Pregnenolone as a Treatment for Cannabis Intoxication

Project Abstract This project aims to assess the potential of pregnenolone, a signaling specific negative allosteric modulator (NAM) of the CB1 cannabinoid receptor, to reverse symptoms of cannabis intoxication. As defined by the DSM- 5, cannabis intoxication involves neuropsychiatric symptoms such as anxiety and impaired motor coordination and physiological symptoms including dry mouth and tachycardia arising shortly after cannabis use. These symptoms can be distressing and associated with significant clinical complications such as car accidents, cardiac arrhythmias, and psychotic episodes. Cannabis’ increasing popularity and potency has seen a surge in emergency room (ER) visits for management of intoxication, yet there are no medications indicated for the treatment of cannabis intoxication. NAMs of the CB1 receptor—the cannabinoid receptor whose activation by tetrahydrocannabinol (THC) facilitates intoxication—have shown promise as novel treatments for cannabis intoxication. Pregnenolone, an endogenous neurosteroid often marketed as a supplement, has been shown to act as a CB1 receptor NAM specifically attenuating the effects of THC. Preclinical studies demonstrating pregnenolone’s capacity to treat cannabis intoxication symptoms have led to interest in applying its mechanism to drug development yet its ability to reverse active intoxication symptoms have not yet been studied in humans. We will therefore set up a within-subjects, double-blind, placebo-controlled human laboratory study investigating whether pregnenolone can treat cannabis intoxication symptoms. Healthy, cannabis-naïve individuals who meet inclusion criteria will be randomized to one of four conditions: cannabis brownie and placebo capsule, cannabis brownie and 250 mg pregnenolone capsule, cannabis brownie and 500 mg pregnenolone capsule, and placebo brownie and placebo capsule (all cannabis brownies will contain 25 mg THC). Following study drug administration, participants will complete questionnaires evaluating subjective effects (via the Drug Effect Questionnaire), psychotomimetic symptoms (via the Positive and Negative Syndrome Scale) and cognitive/psychomotor impairment (via a battery of cognitive assessments). Heart rate will also be assessed. Blood will also be collected at various timepoints for later measurements of serum pregnenolone, THC, and THC’s metabolites 11-OH-THC and THCCOOH to assess any dose-dependent effects of pregnenolone on cannabis intoxication. We hypothesize that pregnenolone administration will be associated with significantly fewer cannabis intoxication symptoms compared to placebo as evidenced by lower scores on the questionnaires, and that higher levels of pregnenolone will also be associated with fewer subjective effects and signs of impairment associated with cannabis intoxication. Results from this study will provide information on whether agents that act as CB1-NAMs can serve as rescue therapies for cannabis intoxication symptoms, while also giving insights into whether pregnenolone itself could fulfill this role.