ABSTRACT
There is an urgent need to develop novel pharmacological treatment for alcohol use disorder (AUD). Recently,
psychedelic compounds have attracted great attention in treatment of different psychiatric disorders following
their reported fast-acting and long-lasting effects. Preliminary evidence from observational studies, supported
by animal studies, is promising for the potential therapeutic effects of psychedelic N,N-dimethyltryptamine
(DMT) for AUD. Here, we propose to investigate the therapeutic potential of a single dose of intravenous DMT
plus a brief course of psychotherapy (including Motivational Enhancement Therapy (MET)) on alcohol
consumption in non-treatment seeking individuals with AUD, in a proof-of-concept, randomized (1:1), placebo-
controlled, double-blind, parallel group, laboratory study and clinical trial.
Methods: Otherwise healthy individuals with diagnosis of moderate to severe AUD (based on DSM5) will be
randomized to receive a single dose of intravenous DMT or active placebo (diphenhydramine). Vitals will be
closely monitored, tolerability will be measured using a Visual Analogue Scale (VAS), and DMT acute
psychedelic effects will be assessed using the Mystical Experience Questionnaire (MEQ), at the end of the
dosing day. Adverse events will be assessed using the Systematic Assessment for Treatment Emergent
Effects (SAFTEE) interview on the dosing day and weekly follow up sessions (4 weeks). One day following
drug administration, participants will attend an experimental session using Alcohol Drinking Paradigm (ADP).
All participants will consume a priming dose of alcohol at the beginning of the experimental session, which will
be followed by two 1-hour self-administration drinking sessions, over which participants will have a choice of
consuming a total of 8 drinks or receiving $5 for each drink that is not consumed. The total number of
consumed drinks is the main primary outcome. All participants will receive a brief course of psychotherapy
(including MET). We will explore the effects of DMT (plus brief psychotherapy) on participants' natural alcohol
consumption weekly for 4 weeks, using Timeline follow-back (TLFB), to measure the percentage of heavy
drinking days, abstinent days, and total amount of alcohol consumption and categorical outcomes of
abstinence, no heavy drinking and a 2-level reduction in WHO drinking risk will be compared.
Hypotheses: Relative to control (diphenhydramine, IV, 25 mg plus MET), a single psychedelic dose of
intravenous (IV) DMT (0.3 mg/kg) plus brief psychotherapy (including MET) in individuals with AUD will 1) be
safe and well-tolerated, 2) reduce alcohol consumption measured in the laboratory using Alcohol Drinking
Paradigm, the day after, and 3) reduce alcohol drinking over the following 4 weeks.
