Developments in Cannabis Withdrawal and Addiction Treatment

Ginger Constantine, MD, discussed the mechanism of action of PP-01, PleoPharma's investigational dual-mechanism compound currently under evaluation in an active phase 3 clinical trial for cannabis use disorder and cannabis withdrawal.

Constantine described PP-01 as a combination capsule with 2 active components working through distinct but complementary mechanisms. The first component is a partial agonist at the cannabinoid type 1 (CB-1) receptor, the primary brain receptor through which delta-9-tetrahydrocannabinol (THC)—the main psychoactive element of cannabis—exerts its effects. Constantine explained the neurobiological rationale for this target: chronic heavy cannabis use leads to downregulation of cortical CB-1 receptors, a finding directly demonstrated in humans via positron emission tomography imaging.¹ The partial agonist component is designed to gradually normalize or upregulate CB-1 receptor density during the withdrawal period. The second component acts on the mesolimbic dopaminergic pathway, addressing the acute downstream consequences of CB-1 receptor underactivity that manifest during withdrawal as craving and dysphoria.

Constantine argued that the failure of prior pharmacological trials in cannabis use disorder reflects the complexity of the neuroadaptations involved, and that a dual mechanism simultaneously addressing both CB1 receptor normalization and mesolimbic dopamine dysregulation is likely necessary for meaningful clinical efficacy. She reported that the phase 2 randomized, placebo-controlled trial of PP-01 demonstrated reductions in cannabis withdrawal symptoms, with significantly greater rates of abstinence and more abstinent weeks in PP-01 treated participants compared with placebo.² The FDA granted PP-01 fast-track designation on the basis of this phase 2 data and the recognized unmet need.

Constantine noted that the ongoing phase 3 multicenter trial began randomizing patients 2 weeks prior to the interview and is enrolling at a pace she described as unprecedented in her career—reflecting, she argued, the scale of unmet clinical need. A subsequent adolescent study is also planned, given the particular vulnerability of younger populations to cannabis dependence and the role of withdrawal in preventing successful discontinuation.

Dr Constantine is chief executive officer and cofounder of PleoPharma.

References

1. Hirvonen J, Goodwin RS, Li CT, et al. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry. 2012;17(6):642–649.

2. Bahji A, Stephenson C, Tyo R, et al. Prevalence of cannabis withdrawal symptoms among people with regular or dependent use of cannabis: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(4):e202370.