15, wherein the cannabinoid is chosen from i) the CBD, CBDA, CBDV, CBDVA, CBG, and THCV and ii) the approximately 1:1 equimolar mixture of CBD: CBDA.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i)
  • composition of embodiment 28 or 29, wherein the cannabinoid consists essentially of the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • a pharmaceutical composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • composition of embodiment 32 wherein the pharmaceutical composition comprises an additional cannabinoid chosen from CBC, CBCA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • additional cannabinoid chosen from CBC, CBCA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • NSAIDs nonsteroidal anti-inflammatory drug
  • DMARDs conventional synthetic disease-modifying antirheumatic drug
  • corticosteroid a corticosteroid
  • nonantibody tumor necrosis factor alpha inhibitor a monoclonal antibody TNF inhibitor
  • monoclonal antibody TNF inhibitor monoclonal antibody
  • composition of any one of embodiments 1 to 39 comprising administering an effective amount of the composition to a subject in need thereof.
  • a method for treating or preventing inflammation and/or autoimmunity in a subject comprising administering to the subject a composition comprising an effective amount of a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • autoimmune disease comprises rheumatoid arthritis Crohn’s disease, lupus erythematosus (SLE), Sjogren syndrome, immune thrombocytopenic purpura (ITP), myasthenia gravis, sarcoidosis, Addison’s disease, autoimmune hepatitis, Celiac disease, Grave’s disease, idiopathic thrombocytopenic purpura, multiple sclerosis, primary biliary cirrhosis, psoriatic disease, scleroderma, or systemic lupus.
  • treating or preventing inflammation comprises treating or preventing a symptom of inflammation.
  • [00161] 46 The method of any one of embodiments 41 to 44, wherein the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • [00162] 47 The method of any one of embodiment 41 to 44, wherein the cannabinoid is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • [00165] 50 The method of any one of embodiments 41 to 44, wherein the cannabinoid is chosen from the CBDV, CBL, CBLA, CBN, CBNA, and any combination thereof.
  • [00170] 55 The method of any one of claims 41 to 44, wherein the cannabinoid consists essentially of the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • [00171] 56 The method of any one of embodiment 41 to 44, wherein the cannabinoid consists essentially of the 1 : 1 equimolar mixture of CBD:CBDA.
  • the additional active agent is chosen from a nonsteroidal anti-inflammatory drug (NSAIDs), a conventional synthetic diseasemodifying antirheumatic drug (DMARDs), a corticosteroid, a non-antibody tumor necrosis factor alpha inhibitor, or a monoclonal antibody TNF inhibitor, and any combination thereof.
  • NSAIDs nonsteroidal anti-inflammatory drug
  • DMARDs conventional synthetic diseasemodifying antirheumatic drug
  • corticosteroid a corticosteroid
  • a non-antibody tumor necrosis factor alpha inhibitor or a monoclonal antibody TNF inhibitor
  • a method for inducing autophagy in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising a cannabinoid chosen from: i) CBL, CBLA, and THCVA, and any mixture thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i) CBL, CBLA, and THCVA, and any mixture thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • a method of treating or preventing cancer in a patient in need thereof comprising the method comprising administering to the subject a composition comprising an effective amount of a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof; and ii) an approximately 1:1 equimolar mixture of CBD: CBD A.
  • a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • [00181] 66 The method of embodiment 64 or 65, wherein the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • [00182] 67 The method of any one of embodiments 64 to 66, wherein the cannabinoid is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1: 1 equimolar mixture of CBD:CBDA.
  • any one of embodiments 60 to 76 further comprising administering and additional active agent chosen from a chemotherapeutic agent, a cytokine, an antiviral agent, an immune enhancer, a tyrosine kinase inhibitor, a protein kinase C (PKC) modulator, a signal transduction inhibitor, an antibiotic, an antimicrobial agent, a TLR agonist, an inhibitor of IDO, an adjuvant, and any combination thereof.
  • active agent chosen from a chemotherapeutic agent, a cytokine, an antiviral agent, an immune enhancer, a tyrosine kinase inhibitor, a protein kinase C (PKC) modulator, a signal transduction inhibitor, an antibiotic, an antimicrobial agent, a TLR agonist, an inhibitor of IDO, an adjuvant, and any combination thereof.
  • composition further comprises a pharmaceutical carrier.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i)
  • composition of embodiment 83, wherein the cannabinoid is chosen from: i) the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, THCVA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 83, wherein the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • composition of embodiment 83, wherein the cannabinoid is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 83, wherein the cannabinoid is chosen from: i) the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1:1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 87, wherein the cannabinoid is chosen from the CBCA, CBDA, CBDV, CBDVA, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof.
  • composition of embodiment 88 wherein the cannabinoid is chosen from the CBDV, CBL, CBLA, CBN, CBNA and any combination thereof.
  • the cannabinoid is chosen from i) the CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBL, CBLA, CBN, CBNA, THCV, and THCVA, and ii) the approximately 1:1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 83, wherein the cannabinoid is chosen from i) the CBCA, CBDA, CBDV, CBDVA, CBL, CBLA, CBN, CBNA, and THCVA, and ii) the approximately 1:1 equimolar mixture of CBD:CBDA.
  • cannabinoid is the approximately 1:1 equimolar mixture of CBD:CBDA.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i)
  • composition of embodiment 98, wherein the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • composition of embodiment 98, wherein the cannabinoid is chosen from: i) the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, and any combination thereof, and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • composition of embodiment 98, wherein the cannabinoid is chosen from the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, and THCVA.
  • composition of embodiment 98, wherein the cannabinoid is chosen from the CBDV, CBL, CBLA, CBN, CBNA, and any combination thereof.
  • the cannabinoid is chosen from i) the CBD, CBDA, CBDV, CBDVA, CBG, and THCV and ii) the approximately 1 : 1 equimolar mixture of CBD: CBDA.
