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COWEN COLLABORATIVE INSIGHTS February 25, 2019 _ The Science Of CBD (Nadeau) The Endocannabinoid System Cannabis’ therapeutic potential is due to this valuable overlap between phytocannabinoids (i.e. plant-derived cannabinoids) and the endogenous cannabinoid system in humans, termed a “therapeutic handshake.” However, though THC’s activity in the body has been fairly well elucidated (it acts through G-protein coupled cannabinoid receptor 1 and cannabinoid receptor 2), CBD’s pharmacokinetics are less well understood (no specific receptor for CBD has been identified). The scientific understanding of CBD’s clinical effects is based mostly on studies in specific indications, like epilepsy. GW Pharma’s Epidiolex (highly potent, pure formulation of CBD) was approved by the FDA in 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, and other companies (Tilray, MMJ Phytotech, Insys) have clinical trials underway in seizure disorders as well. Additional possible indications for CBD products include autism spectrum disorders, psychiatric conditions, diabetic neuropathy pain, fibromyalgia, chronic pain, and back pain; clinical trials in these indications are underway. Clinical trial results to date demonstrate few adverse effects from oral CBD doses of up to 1500 mg/day or up to 30mg IV. Specifically, CBD studies have not reported effects on blood pressure, heart rate, or respiratory rate, and no negative changes in mood or psychomotor slowing. Some studies (such as GW’s in Epidiolex) have shown side effects resulting from high doses of CBD (~2g/day) inhibiting hepatic drug metabolism, prompting increased blood levels of some background medications. Additionally, in vitro studies have shown CBD to be pro-apoptotic in lymphocytes and to inhibit IL8 and IL10 production, suggesting that it may suppress the immune system. However, though unknowns remain, the summation of pre-clinical and clinical data suggest that the compound is safe at typical doses seen in over the counter products (5-10mg). = Additionally, other cannabinoids (found in CBD distillate) have been discovered that may have differentiated pharmacological effects. For example, cannabidivarin (CBDV) may have differentiated anticonvulsant effects, tetrahydrocannabivarin (THCV) may have anti-diabetic and appetite suppressant effects, cannabidiol-acid (CBDA) may have anti- nausea effects, and bannabigerol (CBG) may have anti-cancer effects. Further research is needed to elucidate the clinical effects of these compounds. 10 COWEN.COM HOUSE_OVERSIGHT_024826