Cannabinol for acute treatment of insomnia disorder in a randomized placebo‐controlled crossover trial

Insomnia disorder is harmful and requires novel treatments. Cannabinol, an oxidative by-product of Δ9-tetrahydrocannabinol, is claimed to be a hypnotic, but its effects on objective sleep and insomnia remain unknown. This randomized, double-blind, placebo-controlled, three-arm, single-night crossover trial evaluated the acute efficacy and safety of cannabinol for insomnia disorder. Twenty adults (aged 25-65) with physician-diagnosed insomnia disorder (meeting DSM-5 and ICSD-3 criteria; Insomnia Severity Index ≥ 15) were enrolled at the Woolcock Institute of Medical Research (Sydney, Australia) between August 2022 and September 2023. Participants received a single 2 mL oral dose of 30 mg (1.5%) or 300 mg (15%) cannabinol, or matched placebo (2-week washout). All participants (17 female and 3 males; mean ± SD age 42 ± 13 years) completed the protocol and were statistically analysed. The primary outcome was wake after sleep onset (WASO) minutes, measured by overnight polysomnography. Cannabinol did not significantly change WASO (300 mg: -6.3 min [95% CI: -18.2, +5.5], p = 0.29, dz = -0.22; 30 mg: -4.0 min [-15.9, +7.9], p = 0.50, dz = 0.11). However, 300 mg cannabinol increased non-rapid eye movement-2 sleep (p = 0.03, dz = 0.54), subjective sleep quality (p = 0.005, dz = 0.56); and reduced sleep onset latency (p = 0.004, dz = -0.74) and electroencephalographic arousal indices (p = 0.02, dz = -0.65). There were 247 mild-to-moderate adverse events across arms. Larger, longer trials are warranted. ClinicalTrials.gov Identifier: NCT05344170.