Treating Cannabis Addiction and Withdrawal: Latest Clinical Data

Ginger Constantine, MD, discussed PleoPharma's investigational compound PP-01, currently in a phase 3 clinical trial for cannabis use disorder, and presented findings from 2 posters at the College on Problems of Drug Dependence annual meeting examining the phenomenology and treatment of cannabis withdrawal.

Constantine contextualized the public health scope of the problem: according to SAMHSA data, approximately 21.6 million people engaged in daily or near-daily cannabis use in 2024, of whom approximately 20.6 million met criteria for cannabis use disorder. Cannabis use disorder is formally codified diagnosis in the DSM-5, which also includes cannabis withdrawal syndrome as a component criterion. Constantine emphasized that cannabis withdrawal occurs in an estimated 50% to 95% of heavy daily users, and that withdrawal-related distress is a primary driver of continued use and relapse, rather than simply a consequence of cessation.¹

The first poster presented findings from a qualitative study of 15 participants—male and female, diverse in socioeconomic background—who were current heavy cannabis users (averaging at least 1.5 g/day) with prior withdrawal experience. Participants reported an average of 8.5 withdrawal episodes in the preceding year, with some reporting over 200 lifetime quit attempts. A key finding was the rapidity of symptom onset, with most participants reporting the emergence of withdrawal symptoms within 2 to 12 hours of cessation—a timeline consistent with the group's phase 2 clinical trial data. Prominent symptoms included irritability, aggression, cravings, and sleep disturbance.

The second poster reported a post hoc analysis of PP-01's phase 2 randomized, placebo-controlled trial, examining the irritability domain specifically. PP-01-treated participants demonstrated a 42% reduction in irritability relative to placebo, with placebo-treated participants continuing to experience elevated irritability across the full 34-day treatment period. Constantine noted that the mean age of the phase 2 population was approximately 31 to 32 years, with an average of 16 to 17 years of cannabis use and an initiation age of approximately 16—findings consistent with the broader literature on cannabis use disorder demographics.² Constantine concluded by noting a particular interest in the relationship between cannabis withdrawal—specifically its irritability, aggression, and anger dimensions—and broader patterns of societal violence.

Dr Constantine is chief executive officer and cofounder of PleoPharma.

References

1. Livne O, Shmulewitz D, Lev-Ran S, et al. DSM-5 cannabis withdrawal syndrome: demographic and clinical correlates in US adults. Drug Alcohol Depend. 2019;195:170–177.

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.