Treatment Outcomes of Ketamine-Assisted Psychotherapy Associated With Temporary Neural Changes

A systematic review found that changes in neural mechanisms as a result of ketamine treatment could play a role in treatment outcomes of ketamine-assisted psychotherapy.

The effectiveness of ketamine-assisted psychotherapy (KAP) was affected by the neural changes caused by ketamine treatment, according to a review published in the Journal of Affective Disorders.

Ketamine has been demonstrated as a treatment for treatment-resistant depression (TRD) and substance use disorders, and it has also been found to be a positive treatment for chronic alcohol admission and abstinence. Combining psychotherapy and antidepressants is also more effective than medication alone. The current review aimed to provide an overview of putative mechanisms of action in literature reporting on KAP for treatment of mental health disorders.

The researchers used PubMed and PsycInfo to search for studies from inception through October 31, 2021. Supplementary searchers were also done using Studies were included if they had adult subjects meeting criteria for any Diagnostic and Statistical Manual of Mental Disorders 5 or 4 diagnosis, had an intervention featuring both ketamine and psychotherapy, had randomized clinical trials, and reported either quantitative or qualitative data. Studies with non-human trials or that combined ketamine with other medical interventions were excluded.

There were 5 studies included in this review, all of which were randomized controlled trials. There was 1 study that recruited participants with alcohol use disorder, 1 study that recruited participants with cocaine use disorder, 2 studies that recruited participants with heroin use disorder, and 1 study that recruited patients with TRD. Psychotherapy was given before, during, and after ketamine infusions in 2 studies and 3 trials provided psychotherapy when participants were not under the acute effects of ketamine.

In the trial featuring participants with TRD, the aim was to evaluate the efficacy of ketamine and cognitive behavioral therapy (CBT) as an antidepressant in adults with TRD. Participants had 6 ketamine infusions and were separated into 2 groups that either received CBT and treatment as usual. There was no benefit for KAP in this trial and the interaction of treatment group and time was not statistically significant when measured by the Montgomery-Asberg Depression Rating Scale. It was significant when measured by the Quick Inventory of Depressive Symptomatology, Self-Report 16-item (moderate-large effect size, 0.71; 95% CI, –0.30 to 1.70).

A second trial evaluating participants with heroin use disorder examined the efficacy of KAP on abstinence in adults with the disorder. Ketamine was given with 10 hours of psychotherapy over multiple sessions before the dosing and 5 hours of psychotherapy after.

In abstinence measured monthly, participants rated their locus control as significantly more internal after KAP (high dose group increased from mean [SD], 4.1 [1.5] to 5.2 [2.1]; low dose group increased from mean [SD], 3.8 [1.3] to 4.5 [1.4]). Locus of control in the area of failures also became more internal in the high dose group after KAP (from 4.2 [2.0] to 5.2 [1.8]). There was also an increase in spiritual development after a session of KAP in both groups (high dose group, mean 27.2 [9.3]; low dose group, mean 25 [9.6]).

A third trial that also evaluated adults with heroin use disorder focused on retention in treatment and abstinence rates. This trial found that 50% of the participants who had 3 sessions of KAP remained abstinent compared with 22.2% of participants who only attended a single KAP session.

A trial evaluating the efficacy of KAP on alcohol use disorder was used, where a time-by-treatment interaction was found when examining abstinent days 21 days after infusion. In a trial assessing the efficacy of KAP on adults with cocaine use disorder, 48.2% of participants who were in the ketamine group maintained abstinence in the last 2 weeks of the trial compared with 10.7% of the participants who took midazolam instead. The odds of abstinence by the end of study were nearly 6 times higher in the ketamine compared with the midazolam group (odds ratio, 5.7; 95% CI, 1.3-25.1) when controlled for route of use.

There were some limitations to this review. There were no large, replicated clinical trials with rigorous designs included in this review. Synergistic effects could not be inferred due to the design of the featured studies. There were also no studies examining mechanisms of action of KAP included in the review.

The researchers concluded that treatment outcomes are affected by changes in neural mechanisms from ketamine.


Joneborg I, Lee Y, Di Vincenzo JD, et al. Active mechanisms of ketamine-assisted psychotherapy: a systematic review. J Affect Disord. 2022;315:105-112. doi:10.1016/j.jad.2022.07.030

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