Ketamine-Assisted Therapy for Substance Use Disorders: Clinical Trials Review

Ketamine-assisted therapy for substance use disorders is an experimental approach with early clinical trial signals, not an established replacement for evidence-based addiction treatment. The strongest human evidence so far is in alcohol and cocaine use disorders, where small randomized studies have paired supervised ketamine with structured psychotherapy. Results are promising but limited by small samples, differing doses, and short follow-up.

Substance use disorders are treatable medical conditions, and treatment plans should be developed with qualified addiction-care professionals. The National Institute on Drug Abuse describes addiction as a chronic, relapsing disorder involving compulsive drug seeking despite harmful consequences.

Why researchers are studying ketamine in addiction

Addiction is associated with lasting changes in brain circuits involved in reward, motivation, stress, and behavioral control. Researchers have proposed that ketamine's effects on glutamate signaling and synaptic plasticity may create a period in which psychotherapy and relapse-prevention work are more effective. This is a hypothesis under active study, not a proven mechanism for treating addiction.

Neuroplasticity refers to the brain's capacity to change its connections and activity in response to experience. In ketamine research, that concept is relevant because treatment is often paired with therapy aimed at changing responses to triggers, cravings, and substance-related habits.

Another research question concerns memory reconsolidation. Drug-associated cues can become linked to craving through learning and repeated substance use. Laboratory research suggests NMDA receptor signaling plays a role in reconsolidation, but whether ketamine can reliably weaken drug-related memories in people with substance use disorders remains uncertain.

What clinical trials have found

Alcohol use disorder

Alcohol use disorder has the most developed ketamine literature among substance use conditions. An earlier randomized study by Krupitsky and colleagues compared ketamine-assisted psychotherapy with an active control approach in detoxified patients with alcohol dependence. The authors reported higher abstinence in the ketamine-assisted psychotherapy group at one year, although the intervention used intramuscular ketamine at a dose and therapeutic model that differ from many current low-dose protocols.

A later proof-of-concept randomized trial by Dakwar and colleagues paired intravenous ketamine with motivational enhancement therapy. The study enrolled 40 adults with alcohol use disorder and compared ketamine with midazolam, an active control. The authors reported more abstinent days during the short post-infusion follow-up in the ketamine group. The study is available through PubMed, but its small size and short follow-up mean the result should not be treated as a definitive estimate of benefit.

Cocaine use disorder

Small studies have also examined ketamine for cocaine use disorder. Early work by Dakwar and colleagues found changes in laboratory cocaine self-administration and motivation to quit after a single infusion. A subsequent randomized trial combined repeated ketamine infusions with mindfulness-based relapse prevention. The investigators reported improved end-of-treatment abstinence and lower craving relative to the active-control group. These findings support continued research, but they do not establish ketamine as standard care for cocaine use disorder.

Opioid and tobacco use disorders

Evidence for opioid use disorder and tobacco use disorder is much earlier and less consistent. Some studies have explored ketamine during medically supervised opioid withdrawal or as part of psychotherapy-oriented protocols. These studies should not be interpreted as evidence that ketamine replaces medications for opioid use disorder, such as buprenorphine, methadone, or naltrexone, when those medications are clinically appropriate.

According to the Substance Abuse and Mental Health Services Administration, the National Helpline provides free, confidential treatment referral and information for people facing mental health or substance use disorders in the United States.

Why psychotherapy and follow-up matter

Most of the notable trials did not test ketamine as a stand-alone intervention. They paired it with approaches such as motivational enhancement therapy, mindfulness-based relapse prevention, or existential psychotherapy. That distinction matters. A ketamine session does not substitute for withdrawal management, ongoing addiction treatment, recovery supports, or treatment of co-occurring mental health conditions.

Ketamine integration therapy describes the work of reflecting on and applying insights from treatment in daily life. For a person with a substance use disorder, a clinically appropriate plan may also include trigger planning, medication review, counseling, peer support, and coordination with addiction specialists.

Safety and misuse considerations

Ketamine is a Schedule III controlled substance in the United States. In research settings, it is generally administered under supervision rather than supplied for unsupervised use. Acute effects can include dissociation, nausea, increased blood pressure, and perceptual changes. Individual risk assessment is essential, especially for people with a history of ketamine misuse, active polysubstance use, psychosis-spectrum symptoms, uncontrolled cardiovascular conditions, or other factors a clinician identifies.

Published studies in substance use populations have generally reported transient acute adverse effects, but follow-up periods have often been limited. That leaves uncertainty about delayed harms and the risk of problematic ketamine use after treatment. Readers considering care can review common ketamine side effects and discuss their full substance-use and medication history with a licensed clinician. Alcohol can create additional safety concerns, covered in this guide to ketamine and alcohol interaction risks.

Bottom line

Ketamine-assisted therapy is a research-supported area of interest for substance use disorders, particularly alcohol and cocaine use disorders, but the evidence remains preliminary. The most responsible interpretation is cautious: early trials justify larger studies, while established addiction treatments remain the foundation of care. Anyone considering ketamine should seek an individualized assessment from a clinician experienced in both ketamine treatment and substance use care.