evidence·last verified august 18, 2026

ketamine vs esketamine: what is actually FDA-approved

these are two different regulatory situations that share a molecule and get written about as if they were one thing. esketamine — the nasal spray sold as Spravato — is FDA-approved for two depression indications and can only be given in a certified setting with at least two hours of observation. racemic ketamine, the generic drug used in infusion clinics and at-home telehealth programmes, is approved as an anesthetic; every psychiatric use of it is off-label, and FDA issued a specific warning about compounded at-home ketamine in october 2023. one of those has an FDA efficacy review behind it. the other has good independent trials but no FDA review at all.

the two regulatory situations, side by side

last verified: august 18, 2026. every regulatory claim below is traced to an FDA document or a dated sponsor release, and every trial was re-fetched from PubMed during verification. numbered references link to sources at the bottom of the page.

what it is	FDA status	where you can get it	evidence behind it	sources
esketamine (Spravato) nasal spray	APPROVED. march 5, 2019 for treatment-resistant depression, taken with an oral antidepressant. august 3, 2020 for depressive symptoms in major depressive disorder with acute suicidal ideation or behavior, again with an oral antidepressant. january 21, 2025 as the first monotherapy for treatment-resistant depression.	restricted under a REMS: a certified healthcare setting, self-administered under direct observation, with at least two hours of monitoring afterwards. the REMS was modified on march 24 and october 9, 2025 and remains in force.	one positive short-term pivotal trial (TRANSFORM-2, n=227: 4.0 MADRS points better than placebo spray at day 28) alongside two sibling trials that missed their primary endpoints, plus a relapse-prevention trial (SUSTAIN-1, n=297) showing that continuing esketamine roughly halved relapse risk. the 2025 monotherapy approval rested on TRD4005: remission 22.5% versus 7.6% on placebo at week 4.	[1] [2] [3] [5] [6]
racemic ketamine (generic, e.g. Ketalar)	approved as an ANESTHETIC only. there is no FDA-approved psychiatric indication and no registered application seeking one. every use of racemic ketamine for depression — IV infusion clinics, intramuscular, sublingual troches, at-home telehealth — is off-label.	no REMS and no FDA-mandated monitoring for psychiatric use, because there is no psychiatric approval to attach conditions to. FDA warned patients and providers about compounded ketamine products, including at-home oral formulations, on october 10, 2023.	paradoxically better independent evidence than esketamine on one axis: ELEKT-D randomised 403 patients with nonpsychotic treatment-resistant depression and found IV ketamine noninferior to ECT over three weeks (response 55.4% vs 41.2%) with less memory impairment — funded by the Patient-Centered Outcomes Research Institute, not a manufacturer.	[4] [7]

why the distinction gets blurred

press coverage, clinic marketing and most explainer pages use "ketamine therapy" as a single category, and the regulatory facts underneath it are genuinely different. a person searching "is ketamine FDA-approved for depression" is usually asking one of two questions without knowing it: can I get this covered and monitored? (esketamine, yes; racemic, generally no) or is there evidence it works? (both, with different strengths and different funders).

the commercial incentives point the same way. an infusion clinic offering racemic ketamine benefits from the halo of a real FDA approval that applies to a different product. a telehealth company shipping oral ketamine benefits from that too, while operating further still from the conditions under which any of the supporting trials were run — which is exactly what FDA’s october 2023 warning was about [4].

