Endocannabinoids, which are present throughout the central nervous system (CNS), can activate cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 and CB2 agonists exhibit broad anti-inflammatory properties, suggesting their potential to treat inflammatory diseases. However, careful evaluation of abuse potential is necessary. This study evaluated the abuse potential of lenabasum, a selective CB2 receptor agonist in participants (n = 56) endorsing recreational cannabis use. Three doses of lenabasum (20, 60, and 120 mg) were compared with placebo and nabilone (3 and 6 mg). The primary endpoint was the peak effect (Emax) on a bipolar Drug Liking visual analog scale (VAS). Secondary VAS and pharmacokinetic (PK) endpoints and adverse events were assessed. Lenabasum was safe and well tolerated. Compared with placebo, a 20-mg dose of lenabasum did not increase ratings of Drug Liking and had no distinguishable effect on other VAS endpoints. Dose-dependent increases in ratings of Drug Liking were observed with 60 and 120 mg lenabasum. Drug Liking and all other VAS outcomes were greatest for nabilone 3 mg and 6 mg, a medication currently approved by the US Food and Drug Administration (FDA). At a target therapeutic dose (20 mg), lenabasum did not elicit subjective ratings of Drug Liking. However, supratherapeutic doses of lenabasum (60 and 120 mg) did elicit subjective ratings of Drug Liking compared with placebo. Although both doses of lenabasum were associated with lower ratings of Drug Liking compared with 3 mg and 6 mg nabilone, lenabasum does have abuse potential and should be used cautiously in clinical settings.

SIGNIFICANCE STATEMENT This work provides evidence that in people with a history of recreational cannabis use, lenabasum was safe and well tolerated, although it did demonstrate abuse potential. This work supports further development of lenabasum for potential therapeutic indications.

This work was funded by Corbus Pharmaceuticals and by National Institutes of Health National Institute on Drug Abuse (NIDA) [Grant 5T32DA007294-22] (to R.L.).

R.L., G.M., and R.S. have no financial disclosures or conflicts of interest to declare. In the past 3 years, S.D.C. has received research funding from BioXcel Therapeutics and Janssen and partial salary support through NIDA grants with Go Medical, Intracellular Therapies, and Lyndra. In the past 3 years, S.D.C. has also consulted for Alkermes, Opiant, and Otsuka. Finally, she has received honoraria from the World Health Organization in compensation for her work on the Expert Committee on Drug Dependence. None of these financial interests relate to the subject matter or materials discussed in the manuscript. I.H. is a director/employee of Corbus International Ltd and nonexecutive director of MDE Services Group Ltd. A.K. is a shareholder and employee of Corbus Pharmaceuticals.

dx.doi.org/10.1124/jpet.124.002129.