Verified by 
Key points
- In a handful of randomized clinical trials, ketamine reduces substance use, and effects are long-lasting.
- On the other hand, the studies are small, safety is not established, and results need replication before widespread use.
- Ketamine may become a viable treatment option in the near future, especially for treatment-refractory individuals.
In the last couple of decades, there has been an explosion of research on ketamine, an anesthetic that can induce a hallucinogenic trance-like state, to treat various mental health problems.
Many studies indicate possible benefits. In fact, in 2019, an intranasal form of a molecularly-similar compound (esketamine) was given FDA approval for depression treatment.
Unlike esketamine, ketamine [taken orally, through intramuscular (IM) injection or intravenously (IV)] is only FDA-approved for use as an anesthetic. This is because it alters the level of consciousness.
However, studies show it can reduce depression, improve chronic pain symptoms and even reduce pain medication use after surgery if given intraoperatively. Therefore, there is increasing use of ketamine off-label for major depressive disorder and pain.
Pain and depression can fuel more substance use in people with or at risk for substance use disorder (SUD), the clinical term for what is more colloquially referred to as addiction.
Fueled by this knowledge and results from preclinical studies indicating that ketamine and similar compounds improve withdrawal symptoms, craving, and drug use, several important, albeit small, clinical trials have recently been run in people with SUD to probe for effects in this population.
Findings From Key Studies
In a 2020 article, researchers reported some exciting results from a trial in forty people with alcohol use disorder. All participants received motivational enhancement therapy, but half were randomized to a single IV ketamine session, and the others to midazolam.
Midazolam, a benzodiazepine, was chosen for the control group because it can also change the level of consciousness. Those in the ketamine group experienced more abstinence and less heavy drinking, and the effects persisted at six months follow-up.
In a still more recent study, ninety-six people with alcohol use disorder were randomized to one of four groups: 1.) three weekly ketamine infusions (IV) plus mindfulness therapy, 2.) three saline infusions plus mindfulness therapy, 3.) three ketamine infusions plus alcohol education, or 4.) three saline infusions plus alcohol education.
In this study, saline was used as the placebo control, so it was likely easy for participants to identify whether they had been assigned to the active or the placebo group. Ketamine resulted in more days abstinent at six-month follow-up than placebo, with the greatest reduction in the ketamine plus therapy group.
Stimulants
Another recent randomized-controlled clinical trial in people with cocaine use disorder indicates ketamine might benefit people with problems with stimulants, too. In this study, 55 participants received either a single IV ketamine or midazolam session, and all had several mindfulness-based relapse prevention therapy sessions.
At fourteen days, 48 percent of participants in the ketamine group remained abstinent compared with 11 percent in the midazolam group. Craving scores were lower in the ketamine group, and, at the six-month follow-up, 44 percent of the ketamine group reported cocaine abstinence, whereas none in the midazolam group were abstinent.
Heroin
The same research group has performed two randomized clinical trials in people with heroin use disorders. Unlike in the alcohol and cocaine studies, in these, ketamine was given IM, and therapy was done during the ketamine sessions rather than a day or so afterward.
The first trial measured the differences in clinical outcomes between a higher and lower dose of ketamine in seventy detoxified heroin-dependent individuals, the lower dose acting as a control group. The higher dose had a larger beneficial effect on craving and drug use, and benefits lasted until at least 24 weeks.
In their second study, three sessions were compared to one session in 53 heroin-dependent patients. Three sessions were more effective, with higher abstinence rates (50 percent compared with 22 percent) at the one-year follow-up.
Studies have also shown that ketamine may be useful for withdrawal management.
Pitfalls, Limitations, and Unanswered Questions
Although these trial results are encouraging, there are limitations to the work that has been done so far and unanswered questions about potential problems with using ketamine for SUD treatment. Following are some important considerations.
- Placebo effects can influence results. Clinical trials are most informative if participants are assigned to either active treatment or placebo treatment randomly and if they don’t know which group they are assigned to.
Placebos are used in clinical trials because everyone tends to improve in a clinical trial regardless of treatment group assignment. To accurately isolate and measure the effect of the active treatment, outcomes need to be compared between groups to obtain valid information about the therapeutic potential of a treatment.
It is particularly challenging to blind participants to treatment group assignment in a study of a mind-altering substance, like ketamine, because people know they are getting a placebo if they don’t feel a change.
This could especially have been the case in one of the alcohol studies, where saline was used as the control (Grabski et al., 2022), which might have made ketamine look more effective than it actually was.
- Ketamine has psychoactive effects and therefore has abuse potential. Experts have raised concerns that it could just become someone’s new addiction. Although this has not been reported in the literature thus far in the setting of using it for SUD treatment, the jury is still out on this question.
- Ketamine may not be effective when people are on medication-assisted treatment (MAT) for opioid use disorder. Ketamine may bind to opioid receptors and activate them, and this may be one of the mechanisms by which it reduces depression symptoms (although this finding has not been seen in all studies).
Whether ketamine will still be effective as a treatment for SUD when opioid agonists (buprenorphine) or antagonists (naltrexone) are in the system is unknown.
- Research into ketamine for SUD is in its nascent phases, and much more needs to be done. The studies have been small, and whether these findings will be replicated in other settings needs to be determined. Work is also needed to identify the ideal dose, route of administration, number of sessions, and most effective psychotherapy add-on. Whether esketamine has the potential to reduce substance use and craving is also not yet known.
- There are risks and side effects associated with ketamine infusions. In addition to some minor transient, uncomfortable side effects (nausea, dizziness, drowsiness, etc.) that dissipate after one to two hours, high blood pressure and changes in heart rate have been observed. People can also experience dysphoria, anxiety, and even increased suicidal thoughts during and just after a session. In rare instances, adverse psychiatric symptoms last days.
In Conclusion
In summary, studies show that ketamine infusions may reduce craving and promote recovery for people with alcohol, stimulant, and opioid use disorders. That the effects of ketamine on craving and substance last months across studies are especially exciting. For depression treatment, by contrast, effects usually only last a few weeks.
That said, research into using ketamine for SUD treatment is still in its early phase, and more work needs to be done before it can be recommended for widespread use. Evidence-based approaches for SUD treatment should be tried first, including medications to reduce craving (especially for alcohol and opioid use disorder) and numerous well-studied group, individual, and family-based behavioral interventions.
On the other hand, for disorders for which we have few pharmacologic treatments, such as cocaine use disorder, or for people who have failed standard treatments, we may see off-label use of ketamine for relapse prevention grow increasingly common in the not-so-distant future.
