Ketamine for Substance Use Disorders: Emerging Research

Ketamine infusion given in a clinical setting has far more research behind it than sublingual troches when it comes to opioid and heroin cravings. If you are trying to compare ketamine infusion versus troches for treating heroin addiction cravings, the short answer is that existing clinical trials rely on IV ketamine administered under medical supervision, not at-home troches, and even that infusion research on opioid use disorder (OUD) remains limited. Ketamine shows the strongest evidence for alcohol use disorder, weaker evidence for cocaine use disorder, and the least developed evidence for opioid and heroin dependence specifically.

This guide breaks down what the research actually supports for each substance use disorder, how infusion and troche formulations differ in absorption and control, and why most addiction medicine clinicians do not consider at-home troches appropriate for someone with active heroin cravings.

How Ketamine Might Affect Addiction and Cravings

Researchers have proposed several mechanisms to explain why ketamine, itself a substance with documented abuse potential, might help treat substance use disorders.

Disrupting Drug Memory Reconsolidation

Addiction involves strongly encoded associative memories. Cue-triggered cravings arise when drug-associated stimuli, such as locations, people, or paraphernalia, reactivate these memories and drive drug-seeking behavior even in people motivated to abstain. Ketamine blocks NMDA receptors, a type of glutamate receptor involved in learning and memory. Some researchers believe this blockade can interfere with the reconsolidation of drug-related memories when they are retrieved during a treatment session, a mechanism also studied in ketamine treatment for PTSD.

Restoring Prefrontal Function

Chronic substance use damages prefrontal cortical function, impairing the executive control that normally regulates impulsive behavior and drug seeking. Ketamine triggers BDNF-mediated synaptogenesis, a process that promotes new synaptic connections, which may help restore some of this prefrontal function.

Treating Depression That Drives Relapse

Negative affect, including depression and anxiety, is one of the most powerful drivers of relapse in substance use disorders. According to the National Institute of Mental Health, depression is a leading cause of disability and commonly co-occurs with substance use disorders. The World Health Organization similarly identifies depression as a major contributor to global disease burden. Ketamine's rapid antidepressant and anti-anxiety effects may reduce the negative emotional states that drive people to self-medicate with alcohol or other substances.

Reducing Cravings Directly

Some clinical reports describe reductions in craving that outlast ketamine's acute pharmacological effects. The mechanism is not fully understood, but it may involve NMDA receptor changes, neuroplasticity effects, or the psychological impact of the dissociative experience on rigid motivational patterns.

Alcohol Use Disorder: The Strongest Evidence

Alcohol use disorder (AUD) is the most studied substance use condition in ketamine research. The KARE (Ketamine for the Reduction of Alcoholic Relapse) program in the United Kingdom has produced the most rigorous clinical work in this area.

The KARE-1 and KARE-2 trials, led by Grabski and colleagues starting in 2022, tested three sessions of IV ketamine combined with psychological therapy against lorazepam plus therapy. Preliminary data from KARE-2 reported significantly higher full abstinence rates at six months with ketamine (87 percent) compared with the control group (23 percent). These numbers are striking, but they come from relatively small trials and require replication in larger studies before they can be considered established treatment outcomes.

Reconsolidation disruption is particularly relevant here, since alcohol cue reactivity is a major driver of relapse, and ketamine's antidepressant effects target the negative affect cycle common in alcohol dependence.

Cocaine and Stimulant Use Disorders

Cocaine use disorder has no FDA-approved pharmacotherapy, making it one of the most treatment-refractory addiction conditions. Ketamine's proposed mechanisms, including dopamine system modulation, prefrontal restoration, and disruption of cocaine-related memories, offer theoretical promise. Clinical evidence is at an earlier stage than for alcohol use disorder, consisting primarily of case reports, small open-label studies, and preliminary trial data. Results are encouraging but not definitive.

Opioid and Heroin Use Disorder: Where the Evidence Is Weakest

Ketamine's role in opioid use disorder is primarily as a pain management adjunct, helping patients with chronic pain reduce opioid doses by addressing central sensitization. It is not a primary treatment for heroin or opioid addiction itself. Methadone and buprenorphine remain the evidence-based standards for opioid use disorder.

A 2024 rapid review by Canada's Drug Agency (CDA-AMC) searched the literature from January 2018 through November 2023 and identified only two systematic reviews and one randomized controlled trial examining ketamine for substance use disorders, including opioid use disorder. The review concluded that evidence for ketamine's effect on opioid use disorder is inconclusive due to small sample sizes, and it found no cost-effectiveness studies or evidence-based clinical guidelines that met its inclusion criteria. The authors called for larger, blinded randomized controlled trials with low risk of bias before ketamine's role in opioid use disorder can be established.

For patients with both opioid use disorder and comorbid depression, ketamine's antidepressant effects may indirectly support recovery by addressing the depressive component of craving and relapse risk, but this is distinct from treating heroin cravings directly. See how troche and infusion outcomes compare for more on format-specific research gaps.

Why Home-Based Troches Are Not Appropriate for Most Patients With Heroin Cravings

The at-home troche format requires patients to store and self-administer a controlled substance without direct supervision. For patients with active, severe substance use disorders, including heroin dependence, this creates real risks: diversion (using more than prescribed, sharing, or selling the medication), development of a substitute ketamine use pattern, and impaired judgment during relapse periods. These risks make clinic-based administration far more appropriate for this population.

There is also no established, validated sublingual ketamine protocol for substance use disorders. The research that exists, including the KARE trials, uses IV ketamine in clinical settings paired with structured psychotherapy. Extrapolating that research to home-based troches for heroin or opioid cravings is not supported by current evidence. For background on how the formulations differ pharmacologically, see how troche and oral capsule bioavailability compare and this guide to sublingual ketamine therapy.

Who Might Be Considered for Ketamine-Assisted Addiction Treatment

Based on current research, the population for whom ketamine-assisted treatment might reasonably be considered is narrow. It generally includes patients who are in stable recovery rather than actively using, who have significant comorbid depression or anxiety driving relapse risk, who remain engaged in formal addiction treatment programs, who have failed standard pharmacotherapy and behavioral interventions, and whose prescriber has experience in both addiction medicine and ketamine treatment.

For most people with active substance use disorders, including active heroin use, the risks of ketamine treatment outweigh the benefits outside of specialized research or addiction-medicine settings. Discuss any consideration of ketamine for cravings with your addiction treatment provider first; see working with your provider for guidance on that conversation.