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The Past, Present and Future of Cannabinoid Therapeutics Disclosure 8/4/2020 The Past, Present and Future of Cannabinoid Therapeutics The Endocannabinoid SystemSystem,, CBDCBD,, and Beyond Disclosure: TheralogixTheralogix,, LLC: • Chief Science Officer • Shareholder 1 8/4/2020 A History of Cannabinoid Science The Endocannabinoid System CBD : Efficacy, Safety and Legality PEA: An Endogenous and Exogenous Cannabinoid What’s Next? A History of Cannabinoid Science The Endocannabinoid System CBD : Efficacy, Safety and Legality PEA: An Endogenous and Exogenous Cannabinoid Next Steps 2 8/4/2020 The History of Cannabinoid Science… The Pen‐TTsao'sao Ching, the oldest pharmacopoeia in existence, documents the use of cannabis in China around 200 AD as treatment for rheumatic pain, constipation, female reproductive disorders and malaria. 1963 ‐1964–Dr. Raphael Mechoulam isolates and characterizes cannabidiol (CBD) and 9‐THC, the two primary bioactive components of cannabis 1990 – Cannabinoid receptors CB1 and CB2 identified and cloned 1992 –first endocannabinoid ligand identified – anandamide (arachidonoyl ethanolamide or AEA ) – the ‘bliss’ molecule 1995 –second endocannabinoid ligand identified –2‐AG (2‐arachidonoyl glycerol) …is similar to the history of opioid science • The analgesic effects of the opium poppy have been known for centuries • 1825 ‐ Morphine, found naturally in opium poppy extract, was first identified and characterized • 1827 –Merck starts to market morphine commercially • 1971 –opioid receptors identified in the CNS • 1975 –79 – endogenous opioid receptor ligands identified –i.e. endorphin 3 8/4/2020 The Endocannabinoid System The endocannabinoid system The ECS is comprised of 3 components – the endocannabinoid signaling molecules, their regulatory enzymes, and their receptors Evolved 500 million years ago, present in all vertebrates The ECS serves to maintain bodily homeostasis – returning us to a baseline physiological state after our body reacts to changes in the environment Primarily functions in the CNS and immune system Involved in pain, memory, mood, appetite, stress, sleep, metabolism, immune and reproductive function 4 8/4/2020 The endocannabinoid system • Endogenous cannabinoid ligands (signaling molecules) • AEA (arachidonoyl ethanolamide or ‘anandamide’) • 2‐AG (2‐arachidonoyl glycerol) • Regulatory enzymes • Synthesis • Breakdown • NAPE‐PLD • FAAH • DAGL • MAGL • Primary cannabinoid receptors • CB1 • CB2 The endocannabinoid system • Additional cannabinoid receptors • PPAR‐ – identified in 1980s, cannabinoid activity discovered in 2008 • TRPV‐1 – identified in 1997 5 8/4/2020 Four endocannabinoid receptors • CB1 receptors are in the CNS • Activated via retrograde signaling, which reduces neurotransmitter release • Not directly involved in reducing pain and/or inflammation CB1 6 8/4/2020 • CB2 receptors are found in the immune system • Activation modulates immune response and serves as a natural anti‐inflammatory CB2 • PPAR‐ receptors are found on immune system mast cells • Activation reduces mast cell release of chemokines and cytokines • Like CB2, also produces a natural anti‐inflammatory effect PPAR‐ 7 8/4/2020 • TRPV‐1 receptors are found on the surface of pain neurons and initiate pain sensation • Certain cannabinoids desensitize TRPV‐1 receptors, reducing pain sensation TRPV‐1 CB1 CB2 PPAR‐ TRPV‐1 (CNS) (Immune cells) (Mast cells) (Pain neurons) 8 8/4/2020 2‐AG CB1 CB2 PPAR‐ TRPV‐1 (CNS) (Immune cells) (Mast cells) (Pain neurons) AEA CB1 CB2 PPAR‐ TRPV‐1 (CNS) (Immune cells) (Mast cells) (Pain neurons) 9 8/4/2020 CB1 CB2 PPAR‐ TRPV‐1 (CNS) (Immune cells) (Mast cells) (Pain neurons) A History of Cannabinoid Science The Endocannabinoid System CBD : Efficacy, Safety and Legality PEA: An Endogenous and Exogenous Cannabinoid 10 8/4/2020 CBD SLIDES 11 8/4/2020 CBD : Mechanism of Action Second most prevalent bioactive component of cannabis No direct activation of CB1 or CB2 Negative allosteric modulator of CB1 receptor, which inhibits binding of THC, reducing its psychoactive effects Increases tissue levels of endocannabinoids by competing for their breakdown enzymes ((/),FAAH/FAGL), which increases “endocannabinoid tone” TRPV‐1 receptor agonist – reduces nociception Indirectly activates serotonin 5‐HT1a receptor –anti‐anxiety 12 8/4/2020 CB1 CB2 PPAR‐ TRPV‐1 (CNS) (Immune cells) (Mast cells) (Pain neurons) CB1 CB2 PPAR‐ TRPV‐1 (CNS) (Immune cells) (Mast cells) (Pain neurons) 13 8/4/2020 CBD : Clinical Trial Evidence Epilepsy Strong evidence of benefit in Dravet syndrome Epidiolex (GW Pharma) approved by FDA 4/18 Anxiety Only one study in subjects with social anxiety Most studies have been small and used artificial stressors Several studies using ‘public speaking stress’ showed