  • composition of any one of embodiments 104 to 106, wherein the cannabinoid consists essentially of a 1 : 1 equimolar mixture of CBD:CBDA.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i)
  • CBL, CBLA, and THCVA and any mixture thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA, and an omega fatty acid, wherein the pharmaceutical composition is formulated to induce autophagy in vivo or in vitro.
  • composition of embodiment 108, wherein the cannabinoid is chosen from: i) the CBL, CBLA, and a mixture thereof; and ii) the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • composition of embodiment 109, wherein the cannabinoid is chosen from the CBL, CBLA, and a mixture thereof.
  • composition of embodiment 108 or 109, wherein the cannabinoid is chosen from the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • composition of embodiment 111 or 112, wherein the cannabinoid consists essentially of the approximately 1 : 1 equimolar mixture of CBD:CBDA.
  • a pharmaceutical composition comprising an approximately 1 : 1 equimolar mixture of CBD:CBDA and an omega fatty acid.
  • composition of embodiment 115 wherein the pharmaceutical composition comprises an additional cannabinoid chosen from CBC, CBCA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • composition of any one of claims 83 to 119, wherein the composition further comprises a pharmaceutical carrier.
  • NSAIDs nonsteroidal anti-inflammatory drug
  • DMARDs conventional synthetic disease-modifying antirheumatic drug
  • corticosteroid a corticosteroid
  • nonantibody tumor necrosis factor alpha inhibitor a monoclonal antibody TNF inhibitor
  • composition of any one of embodiments 83 to 121, wherein the composition is formulated for use as an anti-cancer agent.
  • omega fatty acid comprises a plurality of omega fatty acids, and a majority of the omega fatty acids of the plurality of omega fatty acids is DHA.
  • omega fatty acid comprises a plurality of omega fatty acids, and a majority of the omega fatty acids of the plurality of omega fatty acids is EPA.
  • omega fatty acid comprises a plurality of omega fatty acids, and a majority of the plurality of omega fatty acids is a mixture of DHA and EPA.
  • a method for treating or preventing inflammation and/or autoimmunity in a subject comprising administering to the subject a composition comprising an effective amount of a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD: CBDA, and an omega fatty acid.
  • a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • autoimmune disease comprises rheumatoid arthritis Crohn’s disease, lupus erythematosus (SLE), Sjogren syndrome, immune thrombocytopenic purpura (ITP), myasthenia gravis, sarcoidosis, Addison’s disease, autoimmune hepatitis, Celiac disease, Grave’s disease, idiopathic thrombocytopenic purpura, multiple sclerosis, primary biliary cirrhosis, psoriatic disease, scleroderma, or systemic lupus.
  • treating or preventing inflammation comprises treating or preventing a symptom of inflammation.
  • the additional active agent is chosen from a nonsteroidal anti-inflammatory drug (NSAIDs), a conventional synthetic diseasemodifying antirheumatic drug (DMARDs), a corticosteroid, a non-antibody tumor necrosis factor alpha inhibitor, or a monoclonal antibody TNF inhibitor, and any combination thereof.
  • NSAIDs nonsteroidal anti-inflammatory drug
  • DMARDs conventional synthetic diseasemodifying antirheumatic drug
  • corticosteroid a corticosteroid
  • a non-antibody tumor necrosis factor alpha inhibitor or a monoclonal antibody TNF inhibitor
  • a method for inducing autophagy in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising a cannabinoid chosen from: i) CBL, CBLA, and THCVA, and any mixture thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA, and an omega fatty acid.
  • a pharmaceutical composition comprising a cannabinoid chosen from: i) CBL, CBLA, and THCVA, and any mixture thereof; and ii) an approximately 1 : 1 equimolar mixture of CBD:CBDA, and an omega fatty acid.
  • a method of treating or preventing cancer in a patient in need thereof comprising the method comprising administering to the subject a composition comprising an effective amount of a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof; and ii) an approximately 1:1 equimolar mixture of CBD:CBDA, and an omega fatty acid.
  • a cannabinoid chosen from i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA, and any combination thereof.
  • a chemotherapeutic agent chosen from a chemotherapeutic agent, a cytokine, an antiviral agent, an immune enhancer, a tyrosine kinase inhibitor, a protein kinase C (PKC) modulator, a signal transduction inhibitor, an antibiotic, an antimicrobial agent, a TLR agonist, an inhibitor of IDO, an adjuvant, and any combination thereof.
  • a method for inducing autophagy in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising: i) a cannabinoid; ii) an approximately 1: 1 equimolar mixture of CBD:CBDA; and iii) an omega fatty acid.
  • the Examples describe the identification of the antioxidant, anti-inflammatory, and immunosuppressant activity, as well as induction of autophagy, of a number of non-psychotropic cannabinoids and cannabinoid-omega fatty acid compositions.
  • CBDA cyclopentadiene
  • LPS lipopolysaccharide
  • CBDA cannabichromenic acid
  • CBDA cannabidiolic acid
  • CBDVA cannabidivarinic acid
  • CBDVA cannabigerolic acid
  • THCVA tetrahydrfocannabivarinic acid
  • CBC cannabichromenic acid
  • CBDA cannabidiolic acid
  • CBDVA cannabidivarinic acid
  • CBDA cannabigerolic acid
  • THCVA tetrahydrfocannabivarinic acid
  • CBC cannabichromene
  • CBD cannabidiol
  • CBDDV cannabidivarin
  • CBG cannabigerol
  • THCV tetrahydrocannabivarin
  • CBDA cannabichromenic acid
  • CBDA cannabidiolic acid
  • CBDVA cannabidivarinic acid
  • CBDA cannabigerolic acid
  • THCVA cannabigerolic acid
  • THCVA tetrahydrfocannabivarinic
  • the major cannabinoids CBCA, CBDA, CBDVA, CBGA and THCVA and their decarboxylated derivatives, CBC, CBD, CBDV, CBG, and THCV were obtained from Cerilliant Corporation (Round Rock, TX).
  • CBCVA and CBGVA and their decarboxylated derivatives CBCV and CBGV are not commercially available and were not analyzed.