what the trials actually found

study	design	n	funding (as read)	what it found	source
Popova 2019 — TRANSFORM-2	randomised, double-blind, active-controlled	227	UNKNOWN — statement paywalled; most authors are Janssen R&D employees per affiliations	esketamine plus a newly started oral antidepressant beat placebo spray plus antidepressant by 4.0 MADRS points at day 28 — statistically significant, modest in absolute terms, with markedly more dissociation, nausea, vertigo and dizziness. this was the single positive short-term pivotal trial; TRANSFORM-1 and TRANSFORM-3 missed their primary endpoints, which the approval package acknowledged.	[5]
Daly 2019 — SUSTAIN-1	randomised withdrawal, double-blind	297	INDUSTRY — "funded by Janssen Research & Development LLC" (read from the paper)	among patients already stabilised on esketamine, continuing it halved relapse risk versus switching to placebo spray (27% vs 45% in stable remitters; number needed to treat 6). that is evidence for maintenance benefit — and also evidence that stopping carries real relapse risk. randomised-withdrawal designs can overstate maintenance benefit, because abrupt discontinuation effects count as relapse.	[6]
Anand 2023 — ELEKT-D	randomised, open-label, noninferiority	403	INDEPENDENT — "funded by the Patient-Centered Outcomes Research Institute" (read from the paper)	IV racemic ketamine was noninferior to ECT over three weeks in nonpsychotic treatment-resistant depression (response 55.4% vs 41.2%), with less memory impairment than ECT. the largest independent trial of ketamine for depression to date. open-label by necessity — neither ketamine nor ECT can be masked — and the population excluded psychotic depression, where ECT performs best.	[7]
Bahji 2021	systematic review and meta-analysis of 24 randomised trials	1,877	NONE — "this study was not funded" (read from the paper)	both forms beat placebo for unipolar and bipolar depression, and indirect comparison suggested larger response and remission effects for IV racemic ketamine than for intranasal esketamine. that comparison is hypothesis-generating, not head-to-head: it pools trials with different designs and populations. one coauthor is an inventor on ketamine-related patents. an erratum was issued in 2021 — a correction, not a retraction.	[8]
Berman 2000	double-blind crossover — historical anchor	7	UNKNOWN	a single IV ketamine infusion reduced Hamilton depression scores by a mean of 14 points within 72 hours versus no change on saline — the first controlled demonstration of rapid NMDA-pathway antidepressant effects, in a sample far too small for any clinical conclusion. included to show where the field started, not as actionable evidence.	[9]

the funding pattern is worth naming

the two trials that produced the esketamine approval were sponsor-run: SUSTAIN-1 states it was funded by Janssen Research & Development, and TRANSFORM-2’s funding statement sits behind a subscription, so we record it as UNKNOWN rather than inferring it — although most of its authors are Janssen employees by affiliation [5][6]. the largest and most methodologically ambitious trial in the field, ELEKT-D, was funded by the Patient-Centered Outcomes Research Institute and tested the unapproved form of the drug against ECT [7]. the meta-analysis comparing the two forms declares no funding at all [8].

that is an unusual shape for a drug literature, and it cuts against the intuition that the approved product must have the better evidence. approval reflects who ran a registration programme, not who ran the best trial.

what the evidence cannot yet say

dissociation makes true blinding nearly impossible, so every placebo-controlled effect size in this field is inflated by an unknown margin. the pivotal esketamine programme produced two failed short-term trials alongside one success, and the drug–placebo difference in the successful one was about 4 MADRS points [5]. long-term data mainly show that stopping increases relapse [6] — not how long treatment should continue, and not the cumulative safety of years of intermittent dosing across bladder function, cognition and misuse. racemic IV ketamine for depression remains off-label with no FDA efficacy review, and the compounded at-home telehealth market operates outside the monitored-setting conditions under which all of the supporting trials were run [4].

none of that means ketamine or esketamine does not work. it means the honest version of "it works" is narrower than the marketing version, and the difference is worth having in hand before you spend several thousand dollars.

related evidence pages

esketamine is the one FDA-approved psychedelic-adjacent drug in psychiatry; for where psilocybin, MDMA, LSD and the rest actually stand, see the psychedelic therapy FDA status tracker. for the approved-versus-off-label picture across ordinary psychiatric prescriptions, see what 21 psychiatric medications are actually approved for. for the non-prescription side — supplements and substances sold without any approval at all — see supplements and non-prescription substances for mental health.

how we verify

how we verify this page. every regulatory claim here is traced to an FDA document or a dated sponsor release, cited with its URL and access date (2026-08-17). every trial was fetched from PubMed via NCBI E-utilities and confirmed on title, DOI, sample size and effect figures; where a trial registration number was available it was confirmed in the record’s databank list.

funding is read, never inferred. a study is marked INDEPENDENT, INDUSTRY or NONE only where the funding statement could actually be read — from the paper, PubMed Central, or Europe PMC full text. TRANSFORM-2 sits behind a subscription, so its funding is recorded UNKNOWN even though the author affiliations make sponsorship obvious. we do not upgrade a guess into a fact.

retractions and errata are checked. the Bahji meta-analysis carries a 2021 erratum; we checked, and it is a correction rather than a retraction, so the study is included with that noted.

