1 Cannabis is the most used psychoactive substance world-wide. The CNS effects of THC, the 2 main psychoactive constituent of cannabis, and synthetic cannabinoids are largely attributed 3 to their agonism of the cannabinoid receptor type 1 (CB1). CB1 activation can cause effects 4 including feelings of euphoria, sensory distortion, panic attacks, psychosis, and tachycardia. 5 Recent legalization of cannabis use in a growing number of U.S. States has led to a rapid 6 increase in access to a wide range of cannabis products that are more potent, relatively 7 inexpensive, and easier to obtain. More wide-spread use of cannabis has led to an exponential 8 increase in emergency department visits and hospitalization related to either Acute 9 Cannabinoid Intoxication (ACI) or to Cannabinoid Hyperemesis syndrome (CHS), which is 10 characterized by severe, repeated bouts of nausea and vomiting that can last from hours up 11 to weeks. Data from the Agency for Healthcare Research and Quality’s Healthcare Cost and 12 Utilization Project (HCUP) Nationwide Emergency Department Sample (NEDS) indicate that 13 ACI incidence increased by approximately 12% annually between 2006 and 2018, with the 14 largest relative increase in the most recent year among female and pediatric patients. Children 15 are an especially vulnerable group because cannabis edibles are widely available in the form 16 of chocolate and gummies, which are attractive to children and often mistaken for harmless 17 treats. Because of their lower body weight, relative doses are much higher in children, and 18 higher circulating THC concentrations result in greater risk for more serious adverse events 19 associated with ACI, e.g. severe neurological impairment, seizures, loss of consciousness, 20 and coma. Although several CB1 receptor antagonists have shown some promise in inhibiting 21 THC intoxication in early clinical studies, to date no CB1 inhibitor has been approved for 22 treatment of ACI or CHS. To address this serious and growing unmet medical need, Anebulo 23 Pharmaceuticals is developing a novel CB1 antagonist, ANEB-001. The current project aims 24 to advance the development of ANEB-001, so that it can ultimately be approved as an acute 25 intervention for treatment of ACI and CHS in the emergency setting. The purpose of this 26 project is to investigate the safety, pharmacokinetics, and therapeutic potential of an 27 intravenous formulation of ANEB-001 in relevant populations of patients, including pediatric 28 patients, who are particularly at-risk of serious adverse events. Ultimately, ANEB-001 could 29 become available to patients presenting to the emergency department with ACI or CHS, 30 decreasing the burden of these conditions on both patients and the US healthcare system.

PROJECT NARRATIVE Recent legalization of cannabis in a growing number of States across the U.S. has led to a rapid increase in availability and use of cannabis and cannabis products, in a wide range of inhaled and edible forms that are potent and inexpensive, and this in turn has led to an exponential surge in emergency department (ED) visits for acute cannabinoid intoxication (ACI). This project aims to further advance Anebulo Pharmaceutical’s clinical development of an emergency treatment for ACI: ANEB-001, a CB1 antagonist shown to rapidly reverse the key symptoms of ACI after single oral doses in a Phase 2 THC challenge study in healthy subjects. Ultimately, providing ANEB-001 as an intravenous antidote for ACI and potentially cannabis hyperemesis syndrome (CHS) in the ED could address this rapidly growing unmet need, particularly for children and vulnerable patients at greatest risk of potentially life- threating adverse events, while also reducing the burden on the US healthcare system.