  • the CBLA and CBNA cannabinoids, as well as their decarboxylated derivatives CBL and CBN, are the most widely investigated cannabinoids which can be derivatized from the natural cannabinoids that are produced by Cannabis, and were obtained from Cerilliant Corporation (Round Rock, TX).
  • DMSO dimethyl sulfoxide
  • PB phosphate buffer
  • CBD is incredibly toxic to animal or human cells grown via tissue culture and doses of less than 5 pM can cause significant cytotoxicity (Choi et al., 2008; Liu et al., 2010; Mato et al., 2010; Lukhele and Motadi, 2016). For this reason, the doses of CBD that are used in in vitro cellular studies must be carefully determined to ensure they do not cause cytotoxicity.
  • the ability of the cannabinoids to act as potential antioxidants was assessed using the 2,2-diphenyl-l-picrylhydrazyl (DPPH) antioxidant assay.
  • DPPH 2,2-diphenyl-l-picrylhydrazyl
  • the cannabinoids CBDA, CBD, CBDVA, CBDV, CBG, THCV, and the 1 : 1 CBD:CBDA mixture had the highest antioxidant activities with radical scavenging activities of 38.19%, 48.00%, 43.81%, 44.21%, 44.28%, 45.71%, and 43.74%, respectively.
  • the 2,2-diphenyl-l-picrylhydrazyl (DPPH) free radical (Alfa Aesar) was prepared at 0.1 mM in ethanol.
  • the cannabinoids were tested at a final concentration of 100 uM.
  • 2 uL of 7.5 mM stock solutions of the cannabinoids to be tested in DMSO were added to 148 uL of 0.1 mM DPPH to achieve a final concentration of 100 pM in the assay.
  • Ascorbic acid (Thermo Scientific) at a final concentration of 10 mg/ml was used as a positive control.
  • % RSA percent radical scavenging activity
  • Free radical production occurs when the immune system is activated and antioxidants represent potential effective treatments for inflammatory conditions and autoimmune diseases. Since a couple of recent studies have demonstrated the ability of CBD to act as an antioxidant (Hosseinzadeh et al., 2016; Rajan et al., 2016), the antioxidant potential of all of the major cannabinoids that had been evaluated as immunosuppressants was also investigated.
  • the DPPH antioxidant assay can be used to measure the ability of a compound to scavenge free radicals by measuring the ability of compounds to hydrogenate and reduce DPPH.
  • the DPPH assay was conducted on CBCA, CBDA, CBDVA, CBGA, CBLA, CBNA, THCVA, and their decarboxylated derivatives as well as the 1 : 1 CBD:CBDA mixture. Results are shown in Table 5. Table 5: Ability of the non-psychotropic cannabinoids CBCA, CBDA, CBDVA, CBGA, CBLA, CBNA, THCVA, and their decarboxylated derivatives, to hydrogenate and reduce DPPH
  • CBDA, CBD, CBDVA, CBDV, CBG, THCV, and the 1 : 1 CBDUBDA mixture had the highest antioxidant activities with radical scavenging activities of 38.19%, 48.00%, 43.81%, 44.21%, 44.28%, 45.71%, and 43.74%, respectively.
  • Ascorbic acid (10 mg/mL) was used as a positive control, and the ability of compounds to reduce DPPH was calculated as % RSA (radical scavenging activity).
  • One of the most robust in vitro cellular tests that can be performed to evaluate the immunosuppressant potential of a therapeutic agent is to determine whether the agent can suppress the cytokine levels in THP-1 human monocyte cells that have been differentiated into macrophage-like cells using PMA and then had their immune system induced with an immunostimulant, such as LPS (Cochran FR, Finch- Arietta MB, 1989).
  • an immunostimulant such as LPS (Cochran FR, Finch- Arietta MB, 1989).
  • the THP-1 cytokine suppression assay was run as three independent experiments and only cytokines whose expression was induced more than two-fold in the LPS control versus the untreated sample were analyzed for suppression by the dexamethasone control and the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA cannabinoids, or the 1 : 1 CBD:CBDA cannabinoid mixture.
  • THP-1 cells were maintained in RPMI 1640 medium supplemented with 10% heat- inactivated FBS and 1% penicillin/ streptomycin (complete culture medium) at 37°C with 5% CO2 supplemented. Cell concentrations were adjusted to 5 x 105 cells/mL by centrifugation at 500 x g for 5 minutes and resuspended in complete culture medium with 100 nM of phorbol 12-myristate 13-acetate (PMA). Cells were seeded onto 24-, or 12-well plates and incubated for 48 hours to 72 hours to allow for differentiation. Cells were washed with serum-free RPMI 1640 medium before each experiment to remove undifferentiated cells.
  • PMA phorbol 12-myristate 13-acetate
  • Differentiated THP-1 cells were treated with cannabinoids, or the corticosteroid dexamethasone as a control, at a final concentration of 2 DM for 1 hour and then stimulated with 20 ng/mL of lipopolysaccharide (LPS) for 4 hours.
  • LPS lipopolysaccharide
  • Supernatants were collected for quantification of human cytokine levels to assess the cytokine response. Cells remaining after the supernatant collection were tested to ensure they had at least 90% viability as determined by Alamar Blue assays. To conduct the Alamar Blue assays, supernatants were replaced with culture medium containing 1 x Alamar Blue reagent and incubated overnight.
  • Table 7 Suppression of cytokine induction in THP-1 by dexamethasone, the CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA cannabinoids, or the 1:1 CBD:CBDA cannabinoid mixture
  • the 1 : 1 CBD:CBDA mixture exhibited the greatest suppression followed by CBL. CBC and THCVA were not as effective at suppressing cytokine expression compared to the other cannabinoids.
  • the suppression by the 1 : 1 equimolar mixture of CBD:CBDA was 37.28% more effective than CBD and 22.40% more effective than CBDA.
  • the suppression by the 1 : 1 equimolar mixture of CBD:CBDA was clearly synergistic compared to the suppression by CBD or CBDA alone.
