While ketamine is FDA-approved for anesthesia and has strong clinical evidence for off-label use to treat mood disorders such as depression, there remains reasonable concerns that ketamine can be misused and questions about its appropriateness in treating substance use disorder.

There is an illegal black market where ketamine in an unmeasured powder form is inhaled provides a high to users. While this illicit setting does not cause acute overdose, prolonged and regular abuse causes known problem such as neuropsychiatric impairments and in rare cases permanent bladder inflammation (cystitis) and hard to reverse forms of psychosis. In supervised settings and with the doses typically used under appropriate medical care, these adverse events are not seen in the clinical setting.

Addictive drugs such as cocaine, heroin or alcohol increase the levels of dopamine in the nucleus accumbens, an area of the brain connected to the mesolimbic system and facilitates habit formation. The strength of this pathway encoded into the brains of patients suffering from substance use disorder underscores the challenges in breaking the addiction cycle. A recent article in Nature, demonstrated that the complex pharmacology of ketamine relevant to the pleasure reward centers shows a dual action, where ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability. Using a mouse model, a research group based in Geneva Switzerland showed that ketamine does not induce the synaptic plasticity in the nucleus accumbens that is typically observed with addictive drugs in mice, and they did not demonstrate behaviors of uncontrolled self-administration1.

Reinforcing the basic science of ketamine having a low addiction, profile, there is emerging clinical evidence supporting the opportunity to treat substance use disorder. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. In other studies, ketamine reduced craving for and self-administration of cocaine in dependent individuals2. A recent Cochrane review concluded that systematic reviews and meta-analyses provide support for robust, and rapid antidepressant and anti-suicidal effects of ketamine, evidence for addiction, while less robust, suggests similarly positive effects3.

1 Simmler LD, Li Y, Hadjas LC, Hiver A, van Zessen R, Lüscher C. Dual action of ketamine confines addiction liability. Nature. 2022 Aug;608(7922):368-373. doi: 10.1038/s41586-022-04993-7. Epub 2022 Jul 27. PMID: 35896744.

2 Ivan Ezquerra-Romano I, Lawn W, Krupitsky E, Morgan CJA. Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology. 2018 Nov;142:72-82. doi: 10.1016/j.neuropharm.2018.01.017. Epub 2018 Jan 12. PMID: 29339294.

3 Walsh Z, Mollaahmetoglu OM, Rootman J, Golsof S, Keeler J, Marsh B, Nutt DJ, Morgan CJA. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych Open. 2021 Dec 23;8(1):e19. doi: 10.1192/bjo.2021.1061. Erratum in: BJPsych Open. 2022 Jan 18;8(1):e29. PMID: 35048815; PMCID: PMC8715255.

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