Psychedelics for Alcohol Use Disorder: A Narrative Review with Candidate Mechanisms of Action

Psychedelics have been studied since the 1950s as a potential treatment for alcohol use disorder (AUD), with over a dozen clinical trials of lysergic acid diethylamide (LSD), and several contemporary trials of psilocybin and ayahuasca for this indication. Herein, we characterize foundational studies from the 1950s to the present, with emphasis on key design factors that varied considerably between published studies. Critically, those design factors include pharmacological factors, such as presence or absence of a placebo control and the nature of the placebo (e.g., ephedrine, dextroamphetamine, diphenhydramine, or low-dose LSD), and non-pharmacological factors, such as the treatment setting and the presence or absence of psychotherapy. We found that observational studies nearly uniformly show promising results, but trials in which psychedelics were tested against placebo or standard of care control groups have been more inconsistent in both outcomes and methodologies. Given the inconsistency in published results, we review candidate mechanisms of action for psychedelics in the context of AUD. We take a biopsychosocial approach, reviewing mechanisms spanning several different hierarchical levels of analysis, including cellular neuroplasticity, cognitive neuroscience, subjective experience, and social connection. Taken together, this review highlights key findings on both the efficacy and potential mechanisms of psychedelics for the treatment of AUD, which could motivate future studies in this rapidly developing field.