  • the pharmaceutical definition of synergy is that the interaction of two or more agents should produce a combined effect which is greater than the sum of the separate effects of the agents.
  • the effect of a 1 : 1 CBD:CBDA or ’A CBD and ’A CBDA mixture should be greater than the sum of the individual effects of CBD and CBDA, which are (’AX CBD + ’AX CBDA); i.e., the 45.51% suppression by 1 : 1 CBD:CBDA was greater than the 35.17% expression expected by ’AX CBD + ’AX CBDA.
  • the THP-1 cytokine suppression assay was run as four independent experiments and only cytokines whose expression was induced more than two-fold in the LPS control versus the untreated sample in at least three out of the four experiments were analyzed for suppression by the dexamethasone control and the CBD and CBDA cannabinoids or the 1 : 1 equimolar mixture of the CBD:CBDA cannabinoids.
  • Table 8 The results are summarized in Table 8.
  • Table 8 Suppression of cytokine induction in THP-1 by dexamethasone, CBD, CBDA or the
  • the expression levels of all of these cytokines was induced more than two-fold by LPS with the exception of IL-2 and 11-17.
  • the expression levels of 7 out of the 7, or 100.00%, of the inflammatory cytokines whose expression levels were induced more than two-fold by LPS, could be strongly suppressed by the cannabinoids.
  • the IL-IRA, IL-4, IL-10, IL-11, IL-13 and TGF0 cytokines are widely recognized to be antiinflammatory cytokines and all of them were included in the cytokines that were analyzed except for IL-11 and TGF0.
  • the expression levels of only 1 out of the 4, or 25% of the anti-inflammatory cytokines that were analyzed could be induced at least two-fold by LPS and strongly suppressed by the cannabinoids.
  • the cannabinoids preferentially targeted the suppression of inflammatory cytokines as opposed to anti-inflammatory cytokines.
  • the suppression of FGF-2, IL-15, IL-18 could only be achieved by the cannabinoids and not dexamethasone and that IL- 15 and IL- 18 are generally recognized as two of the more important inflammatory cytokines.
  • the suppression by the 1 : 1 equimolar mixture of CBD:CBDA was 31.70% more effective than CBD and 22.98% more effective than CBDA and the effectiveness of the suppression by the 1 : 1 equimolar mixture of CBD:CBDA versus CBD and CBDA was very similar to the results that were achieved in the experiments that compared all of the cannabinoids.
  • the suppression by the 1 : 1 equimolar mixture of CBD:CBDA was clearly synergistic compared to the suppression by CBD or CBDA alone.
  • the 52.18% suppression by 1 : 1 CBD:CBDA was greater than the 41.03% expression expected by ’AX CBD + ’AX CBDA.
  • EXAMPLE 3 Mouse LPS cytokine animal model
  • mice Similar to the in vitro THP-1 LPS assay, compounds are then analyzed for their ability to suppress the immune response by measuring the cytokine levels.
  • cytokine levels are then analyzed for their ability to suppress the immune response by measuring the cytokine levels.
  • Four 20 g female C57BL/6 mice were used per group. The experimental mice were first injected with 0.1 mL of the cannabinoids prepared at 1 mg/mL in phosphate buffer (PB) with 5% DMSO to yield a final dose of 5 mg/kg, followed one hour later by the injection of 0.1 mL of 0.02 mg/mL LPS in PB to yield a final dose of 0.1 mg/kg.
  • PB phosphate buffer
  • the mice were then euthanized, heart punctures performed to extract the blood, which was allowed to coagulate on ice for 1 hour before centrifuging to isolate the serum.
  • the levels of 32 of the most common mouse cytokines (Eve Technologies, Calgary, Canada, Table 9) were determined by multi-plex analysis.
  • Table 10 Percent suppression of mouse cytokine induction in mice by CBD, CBDA or a 1:1 equimolar mixture of CBD:CBDA [00307] At least two out of the three cannabinoids that were tested, CBD, CBDA or the 1 : 1 equimolar mixture of CBD: CBDA, suppressed the expression of 16 out of the 23 cytokines that were induced more than two-fold in the LPS versus the untreated samples.
  • the IFNy, IL-1/?, IL- 2, IL-6, IL-12, IL-15, IL-16, IL-17, IL-18, IL-23 and TNFa cytokines are widely recognized to be inflammatory cytokines and all of them were included in the cytokines that were analyzed except for IL-16, IL-18 and IL-23.
  • the expression levels of 7 out of the 8, or 87.50%, of the inflammatory cytokines that were analyzed could be suppressed by the cannabinoids.
  • the IL- 1RA, IL-4, IL-10, IL-11, IL-13 and TGF0 cytokines are widely recognized to be antiinflammatory cytokines and all of them were included in the cytokines that were analyzed except for IL-IRA, IL-11 and TGF0.
  • the expression levels of only 1 out of the 3, or 33.33% of the antiinflammatory cytokines that were analyzed could be induced at least two-fold by LPS and strongly suppressed by the cannabinoids.
  • the cannabinoids preferentially targeted the suppression of inflammatory cytokines as opposed to anti-inflammatory cytokines.
  • the suppression by the 1 : 1 equimolar mixture of CBD:CBDA was clearly synergistic compared to the suppression by CBD or CBDA alone.
  • the 20.96% suppression by 1 : 1 CBD:CBDA was greater than the 13.29% expression expected by ’AX CBD + ’AX CBDA.
  • U-937 pro-monocytic histiocytic lymphoma cells ATCC, Manassas, VA, USA
  • U-937 pro-monocytic histiocytic lymphoma cells ATCC, Manassas, VA, USA
  • U-937 cells were cultured in RPML1640 medium with L-glutamine and sodium bicarbonate (Sigma-Aldrich, St Louis, MO) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin in 25 cm2 tissue flasks at 37°C in a 5% CO2 humidified atmosphere and passaged every 2-3 days.
