Ketamine-Assisted Treatment for Substance Use Disorders

Ketamine-assisted treatment for substance use disorders pairs sub-anesthetic doses of ketamine with structured psychotherapy to reduce cravings, disrupt addiction-related memory patterns, and support long-term abstinence. Substance use disorders (SUDs) are among the most prevalent conditions in global health. According to the World Health Organization, more than 35 million people worldwide have a drug use disorder, and alcohol use disorder affects roughly 400 million people globally. In the United States, the opioid crisis has claimed more than one million lives since 1999, according to the Centers for Disease Control and Prevention, and alcohol-attributable deaths exceed 140,000 per year.

Existing medications for alcohol use disorder, including disulfiram, naltrexone, and acamprosate, have only modest efficacy, and relapse rates stay high across every substance category. That treatment gap has driven growing clinical interest in ketamine, a dissociative anesthetic already used off-label for treatment-resistant depression, as a possible tool in addiction care. For background on the underlying pharmacology, see our guide on how ketamine works in the brain.

Historical Context: From Soviet Psychiatry to Modern Trials

Ketamine's use in addiction treatment is not a recent idea. In the 1980s and 1990s, Russian psychiatrist Evgeny Krupitsky pioneered ketamine-assisted psychotherapy (KAP) for alcohol and heroin dependence. His studies found that ketamine sessions combined with psychotherapy produced significantly higher abstinence rates than conventional treatment alone. The findings drew skepticism from Western psychiatry at the time, but more recent clinical trials have lent them support.

Krupitsky's approach treated the psychedelic-like properties of ketamine, altered states of consciousness, ego dissolution, and mystical-type experiences that can occur at sub-anesthetic to near-anesthetic doses, as therapeutic tools rather than side effects to manage away. That framing lines up with the broader psychedelic-assisted therapy model that has gained scientific traction in recent years.

Clinical Evidence by Substance Type

Alcohol Use Disorder

The strongest evidence for ketamine in addiction treatment comes from alcohol use disorder (AUD) research. A 2022 randomized controlled trial published in the American Journal of Psychiatry, known as the KARE trial, enrolled 96 patients with severe AUD and compared ketamine-assisted psychotherapy to placebo-assisted psychotherapy. Patients in the ketamine group had significantly more days abstinent from alcohol over the six-month follow-up period, 162 days versus 116 days in the placebo group. By the end of the trial, 86% of the ketamine group was completely abstinent, compared to 62% of the placebo group, and the ketamine sessions were well tolerated with no serious adverse events.

Additional studies have tested IV ketamine infusions without a structured psychotherapy component for AUD, with mixed but generally positive results. Taken together, the evidence suggests that ketamine alone may have some anti-craving effect, but pairing it with psychotherapy appears to produce more consistent and durable outcomes.

Opioid Use Disorder

Research into ketamine for opioid use disorder is more limited but growing. A 2019 pilot study examined repeated ketamine infusions in patients with opioid use disorder who were also receiving buprenorphine maintenance therapy. Participants showed reduced craving and improved mood, though the small sample size limits how much can be concluded.

The relationship between ketamine and opioid systems is complex. Ketamine interacts with opioid receptors in addition to NMDA receptors, and researchers have hypothesized that this activity could be either beneficial, by reducing craving, or problematic, by potentially reinforcing addictive circuitry, in people with opioid dependence. That uncertainty is why careful, controlled research is still needed before drawing firm conclusions.

Cocaine Use Disorder

A study by researchers at Columbia University, led by Dakwar and colleagues, examined ketamine for cocaine use disorder. In a 2019 randomized controlled trial, people with cocaine use disorder who received a single ketamine infusion during a period of abstinence showed significantly reduced cocaine use over the following two weeks compared to those who received a control infusion. Ketamine-treated participants also reported reduced craving and greater motivation to quit.

A follow-up study combining ketamine with mindfulness-based relapse prevention therapy showed even stronger effects: 48% of the ketamine-plus-therapy group achieved abstinence by the end of the study, compared to 11% of the control group. These results suggest that pairing ketamine's neuroplastic effects with psychotherapeutic intervention may be especially useful in cocaine addiction.

