A systematic review of 29 studies examined whether the psychoactive effects of ketamine are linked to its therapeutic benefits for psychiatric disorders. About half of the studies (51.72%) found a positive relationship between ketamine-induced altered states of consciousness and clinical outcomes, while 44.83% found no link, and one study found a negative association. For mood disorders like major depressive disorder and bipolar disorder, 48% of studies showed a positive relationship and 48% showed none. All three studies on substance use disorder reported a positive correlation. The authors conclude the relationship remains uncertain due to high variability across studies.
Cognitive-behavioral therapies are being combined with psychedelic substances such as ketamine, psilocybin, and MDMA to treat mental disorders, but the way they are integrated varies widely across studies. A systematic review of 9 clinical trials involving 283 patients found that traditional cognitive behavioral therapy was the most common approach, used in 6 studies, while mindfulness-based cognitive therapy and acceptance and commitment therapy were each used in 2 and 1 studies respectively. The timing of therapy relative to the psychedelic experience—before, during, or after—also differed. The findings highlight the need for more consistent research to clarify how these therapeutic models are best implemented.
A meta-analysis of eleven studies found no significant correlation between the psychoactive (psychomimetic) effects of ketamine and clinical outcomes in mental illness, including depression. The overall correlation was r = 0.06, and for depression specifically r = 0.03, both non-significant. Sub-analyses accounting for patient disorders, intravenous administration, assessment instruments, and timing also yielded no significant findings. High heterogeneity was present. The analysis suggests that altered states of consciousness during ketamine sessions are not directly linked to clinical outcomes, but the limited number of studies and heterogeneity make this conclusion preliminary.
In a small open-label trial of 22 patients with treatment-resistant depression who received seven weekly subcutaneous doses of esketamine, those with elevated baseline C-reactive protein (CRP > 1 mg/L) showed significant reductions in CRP by week 4 and week 8, while patients without inflammation showed no change. By week 8, CRP levels in both groups were comparable. Although the inflammation group had a greater average reduction in depression severity (15.88 points on the MADRS scale versus 11.14 points), this difference was not statistically significant, and changes in CRP did not predict symptom improvement. Larger controlled studies are needed.