  • FBS fetal bovine serum
  • U-937 cells were seeded in 96 well plates at 5 x 105 cells /mL and stimulated with 100 ng/mL PMA to induce differentiation for 24 hours. The cells were then treated with the various cannabinoids at 1.0 pM concentrations for 12 hours. 30 pM chloroquine was used as a positive control. After treatment, the cells were fixed using 3.7% formaldehyde in PBS for 15 minutes at room temperature and washed with PBS to remove the fixative. Permeabilization reagent (0.2 % Triton X-100 in PBS) (Sigma-Aldrich) was added, the cells were incubated for 15 minutes at room temperature and then the cells were washed with PBS to remove the permeabilization reagent.
  • Permeabilization reagent 0.2 % Triton X-100 in PBS
  • LC3B rabbit polyclonal antibody (Invitrogen) was added at a final concentration of 0.5 pg/ml for 1 hour at room temperature and the cells were washed with PBS remove the primary antibody. Secondary conjugated goat anti-rabbit polyclonal antibody (Thermo Scientific) was then added at a final concentration of 2.0 pg/ml for 1 hour at room temperature. The cells were washed, Hoechst dye was added to stain the nucleus and the cells were imaged using an Array scan VTI high-content screening (HCS) reader (Thermo Scientific) with the appropriate filters and the data was analyzed using the vHCS Scan software.
  • HCS high-content screening
  • Autophagy or autophagocytosis, is a complex lysosomal based process that degrades and recycles proteins and cellular components. It has become increasingly evident that autophagy is involved in regulating the immune system (Kuballa et al., 2012) and that autophagy is dysfunctional and downregulated in autoimmune diseases (Wang and Muller, 2015; Wang et al., 2017). Autophagy has been proposed as a potential treatment for inflammatory conditions and autoimmune diseases (Nguyen et al., 2013) and as therapeutics for the treatment of cancer (Mukhtar, et al., 2012; Byun et al., 2017; Jiang et al., 2019).
  • Results are shown in Table 11. While most of the cannabinoids did not induce autophagy, CBL, CBLA, THCVA and the 1 : 1 equimolar mixture of CBD:CBDA did. At a concentration of 1.0 pM, CBL, CBLA, THCVA and the 1 : 1 equimolar mixture of CBD:CBDA increased autophagy 59.30%, 49.78%, 37.72%, and 40.37%, respectively, compared to the untreated control. Chloroquine at a concentration of 30 pM was included as a positive control. The ability to induce autophagy was determined as a percentage with respect to the untreated control.
  • Examples 1 to 4 demonstrate the ability of the major non-psychotropic Cannabis cannabinoids to act as anti-inflammatory agents, immunosuppressants and/or antioxidants, as summarized in Table 12. While all of the tested cannabinoids demonstrated at least some ability to suppress cytokine induction, CBCA, CBDA, CBD, CBDVA, CBDV, CBGA, CBG, CBLA, CBL, CBNA, CBN, THCVA, THCV, and the 1 : 1 equimolar mixture of CBD: CBDA demonstrated the strongest cytokine suppression in these studies.
  • the individual cannabinoids CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBLA, CBL, CBNA, CBN, THCVA, THCV, and a 1 : 1 equimolar mixture of CBD: CBDA were at least half as effective as dexamethasone at reducing elevated cytokine levels in differentiated THP-1 cells that had been treated with LPS.
  • the individual cannabinoids CBL, CBLA, THCVA, and a 1 : 1 equimolar mixture of CBD: CBDA proved to be particularly effective at inducing autophagy in differentiated U937 cells.
  • Exemplary cannabinoid profiles of buds from a harvested and dried hemp Cherry variety, a typical hemp strain with a high CBDA content (Table 13) and Cherry Whine, a typical hemp strain with a high CBDA content (Table 15) were analyzed by Pixis Labs, Portland, Oregon, from hemp flowers sold by Tweedie Farms, Portland, Oregon.
  • mice were injected with LPS, which induced the immune response shortly after the mice were injected with one of the potential antiinflammatory compounds under evaluation (the “test compound”).
  • the efficacy of the test compound was evaluated based on its ability to reduce expression levels of inflammatory cytokines that were elevated due to the immune response.
  • the test compounds included a cannabinoid, an omega fatty acid, and a cannabinoid-omega fatty acid composition.
  • mice were intraperitoneally injected with 0.1 mL of the test compound.
  • the mice were intraperitoneally injected with 0.1 mL of LPS in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • a heart puncture was performed and the blood was allowed to clot to generate serum.
  • 0.1 mL of the serum was diluted 1 :2 with PBS and stored at -80° C.
  • the serum was then sent to a laboratory where a mouse cytokine array/chemokine array 31-plex (MD31) analysis was performed that analyzed the expression levels of the 32 cytokines/chemokines listed in Table 9, above.
  • MD31 mouse cytokine array/chemokine array 31-plex
  • EXAMPLE 6A Determining the Dosing Efficacy of a Cannabinoid in Mice Using the Mouse LPS Cytokine Animal Model
  • CBD has been tested in numerous mice studies and the preferred vehicle for injection is propylene glycol (PG), which poses a significantly lower toxicological risk than dimethyl sulfoxide (DMSO). CBD that has been resuspended in propylene glycol is missed with PBS for injection.
  • PG propylene glycol
  • DMSO dimethyl sulfoxide
  • the LD50 of propylene glycol is 20,000 mg/kg while the LD50 of dimethyl sulfoxide is 14,500 mg/kg.
  • a typical dose of CBD in human adults that is used in the US is 25 to 50 mg and is based on the currently accepted 181 lb. or 82.1 kg average weight value for human adults in the US. This is equivalent to 0.30 to 0.60 mg/kg for a 20 g mouse. Thus, in mice, the most efficacious dose may range from 0.30 to 7.38 mg/kg depending on how CBD is metabolized in mice versus humans. Initially, a study of doses of 10 mg/kg, 3 mg/kg, and 1 mg/kg of 1 : 1 CBD: CBD A in mice was performed using propylene glycol as the vehicle (Study 1, below).