Tobacco and Other Substances

Preliminary work has explored ketamine for nicotine dependence and cannabis use disorder, though the evidence base for these applications remains thin. The theoretical rationale, that ketamine-enhanced neuroplasticity could help patients unlearn addictive behaviors, applies broadly across substance types, but each specific indication still needs its own clinical validation.

How Ketamine May Work Against Addiction

Disrupting Reward-Related Memory

Addiction involves powerful, maladaptive memories that link substance use with reward, environmental cues, and emotional states. These memories drive craving and relapse even after long periods of abstinence. Ketamine may disrupt this process in a few ways: NMDA receptor blockade can interfere with the reconsolidation of drug-associated memories, potentially weakening their hold on behavior. Ketamine-induced neuroplasticity may help form new, adaptive associations that compete with drug-related memories. And the dissociative experience itself, explained in more detail in our guide to understanding dissociation, may offer a novel perspective that helps a person reframe their relationship with a substance.

Enhancing Neuroplasticity

Ketamine's rapid synaptogenic effects, driven by BDNF release, mTOR pathway activation, and AMPA receptor stimulation, may open a window of enhanced neural plasticity during which therapeutic learning is easier to encode. This window is thought to be important for the efficacy of ketamine-assisted psychotherapy, since new patterns of thinking and behavior introduced during that period may be more effectively consolidated into long-term neural circuits.

Normalizing Glutamate Signaling

Chronic substance use is associated with significant glutamatergic dysregulation, including reduced glutamate clearance in the nucleus accumbens, a key reward center, and altered NMDA and AMPA receptor expression. Ketamine's effect on the glutamate system may help normalize these abnormalities, restoring healthier patterns of neurotransmission in reward and decision-making circuits.

Psychological and Existential Mechanisms

At doses that produce meaningful dissociative or psychedelic-like effects, ketamine can bring on significant psychological experiences, including feelings of ego dissolution, interconnectedness, and shifts in perspective on life and mortality. Within structured psychotherapy, these experiences may help build motivation for change, self-compassion, and a renewed sense of meaning. Research has found that the intensity of the mystical-type experience during ketamine sessions correlates with treatment outcome in addiction studies.

The Ketamine-Assisted Psychotherapy (KAP) Model

Treatment Structure

Ketamine-assisted psychotherapy for SUDs typically follows a structured protocol, described in more detail in our guide to ketamine-assisted psychotherapy:

• Preparation sessions: psychotherapy before ketamine administration to build rapport, set intentions, and establish a framework for understanding the experience.
• Ketamine sessions: ketamine is given, typically IV or IM, in a supportive therapeutic setting with a trained therapist present throughout.
• Integration sessions: psychotherapy after ketamine administration to process the experience and translate insights into behavioral change.

Dosing Considerations

Dosing in KAP for addiction often differs from dosing used for depression treatment. Some protocols use higher doses, around 0.5-0.8 mg/kg IV or 3-4 mg/kg IM, to produce more psychedelic-like experiences, based on the theory that the depth of the altered state contributes to the therapeutic outcome. Other protocols use standard antidepressant-range doses of about 0.5 mg/kg IV. The optimal dosing strategy for addiction treatment is still an open question in the research.

Future Directions

Ketamine-assisted addiction treatment is a fast-moving research area. Ongoing work includes larger, multi-site randomized controlled trials for AUD, opioid use disorder, and cocaine use disorder; optimization of dosing protocols and psychotherapy frameworks; identification of biomarkers that predict treatment response; comparisons of ketamine with other psychedelic-assisted approaches such as psilocybin or MDMA; investigation of at-home ketamine protocols for addiction maintenance; and long-term follow-up studies on how durable the treatment effects really are.

The combination of neuroplasticity-based pharmacology and structured psychotherapy in ketamine-assisted treatment marks a meaningful shift in addiction medicine, one that offers real promise for a patient population that has had few effective options.

References and Further Reading

• National Institute on Drug Abuse (NIDA): federal research resource on substance use, addiction neuroscience, and treatment development.
• Substance Abuse and Mental Health Services Administration (SAMHSA): federal agency providing information on substance use treatment and recovery services.
• National Institute of Mental Health (NIMH): information on depression and other conditions that commonly co-occur with substance use disorders.