significant reduction in anxiety with very high doses of CBD (150‐900 mg) Schizophrenia Multiple RCTs have been done 2012 RCT vs. amisulpride (atypical anti‐psychotic) showed equal efficacy using 800 mg daily of CBD CBD : Clinical Efficacy in Pain/Inflammation Many studies in animal pain/inflammation models No human studies using oral or inhalation route of administration One human RCT using CBD cream in TMJ patients ‐ published in October 2019 14 8/4/2020 Nitecka‐BuchtaBuchta,, et al, “Myorelaxant Effect of Transdermal Cannabidiol Application in Patients with TMD: A Randomized Double‐Blind Trial” J of Clin Med, 2019, 8, 1886 227‐234. • 60 patients with TMJ pain randomized to either CBD cream or placebo cream • VAS used to measure pain at day 0 and day 14 BliBaseline Baseline Day 14 Day 14 15 8/4/2020 CBD : Clinical Efficacy in Pain/Inflammation • Many studies in animal pain/inflammation models • No human studies using oral or inhalation route of administration • One human RCT using CBD cream in TMJ patients ‐ published in October 2019 • No studies in OA, RA, fibromyalgia, etc CBD : Safety Issues FDA Epidiolex data revealed significant potential for liver toxicity, prescribers required to monitor LFTs. Epidiolex data also revealed that CBD inhibits CYP2C19, responsible for metabolism of 10% of drugs in clinical use, including : Warfarin, Plavix® Benzodiazepenes PPIs Certain SSRIs (Celexa®, Lexapro®) All tricyclic antidepressants 2017 JAMA study –84 CBD products from 31 companies analyzed: • 69% incorrectly labeled (greater than 10% variance from label claim) 21% contained significant levels of THC Cost per 10mg of CBD ranged from $.80 to $4.50 16 8/4/2020 CBD Regulatory Status CbiCannabis sales are subject to bhboth FdFedera l and State laws 33 states and the District of Columbia have legalized medical cannabis, 11 of those have also legalized recreational use for adults 17 8/4/2020 CBD Regulatory Status CbiCannabis sales are subject to bhboth FdFedera l and State laws 33 states and the District of Columbia have legalized medical cannabis, 10 of those have also legalized recreational use for adults CBD in prescription form (Epidiolex) was approved by FDA in April 2018 for treatment of several forms of drug‐resistant epilepsy –yearly treatment cost 32K At the Federal level, CBD sales are subject to regulation by two agencies –the DEA and the FDA 18 8/4/2020 CBD Regulatory Status : DEA Histor ica lly, no disti ncti on was drawn between hemp and marijuana – both were Schedule 1 under the CSA 2018 Farm bill officially legalized hemp cultivation at the Federal level, subject to state programs mandated in the 2014 Farm bill Hemp defined as cannabis with THC levels <0.3% Removed hemp and hemp‐derived products from CSA State must have ‘hemp cultivation program” in place Most state programs permit import of hemp products into the state – a few don’t CBD Regulatory Status : FDA Exclusion rule any compound that is either under an IND or already an approved drug may NOT be sold as a supplement – unless it was sold as a supplement prior to the IND being filed Epidiolex® (GW Pharma) is demanding an ‘exclusion rule’ prohibition for CBD supplement sales Regulatory definition of a ‘dietary supplement’ requires that the product be absorbed from the GI tract after ingestion. CBD balms, vaped distillates, creams, tinctures, etc. – cannot be marketed as ‘supplements’ –the FDA must regulate them as drugs No ‘disease‐specific’ health claims are permitted FDA has yet to finalize guidelines on CBD 19 8/4/2020 20 8/4/2020 CBD: A practical guide Routes of administration Sublingual/Mucosal (tinctures, buccal/gingival patches) Topical (balms, creams, etc.) Inhalation (vaping) GI (softgels, gummies, etc.) Types of CBD products CBD isolate Hemp oils Full‐spectrum Broad‐spectrum Content/purity testing Not required by FDA Some companies ‘self‐test’ NSF® program underway – independent, third‐party testing of THC and CBD content 21 8/4/2020 CBD: A practical guide Routes of administration Sublingual/Mucosal (tinctures, buccal/gingival patches) Topical (balms, creams, etc.) Inhalation (vaping) GI (softgels, gummies, etc.) Types of CBD products CBD isolate Hemp oils Full‐spectrum Broad‐spectrum Content/purity testing Not required by FDA Some companies ‘self‐test’ NSF® program underway – independent, third‐party testing of THC and CBD content A History of Cannabinoid Science The Endocannabinoid System CBD : Efficacy, Safety and and Legal Issues PEA: An Endogenous and Exogenous Cannabinoid Next Steps 22 8/4/2020 Palmitoylethanolamide (PEA): A History 1957 – anti‐inflammatory agent isolated from egg yy,olk, peanut meal and soy lecithin is identified as palmitoylethanolamide (PEA) ‐ a fatty acid amide 1957 ‐1979 – believed to be a non‐specific
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