  • the third study was performed with doses of 5 mg/kg, 1.67 mg/kg, 0.5 mg/kg, 0.167 mg/kg, and 0.05 mg/kg of 1 : 1 CBD:CBDA using MCT oil as the vehicle to determine the most efficacious dose of 1 : 1 CBD:CBDA in mice.
  • Study 1 10 mg/kg, 3 mg/kg, and 1 mg/kg of 1:1 CBD:CBDA resuspended in 90% PBS, 10% propylene glycol
  • mice 20 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into five groups of four mice each so the average weight of each group was as close as possible to each other.
  • the five groups were (1) Untreated (0.1 mL injection of 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of PBS instead of LPS); (2) LPS control (0.1 mL injection of 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (3) 10 mg/kg 1 : 1 CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (4) 3 mg/kg 1 : 1 CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of LPS in PBS) ; and (5) 1 mg/kg 1 : 1 CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in
  • the 1 : 1 CBD:CBDA test compounds were dosed at 10.0 mg/kg or 0.2 mg per 20 g mouse, 3.33 mg/kg or 0.067 mg per 20 g mouse and 1.0 mg/kg or 0.02 mg per 20 g mouse.
  • the test compounds were prepared as 20 mg/mL, 6.67 mg/mL and 2 mg/mL solutions in propylene glycol and then diluted 1 : 10 with phosphate buffered saline (PBS) and mixed well to create a 2 mg/mL, 0.67 mg/mL and 0.2 mg/mL emulsion for a 0.1 mL injection.
  • the LPS was dosed at 0.1 mg/kg or 0.002 mg per 20 g mouse.
  • the LPS was prepared as a 0.02 mg/mL solution in PBS for a 0.1 mL injection.
  • Table 15 Percent suppression of elevated cytokine levels by different doses of 1:1 CBD:CBDA
  • mice 20 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into five groups of four mice each so that the average weight of each group was as close as possible to each other.
  • the five groups were: (1) Untreated (0.1 mL injection of 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of PBS instead of LPS); (2) LPS control (0.1 mL injection of 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (3) 1 mg/kg 1 : 1 CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (4) 0.5 mg/kg 1 : 1 CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in 90% PBS, 10% propylene glycol, followed 1 hour later by a 0.1 mL injection of LPS in PBS); and (5) 0.25 mg/kg 1 : 1 CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA
  • the 1 : 1 CBD:CBDA test compounds were dosed at 1.0 mg/kg or 0.02 mg per 20 g mouse, 0.5 mg/kg or 0.01 mg per 20 g mouse and 0.25 mg/kg or 0.005 mg per 20 g mouse.
  • the test compounds were prepared as 2 mg/mL, 1 mg/mL and 0.5 mg/mL solutions in propylene glycol and then diluted 1 : 10 with phosphate buffered saline (PBS) and mixed well to create a 0.2 mg/mL, 0.1 mg/mL and 0.05 mg/mL emulsion for a 0.1 mL injection.
  • PBS phosphate buffered saline
  • the LPS was dosed at 0.1 mg/kg or 0.002 mg per 20 g mouse.
  • the LPS was prepared as a 0.02 mg/mL solution in PBS for a 0.1 mL injection.
  • the results of Study 2 are shown below in Table 16.
  • mice 32 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into eight groups of four mice each so that the average weight of each group was as close as possible to each other.
  • the eight groups were: (1) Untreated (0.1 mL injection of MCT oil, followed 1 hour later by a 0.1 mL injection of PBS instead of LPS); (2) LPS control (0.1 mL injection of MCT oil, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (3) 0.5 mg/kg dexamethasone treatment group (0.1 mL injection of dexamethasone in MCT oil, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (4) 0.05 mg/kg CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in MCT oil, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (5) 0.167 mg/kg CBD:CBDA treatment group (0.1 mL injection of 1 : 1 CBD:CBDA in MCT oil, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (6) 0.5 mg/kg CBD:CBDA treatment group (0.1
  • the 1 : 1 CBD:CBDA test compounds were dosed at 5 mg/kg or 0.1 mg per 20 g mouse, 1.67 mg/kg or 0.033 mg per 20 g mouse, 0.5 mg/kg or 0.01 mg per 20 g mouse, 0.167 mg/kg or 0.0033 mg per 20 g mouse and 0.05 mg/kg or 0.001 mg per 20 g mouse.
  • the test compounds were prepared as 1 mg/mL, 0.33 mg/mL, 0.1 mg/mL, 0.033 mg/mL and 0.01 mg/mL solutions in MCT oil for a 0.1 mL injection.
  • the dexamethasone control was dosed at 0.5 mg/kg or 0.01 mg per 20 g mouse.
  • the LPS was dosed at 0.1 mg/kg or 0.002 mg per 20 g mouse.
  • the test compounds were dosed at 5 mg/kg or 0.1 mg per 20 g mouse, 1.67 mg/kg or 0.033 mg per 20 g mouse, 0.5 mg/kg or 0.01 mg per 20
  • Table 17 Percent suppression of elevated cytokine levels by different doses of 1:1 CBD:CBDA
  • the optimal dose of 1 : 1 CBD:CBDA ranged from 0.167 mg/kg to 0.5 mg/kg, and the vehicle that 1 : 1 CBD:CBDA was resuspended in did not affect the outcome. Sometimes the vehicle can dramatically affect the abilities of pharmaceutical agents, but this was not the case.
  • EXAMPLE 6B Determining the Dosing Efficacy of Omega Fatty Acids in Mice Using the Mouse LPS Cytokine Animal Model
  • the minimal dose of fish oil omega-3 that most health organizations recommend is 250 to 500 mg per day. Most people use two or three times this amount, /. ⁇ ., 500 to 1,500 mg of omega-3 fatty acids per day.
  • the most efficacious dose of omega-3 fatty acids in a 20 g mouse could range from 6.09 to 224.73 mg/kg depending on how the omega-3 fatty acid is metabolized in mice versus humans.
