Acute cannabidiol administration reduces alcohol craving and cue-induced nucleus accumbens activation in individuals with alcohol use disorder: the double-blind randomized controlled ICONIC trial

Although alcohol use disorder (AUD) is highly prevalent, only a few medications are approved for its treatment leaving much room for improvement. Cannabidiol (CBD) might be a particularly promising candidate, with preclinical data suggesting that CBD is effective in targeting AUD symptoms and disease processes that drive alcohol use and relapse, due to its anti-craving, stress-reducing, and anti-compulsive effects. Here we report data from the double-blind randomized controlled ICONIC trial that compared the effects of a single dose of 800 mg cannabidiol against placebo (PLC) in N = 28 individuals with AUD. Cue-induced nucleus accumbens (NAc) activation, alcohol craving during a combined stress- and alcohol cue exposure session, as well as craving during an fMRI alcohol cue-reactivity task and CBD plasma levels served as outcomes. Individuals receiving CBD showed lower bilateral cue-induced NAc activation (t_{left_NAc(23)} = 4.906, p < 0.001, d = 1.15; t_{right_NAc (23)} = 4.873, p < 0.001, d = 1.13) and reported significantly lower alcohol craving after a combined stress- and alcohol cue exposure session (F_group(1,26) = 4.516, p = 0.043, eta² = 0.15) and during the fMRI cue-reactivity task (F_group(1,24) = 6.665, p = 0.015, eta² = 0.23). CBD levels were significantly higher in the CBD group (t₍₂₅₎ = 3.808, p < 0.001, d = 1.47) and showed a significant negative association with alcohol craving during the cue exposure experiment (r = -0.394, p_FDR = 0.030) and during fMRI (r = -0.389, p_FDR = 0.030), and with left and right NAc activation (r_left__NAc = -0.459, p_FDR = 0.030; r_right__NAc = -0.405, p_FDR = 0.030). CBD's capacity to reduce stress- and cue-induced alcohol craving and to normalize NAc activation - a region critical to the pathophysiology of AUD - contribute to understanding the neurobiological basis of its clinical effects and support its potential as a treatment option for AUD. Clinical Trials Registry: DRKS00029993.