A signal-and-limitations timeline
Ketamine's story in psychiatry has moved quickly, but the science is best understood milestone by milestone — including what each study did and did not establish. Every entry below is tied to a numbered citation you can verify in the references list at the bottom of the page.
One point matters throughout: ketamine is FDA-approved only as an anesthetic, and its intravenous use for depression, anxiety, and PTSD remains off-label. The only ketamine-related medication FDA-approved for psychiatric indications is intranasal esketamine (Spravato), and only for specific depression indications under its FDA labeling. Research suggests meaningful short-term signals, but results vary and much remains uncertain.
Major moments in ketamine psychiatric research
- 1962
Ketamine is first synthesized
Ketamine was first synthesized by chemist Calvin Stevens at Parke-Davis as part of a search for a safer anesthetic. This was a laboratory and pharmacological milestone, not a psychiatric one — decades of research would pass before its mood effects were studied in controlled trials. [1]
- 1970
FDA approval as an anesthetic
The FDA approved ketamine as an anesthetic, and it has been used in surgery, emergency care, and pain management ever since. This anesthetic approval remains its established, on-label use. It is important to note that this approval does not cover depression, anxiety, PTSD, or other psychiatric conditions. [1] [2]
- 2000
First randomized placebo-controlled trial in depression
Berman and colleagues reported the first randomized, double-blind, placebo-controlled trial suggesting that a single subanesthetic intravenous ketamine infusion was associated with rapid reductions in depressive symptoms. It was a very small study (n=7 in the analyzed sample) and served as an early signal rather than proof of durable benefit. Its size and short follow-up limit how far the findings can be generalized. [3]
- 2006
NIMH replication in treatment-resistant depression
Zarate and colleagues at the National Institute of Mental Health replicated the rapid-response finding in patients with treatment-resistant major depression, reporting improvement often within about 24 hours of a single infusion. The trial was still small and the benefit for many participants was meaningful but temporary, underscoring the need for a broader treatment plan rather than a single intervention. [4]
- 2013
Repeated-infusion and active-comparator studies
Research broadened to repeated infusions and better controls. Murrough and colleagues ran a two-site randomized trial comparing IV ketamine to midazolam (an active placebo) in treatment-resistant depression and reported greater short-term symptom improvement with ketamine. Using an active comparator helped address whether early benefit was simply a placebo response, though follow-up remained short and sample sizes modest. [5]
- ~2018
Research on rapid reduction of suicidal ideation
Meta-analyses pooled individual trials examining whether ketamine could rapidly reduce suicidal ideation. Wilkinson and colleagues reported that ketamine was associated with short-term reductions in suicidal thoughts within a day of treatment across several small studies. These effects were short-term, the underlying trials were small, and the analyses do not establish that ketamine prevents suicide — it is not a substitute for emergency care. [6]
- 2019
FDA approval of intranasal esketamine (Spravato)
In March 2019 the FDA approved esketamine nasal spray (Spravato), a ketamine-derived medication, for treatment-resistant depression, to be used alongside an oral antidepressant. It must be administered in a certified healthcare setting under supervision through a restricted REMS program. This approval is distinct from off-label intravenous racemic ketamine. [7] [8]
- 2020
Esketamine indication expanded to MDD with acute suicidal ideation
In 2020 the FDA expanded the esketamine label to include depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior, again used together with an oral antidepressant and under in-office supervision. The approval addresses depressive symptoms rather than being an emergency treatment, and people in crisis still need immediate emergency care. [8] [9]
- 2020s
Systematic reviews weigh efficacy signals against limitations
Systematic reviews and expert syntheses in the 2020s described consistent rapid antidepressant signals for ketamine and esketamine in carefully selected patients. At the same time they emphasized real limitations: many trials had small samples and short follow-up, blinding is genuinely difficult because ketamine produces noticeable dissociative effects, and the durability of benefit is not well established. In short, research suggests a meaningful short-term signal while long-term questions remain open. [10]
What the evidence supports — and what it doesn't
A promising but still-maturing body of research
Across two decades of study, controlled trials have repeatedly pointed to rapid, short-term reductions in depressive symptoms — and, in some analyses, suicidal ideation — for carefully selected patients. That is a genuine and important signal.
At the same time, many trials were small, follow-up was short, blinding is difficult because ketamine's dissociative effects are noticeable, and the durability of benefit is not well established. No study supports treating ketamine as a cure or guaranteeing an outcome. It is best understood as one part of a broader, provider-led care plan.
Sources
The following sources are cited above. Where a specific press page or PDF may change, the linked PubMed record or DOI provides a durable reference.
- Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016;10:612. View source ↗
- U.S. Food and Drug Administration. Ketalar (ketamine hydrochloride) injection — FDA-approved drug label (anesthetic indication; original approval 1970). Drugs@FDA, NDA 016812. View source ↗
- Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354. PMID: 10686270. View source ↗
- Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864. PMID: 16894061. View source ↗
- Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. PMID: 23982301. View source ↗
- Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150-158. PMID: 28969441. View source ↗
- U.S. Food and Drug Administration. FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor's office or clinic. March 5, 2019. View source ↗
- U.S. Food and Drug Administration. SPRAVATO® (esketamine) nasal spray prescribing information (current labeling). View source ↗
- U.S. Food and Drug Administration. FDA approves new use of Spravato (esketamine) for treatment-resistant depression / depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. 2020. View source ↗
- McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383-399. View source ↗
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Medical disclaimer. This page is for educational purposes only and does not provide medical advice, diagnosis, or treatment. Ketamine is used off-label for mental health conditions, is not appropriate for everyone, and individual results vary. Candidacy is determined only after a clinical evaluation by a licensed medical provider. If you are in crisis or thinking about harming yourself, call or text 988 or go to the nearest emergency room.