A review of two systematic reviews, three randomized controlled trials, and two single-arm safety trials found that various combinations of psychedelics and psychotherapy showed clinical effectiveness lasting weeks to months for mental health conditions. Psilocybin was the most tested psychedelic; others included MDMA, LSD, ayahuasca, ibogaine, ketamine, and nitrous oxide. Ketamine-assisted psychotherapies improved substance use disorder symptoms in two trials, and psilocybin-assisted psychotherapy was efficacious for major depressive disorder in one trial. No serious adverse effects were reported. However, limitations such as small sample sizes (under 20 in most studies), short follow-ups, and heterogeneity mean findings should be interpreted cautiously.
For adults with treatment-resistant depression (TRD), ketamine can lead to immediate improvement in depressive symptoms and suicidal ideation compared to placebo or midazolam, with effects lasting up to 28 days after a dose and serious side effects like dissociation being rare and short-lived. However, it is uncertain whether ketamine is effective or safe for posttraumatic stress disorder (PTSD) due to little evidence. Most studies used intravenous ketamine; evidence for other routes is limited. An economic evaluation found IV ketamine likely cost-effective compared to intranasal esketamine from a US health care perspective but not from a patient perspective. US guidelines suggest ketamine as augmentation for TRD but not for PTSD.
Two randomized controlled trials on repeated IV ketamine for PTSD gave mixed results: one small trial in civilians found significant symptom improvement compared with midazolam, while a larger military trial found no significant difference from placebo. Antidepressant effects of ketamine were rapid but not sustained after a few weeks. One trial found comparable acute antidepressant effects between IV ketamine and IV esketamine for treatment-resistant depression 24 hours after infusion.