Ketamine's hallucinogenic effects do not drive its benefit for alcohol use disorder
A popular theory about how psychedelic-assisted therapies work runs roughly as follows: the intensity of the altered-state experience is itself therapeutic. The depth of the trip, the dissolution of self, the mystical quality of the encounter - these are what drive lasting behavioral change. For ketamine used to treat alcohol use disorder, a new secondary analysis of a rigorous clinical trial directly tests this assumption - and finds it does not hold up.
The study, published in Addiction and conducted by researchers at King's College London and the University of Exeter, used data from the Ketamine for Reduction of Alcoholic Relapse (KARE) trial. It is the largest study to date examining whether the subjective psychological effects of ketamine mediate its therapeutic benefit in substance use disorder treatment.
The KARE trial: what participants experienced
The KARE trial was a randomized, placebo-controlled study conducted at two clinical research facilities in England. It enrolled 96 adults with moderate to severe alcohol use disorder and followed them for six months. Participants in the active treatment arm received three weekly infusions of intravenous ketamine, paired with psychotherapy sessions.
Participants who received ketamine reported marked psychoactive experiences: altered reality, out-of-body sensations, and perceptual distortions compared to those receiving placebo. These effects were consistently strong across all three dosing sessions, with little apparent tolerance developing - participants did not report progressively weaker subjective experiences over the three-week course.
The central finding: no mediation
Despite the pronounced psychoactive effects, statistical analysis found no significant evidence that these experiences mediated ketamine's therapeutic benefit. The percentage of days abstinent from alcohol over six months was not predicted by the intensity of subjective drug effects. Patients who reported more intense experiences did not have better outcomes than those who reported less intense ones.
"We previously showed that ketamine has promise for helping people with alcohol use disorder remain sober and these new findings demonstrate those receiving intravenous ketamine experience the expected subjective effects from the drug," said Dr Will Lawn, lead author and Senior Lecturer at King's College London. "However, our results challenge the popular theory that the therapeutic benefits of ketamine are driven by its acute psychoactive or mystical-like effects. Instead, our findings suggest other possible reasons why ketamine prevents relapse, such as its ability to alter networks in the brain related to addiction or stimulate new neural connections to form."
What might actually be driving the benefit
Ketamine is primarily an NMDA receptor antagonist - it blocks a specific type of glutamate receptor critical to synaptic plasticity, learning, and memory consolidation. At sub-anesthetic doses, it can trigger the rapid formation of new synaptic connections in the prefrontal cortex, a region important for impulse control and decision-making. These neuroplasticity effects are distinct from - and may be more important than - the subjective dissociative experience they accompany.
Alcohol use disorder involves deeply ingrained neural patterns associated with craving, habit, and compulsive use. If ketamine disrupts and restructures these patterns at a neurological level, its therapeutic value would be pharmacological rather than experiential - and would not require a vivid altered-state experience to occur.
Limitations and next steps
The analysis involved 96 participants - a meaningful sample for a psychedelic-assisted therapy trial, but still small by the standards needed to detect moderate-sized mediation effects with statistical confidence. Subgroup analyses to identify whether specific patient profiles respond differently to subjective experience intensity were not powered for definitive conclusions.
The finding also applies specifically to alcohol use disorder, administered as intravenous ketamine paired with psychotherapy. Whether the same dissociation between psychedelic intensity and outcome holds for other substances - psilocybin for depression, MDMA for PTSD - is a separate question that these data cannot answer.
Professor Celia Morgan from the University of Exeter, the KARE study lead, is now running MORE-KARE, a larger UK-wide trial funded by the NHS with additional support from Solvonis Therapeutics. It is currently recruiting participants with alcohol problems to investigate the neural mechanisms of ketamine's therapeutic action in more detail.