  • a number of anti-inflammatory omega-3, -7, and -9 fatty acids can be isolated from fish oil and numerous commercial fish oil products.
  • pollock oil that contained a total omega fatty acid concentration of 456 mg/mL with total omega-3 fatty acids at 209 mg/mL, total omega-7 fatty acids at 85 mg/mL and total omega-9 fatty acids at 144 mg/mL was used.
  • mice 28 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into seven groups of four mice each so that the average weight of each group was as close as possible to each other.
  • the omega fatty acids were dosed at 625.0 mg/kg or 12.5 mg per 20 g mouse, 187.5 mg/kg or 3.75 mg per 20 g mouse, 62.5.0 mg/kg or 1.25 mg per 20 g mouse, 18.75 mg/kg or 0.375 mg per 20 g mouse and 6.25 mg/kg or 0.125 mg per 20 g mouse.
  • the omega fatty acids were diluted with MCT oil to create 125.00 mg/mL, 37.5 mg/mL, 12.5 mg/mL, 3.75 mg/mL and 1.25 mg/mL solutions for the 0.1 mL injections.
  • the LPS was dosed at 0.1 mg/kg or 0.002 mg per 20 g mouse.
  • the LPS was prepared as a 0.02 mg/mL solution in PBS for a 0.1 mL injection.
  • the results of Study 1 appear in Table 18, below.
  • mice 28 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate with unlimited access to food and water. On the day of the study, the mice were weighed and split into six groups of four mice each so that the average weight of each group was as close as possible to each other.
  • the omega fatty acids were dosed at 1,875 mg/kg or 37.5 mg per 20 g mouse, 625.0 mg/kg or 12.5 mg per 20 g mouse, 187.5 mg/kg or 3.75 mg per 20 g mouse and 62.5.0 mg/kg or 1.25 mg per 20 g mouse.
  • the omega fatty acids were diluted with MCT oil to create 375.00 mg/mL, 125.00 mg/mL, 37.5 mg/mL and 12.5 mg/mL solutions for the 0.1 mL injections.
  • the LPS was dosed at 0.1 mg/kg or 0.002 mg per 20 g mouse.
  • the LPS was prepared as a 0.02 mg/mL solution in PBS for a 0.1 mL injection.
  • the results of Study 2 are given in Table 19, below.
  • FIG. 4 depicts a graph of anti-inflammatory omega fatty acids dosed per mouse versus the percent suppression of cytokines that is observed reveals that the antiinflammatory effect starts to saturate at around the dose of 12.5 mg anti-inflammatory omega fatty acids per mouse.
  • EXAMPLE 6C Determining the Dosing Efficacy of Cannabinoid-Omega Fatty Acid Compositions in Mice Using the Mouse LPS Cytokine Animal Model
  • Study 1 Comparing 0.5 mg/kg 1:1 CBD:CBDA, 1,875 mg/kg omega fatty acids, 187.5 mg/kg omega fatty acids, 0.5 mg/kg 1:1 CBD:CBDA combined with 1,875 mg/kg omega fatty acids and 0.5 mg/kg 1:1 CBD:CBDA combined with 187.5 mg/kg omega fatty acids.
  • mice 32 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into eight groups of four mice each so that the average weight of each group was as close as possible to each other.
  • Study 2 Comparing 0.5 mg/kg 1:1 CBD:CBDA, 1,875 mg/kg omega fatty acids, 625 mg/kg omega fatty acids, 187.5 mg/kg omega fatty acids, 0.5 mg/kg 1:1 CBD:CBDA combined with 1,875 mg/kg omega fatty acids, 0.5 mg/kg 1:1 CBD:CBDA combined with 625 mg/kg omega fatty acids and 0.5 mg/kg 1:1 CBD:CBDA combined with 187.5 mg/kg omega fatty acids.
  • mice 40 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into ten groups of four mice each so that the average weight of each group was as close as possible to each other.
  • Study 3 Comparing 0.25 mg/kg 1:1 CBD:CBDA, 1,875 mg/kg omega fatty acids, 625 mg/kg omega fatty acids, 187.5 mg/kg omega fatty acids, 0.25 mg/kg 1:1 CBD:CBDA combined with 1,875 mg/kg omega fatty acids, 0.25 mg/kg 1:1 CBD:CBDA combined with 625 mg/kg omega fatty acids and 0.25 mg/kg 1:1 CBD:CBDA combined with 187.5 mg/kg omega fatty acids.
  • mice 40 female C57BL/6 mice that weighed approximately 20 g each were allowed to acclimate for one week with unlimited access to food and water. On the day of the study, the mice were weighed and split into ten groups of four mice each so that the average weight of each group was as close as possible to each other.
  • Table 23 Percent suppression of elevated cytokine levels by different doses of the omega fatty acids with or without 0.25 mg/kg 1:1 CBD:CBDA
  • EXAMPLE 6D Examining the Efficacy of ALA, DHA, and EPA omega-3 unsaturated fatty acids as anti-inflammatory agents
  • mice 36 female C57BL/6 mice that weighed approximately 20 g each were obtained and allowed to acclimate for one week after arrival with unlimited access to food and water. On the day of the study, the mice were weighed and split into eight groups of four mice each so that the average weight of each group was as close as possible to each other.
  • omega fatty acid samples that were tested were diluted so the dose was 12.5 mg of total omega fatty acids per mouse.
  • the dose of the control dexamethasone was 0.01 mg per mouse.
  • the omega fatty acids samples tested included: (1) pollock oil, 456 mg/mL omega unsaturated fatty acids.
  • the pollock oil contained a mixture of anti-inflammatory omega-3, omega-7 and omega-9 unsaturated fatty acids.
  • the omega-3, omega-7 and omega-9 unsaturated fatty acids constituted 45.8%, 18.6% and 31.6%, respectively, of the omega fatty acids contained in the pollock oil.
  • the DHA:EPA ratio was 0.67: 1.
