In brief
- A systematic review published on October 1 in Frontiers in Psychiatry includes 106 articles selected from a total of 11,745 records.
- It places the strongest evidence in treatment-resistant depression; for PTSD, bipolar disorder, and anxiety, it rates the evidence as moderate or low-to-moderate.
- It highlights major gaps: long-term safety, oral ketamine prescribed without standardized protocols, and functional unblinding caused by the drug’s psychoactive effects.
Two researchers, Matthew M. Kinney and Zackary L. Bowers, have set out to bring order to a field expanding faster than it is solidifying: the use of ketamine in psychiatry. Their systematic review, published on October 1, 2026, surveys clinical indications, safety concerns, and regulatory hurdles, concluding with a clear look at what still remains unknown.
How it was conducted and what it found
The authors searched PubMed, SCOPUS, Embase, PsycINFO, ProQuest, and Google Scholar for studies published between January 2000 and June 2026, adhering to PRISMA 2020 guidelines. From an initial 11,745 records, they removed 3,722 duplicates, screened 8,023, and assessed 510 full texts. Ultimately, 106 peer-reviewed English-language articles met their criteria.
The review identifies the highest level of evidence for treatment-resistant depression using intravenous racemic ketamine and intranasal esketamine, as well as for major depression with acute suicidal ideation—noting, however, that esketamine alone has not been proven to reduce suicidal ideation independently. For PTSD and bipolar disorder, the evidence is considered moderate. For social anxiety and generalized anxiety disorder, evidence remains low-to-moderate, and clinical use remains off-label. Regarding bipolar disorder, the authors point to weak-to-moderate evidence for esketamine and a distinct lack of long-term data.
Safety, access, and gaps
Addressing adverse effects, the review distinguishes between acute reactions (tachycardia, hypertension, dissociation, dizziness) and those tied to repeated or extended use: cognitive deficits involving memory, attention, and executive function; ketamine-induced cystitis (urinary tract damage that, as the review notes, can become irreversible); psychotic-like symptoms and persistent paranoia; and dependence characterized by tolerance and craving. The authors cite rising figures for recreational use, with U.S. drug seizures jumping from 57.8 to 703.3 kilograms between 2017 and 2022—though these numbers reflect supply trends rather than individual harm rates.
A striking finding is the regulatory asymmetry. The FDA REMS program, which mandates administration in a certified healthcare setting followed by two hours of monitoring, applies to esketamine but not to racemic ketamine. According to the review, 43.5% of outpatient ketamine clinics offered oral or sublingual ketamine for at-home use, despite the absence of standardized dosing schedules, frequencies, or follow-up protocols. The authors also emphasize that clinical access remains severely constrained for individuals living in rural or underserved areas.
Methodological challenges also stand out. Ketamine’s dissociative effects make it easy for participants to guess whether they received the active drug, introducing significant expectancy bias. While active placebos such as midazolam help preserve blinding, they also make distinguishing therapeutic differences far more difficult. As an example, the authors point to the KARMA-Dep 2 trial, which found no statistically significant difference compared to midazolam; we reported on it here.
What it means
This paper is a review, not a clinical trial, and its authors acknowledge several limitations: it was restricted to English-language publications, faced substantial heterogeneity among studies, and suffered from a dearth of long-term outcome data, particularly in adolescents and older adults. While it does not deliver new empirical data, it offers a valuable inventory separating what is supported by solid clinical trials from what is currently practiced on fragile ground.
For those interested in ketamine and dissociatives, the takeaway is twofold. There is substantive backing for its application in treatment-resistant depression, yet there remains a wide, poorly charted territory—at-home oral use and repeated maintenance regimens—where current evidence cannot yet guide precise clinical decisions. Understanding where the evidence ends allows individuals to evaluate risks and expectations on their own terms, forming the core of informed harm reduction.
Source
- Kinney MM, Bowers ZL. Frontiers in Psychiatry. Ketamine in psychiatry: a systematic review of clinical applications, safety considerations, and emerging challenges. Frontiers in Psychiatry, October 1, 2026.
Educational content written from a harm reduction perspective and with respect for individual freedom. It is not a substitute for advice from a healthcare professional and is not intended to encourage or condemn any drug use.
