Proof-of-concept trial of PP-01 for mitigating cannabis withdrawal syndrome in participants with cannabis use disorder.

Slagle A.; Constantine J.; Kushner H.; Graham S.; Constantine G. · The American journal on addictions · 2026

**Background & Methods** This Phase 1b/2a randomized, double-blind, placebo-controlled crossover trial evaluated PP-01 (nabilone and gabapentin combination) in 14 adults with moderate to severe cannabis use disorder (CUD) experiencing daily/near-daily cannabis use (≥1 gram/day). The 5-night inpatient study compared PP-01 versus placebo, with withdrawal severity and bothersomeness assessed via patient daily diaries and analyzed using mixed model repeated measures ANOVA. **Key Findings** • PP-01 significantly reduced withdrawal symptom severity (p=0.0222) and bothersomeness (p=0.0063) within 10 hours and 4 hours post-first dose, respectively, compared to placebo • Sleep quality and cannabis cravings showed statistically significant improvement from first dose through discharge in the PP-01 group • Objective withdrawal measures demonstrated significant improvement with PP-01 treatment **Dosage & Administration** Specific doses of nabilone and gabapentin components are not reported in the abstract. **Safety & Adverse Effects** PP-01 was well-tolerated with only mild-severity adverse events reported. No serious adverse events (SAEs) were documented during the trial. **Evidence Quality** This proof-of-concept study represents early-stage evidence (Phase 1b/2a) with significant limitations. The very small sample size (n=14) and short 5-night inpatient duration limit generalizability to real-world outpatient settings and long-term efficacy assessment. The crossover design in an inpatient controlled environment may not reflect typical cannabis withdrawal patterns. No comparison to standard-of-care treatments or other pharmacological interventions was provided. The study addresses an important unmet medical need, as no FDA-approved medications currently exist for cannabis withdrawal syndrome. Further large-scale, Phase 2b/3 randomized controlled trials are needed to establish efficacy, optimal dosing, durability of effect, and safety in diverse populations before potential regulatory submission. The combination approach targeting multiple neurobiological mechanisms of cannabis withdrawal is mechanistically rational and warrants further investigation.

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