  • the major omega unsaturated fatty acids found in most commercially utilized fish oils are DHA and EPA at a DELAEPA ratio of 0.67: 1 to 0.75: 1, where EPA is in greater abundance than DHA.
  • a 12.5 mg dose contained 1.72 mg of DHA and 2.58 mg of EPA in the triglyceride form.
  • the flaxseed oil contained a mixture of anti-inflammatory omega-3 and omega-9 unsaturated fatty acids.
  • the omega-3 and omega-9 unsaturated fatty acids constituted 77.6% and 28.8%, respectively, of the anti-inflammatory omega fatty acids contained in the flaxseed oil.
  • a 12.5 mg dose contained 9.7 mg of ALA in the triglyceride form.
  • a 12.5 mg dose contained 7.81 mg of DHA and 3.91 mg of EPA.
  • the omega-3 unsaturated fatty acids were in the free mono form.
  • a 12.5 mg dose contained 3.85 mg of DHA and 7.69 mg of EPA.
  • the omega-3 unsaturated fatty acids were in the free mono form.
  • a 12.5 mg dose contained 7.88 mg of DHA and 3.94 mg of EPA.
  • the omega-3 unsaturated fatty acids were in the triglyceride form.
  • a 12.5 mg dose contained 3.60 mg of DHA and 7.19 mg of EPA.
  • the omega-3 unsaturated fatty acids were in the triglyceride form.
  • mice were divided into nine groups: (1) Untreated (0.1 mL injection of medium-chain trygliceride (MCT) oil, followed 1 hour later by a 0.1 mL injection of PBS instead of LPS); (2) LPS (0.1 mL injection of MCT oil, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (3) LPS plus 0.01 mg dexamethasone in MCT oil (0.1 mL injection of 100% MCT oil containing 0.1 mg/mL dexamethasone, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (4) LPS plus 12.50 mg omega fatty acids (0.1 mL injection of 125.00 mg/mL omega fatty acids diluted in MCT oil, followed 1 hour later by a 0.1 mL injection of LPS in PBS); (5) LPS plus 12.50 mg ALA omega-3 (0.1 mL injection of 125.00 mg/mL ALA omega-3 diluted in MCT oil, followed 1 hour later by a 0.1 mL injection of
  • Table 24 Percent suppression of elevated cytokine levels by tri ALA, mono 2:1 DHA:EPA, mono 1:2 DHA:EPA, tri 2:1 DHA:EPA, and tri 1:2 DHA:EPA
  • Table 25 shows the average percent suppression versus the major omega fatty acids that are present in the sample.
  • Example 6D Average suppression vs. major omega fatty acids [00356] The study of Example 6D shows that DHA has the highest anti-inflammatory capability of the three omega-3 unsaturated fatty acids most commonly found in nature, ALA, DHA and EP A, and that the natural triglyceride form of DHA and EPA are more effective than the mono form of DHA and EPA.
  • Cochran FR Finch- Arietta MB, 1989. Regulation of interleukin- 1 beta and tumor necrosis factor secretion by the human monocytic leukemia cell line, THP-1. Agents Actions. 27:271-273.
  • Fine PG Rosenfeld MJ (2013) The endocannabinoid system, cannabinoids, and pain.
  • Fritsche KL 2015. The science of fatty acids and inflammation. Adv Nutr. 6:293S- 301S.

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Abstract

La présente divulgation concerne des compositions comprenant des cannabinoïdes et des acides gras oméga et des méthodes d'utilisation de ces compositions notamment, par exemple, pour traiter ou prévenir une inflammation, en tant qu'immunosuppresseur et/ou en tant qu'agent thérapeutique anticancéreux. Selon certains aspects, le cannabinoïde est choisi parmi i) CBC, CBCA, CBD, CBDA, CBDV, CBDVA, CBG, CBGA, CBL, CBLA, CBN, CBNA, THCV, THCVA et toute combinaison de ceux-ci, et ii) un mélange de CBD:CBDA équimolaire d'environ 1:1. Dans certains aspects, l'acide gras oméga est choisi parmi un acide gras oméga-3 (tel que ALA, DHA ou EPA), un acide gras oméga-7, ou un acide gras oméga-9.
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WO2017025712A1 (fr) * 2015-08-10 2017-02-16 Gw Pharma Limited Utilisation de cannabinoïdes dans le traitement de l'épilepsie
US9962341B2 (en) * 2014-06-27 2018-05-08 Gw Pharma Limited Active pharmaceutical ingredient (API) comprising cannabinoids for use in the treatment of cancer
US20190336471A1 (en) * 2018-05-02 2019-11-07 Omax Health Compositions containing omega-3 fatty acids concentrates, cannabanoids and l-theanine and use thereof
US20190374502A1 (en) * 2017-02-09 2019-12-12 Bodhi Research & Development Inc. Cannabinoid-Containing Fatty Acid Formulations for Treating Disorders of the Nervous System
WO2020223510A1 (fr) * 2019-04-30 2020-11-05 Greenway Herbal Products, Llc Compositions de cannabinoïdes et procédés d'utilisation

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US9962341B2 (en) * 2014-06-27 2018-05-08 Gw Pharma Limited Active pharmaceutical ingredient (API) comprising cannabinoids for use in the treatment of cancer
WO2017025712A1 (fr) * 2015-08-10 2017-02-16 Gw Pharma Limited Utilisation de cannabinoïdes dans le traitement de l'épilepsie
US20190374502A1 (en) * 2017-02-09 2019-12-12 Bodhi Research & Development Inc. Cannabinoid-Containing Fatty Acid Formulations for Treating Disorders of the Nervous System
US20190336471A1 (en) * 2018-05-02 2019-11-07 Omax Health Compositions containing omega-3 fatty acids concentrates, cannabanoids and l-theanine and use thereof
WO2020223510A1 (fr) * 2019-04-30 2020-11-05 Greenway Herbal Products, Llc Compositions de cannabinoïdes et procédés d'utilisation

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