Cannabinol for Acute Treatment of Insomnia Disorder in a Randomized Placebo‐Controlled Crossover Trial

ABSTRACT 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.