we are not clinicians. this page reports regulatory status and published evidence. it is not medical advice and it cannot account for your situation — talk to your prescriber.

this is not medical advice — talk to your prescriber about whether either of these is appropriate for you, and about what monitoring you would have. ketamine and esketamine are controlled substances with real misuse potential, and neither is a first-line treatment. if you're in crisis, call or text 988 (u.s.), 24/7, free.

questions

is ketamine FDA-approved for depression?

racemic ketamine — the generic drug — is not. it is approved as an anesthetic, and every psychiatric use of it is off-label. esketamine, one mirror-image half of the ketamine molecule sold as the nasal spray Spravato, is FDA-approved: for treatment-resistant depression since march 5, 2019, for depressive symptoms in major depressive disorder with acute suicidal ideation or behavior since august 3, 2020, and as a monotherapy for treatment-resistant depression since january 21, 2025.

what is the actual difference between ketamine and esketamine?

ketamine is a mixture of two mirror-image forms of the same molecule. esketamine is just one of them, isolated, formulated as a nasal spray, and taken through the FDA approval process by Johnson & Johnson. the practical differences are regulatory and logistical rather than mystical: esketamine has an FDA efficacy review, an approved label, a REMS safety programme, and insurance coverage pathways; racemic ketamine has none of those for psychiatric use, but it is generic, cheap, and can be given intravenously.

why is Spravato only given in a clinic?

because its approval is conditioned on a REMS — a risk evaluation and mitigation strategy. the drug must be self-administered in a certified healthcare setting under direct observation, with at least two hours of monitoring afterwards, because of dissociation, sedation and the potential for misuse. the REMS was modified on march 24 and october 9, 2025 and remains in force. you cannot take Spravato home.

is at-home ketamine legal?

prescribing compounded ketamine for at-home use is not itself illegal — off-label prescribing is legal, and compounded products exist in a separate regulatory lane from approved drugs. but FDA issued a specific warning on october 10, 2023 about the risks of compounded ketamine products including at-home oral formulations, and the honest framing is this: every trial that supports ketamine for depression was run in a monitored setting. the at-home telehealth market operates outside the conditions under which the supporting evidence was generated.

is ketamine as good as ECT?

in one large independent trial, for one population, over three weeks: yes, and with less memory impairment. ELEKT-D randomised 403 patients with nonpsychotic treatment-resistant depression and found IV ketamine noninferior to ECT (response 55.4% vs 41.2%). two caveats do real work. the trial was open-label — neither treatment can be masked — so subjective outcomes may favour whichever treatment patients preferred. and it excluded psychotic depression, which is precisely where ECT performs best.

is racemic ketamine better than esketamine?

nobody has run the head-to-head trial that would answer this. a meta-analysis of 24 trials in 1,877 people found indirect evidence suggesting larger response and remission effects for IV racemic ketamine than for intranasal esketamine — but indirect comparison across trials with different designs and populations is a hypothesis, not a result. treat anyone who states this as settled with suspicion.

how big is the effect, really?

the pivotal short-term esketamine trial showed a 4.0-point difference on the MADRS depression scale at day 28 versus placebo spray, with both groups also starting a new oral antidepressant. that is statistically significant and modest in absolute terms. it is also worth knowing that two sibling trials in the same programme missed their primary endpoints, which the approval package acknowledged. dissociation makes true blinding nearly impossible in every trial in this field, so placebo-controlled effect sizes are inflated by an unknown margin.

what does the long-term evidence show?

mainly that stopping increases relapse. the maintenance trial showed that continuing esketamine roughly halved relapse risk compared with switching to placebo spray. what the evidence does not establish is how long treatment should continue, or the cumulative safety of years of intermittent dosing — bladder effects, cognition, and misuse potential are all open questions rather than settled ones.

sources

FDA approval letter and REMS history for Spravato (esketamine) — original approval March 5, 2019; REMS modifications March 24 and October 9, 2025. Accessed 2026-08-17. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2026/211243Orig1s027ltr.pdf
Janssen press release — FDA approval of Spravato for depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior, August 3, 2020 (ASPIRE I/II). Note: an effect on suicidal ideation itself was not demonstrated. Accessed 2026-08-17. https://www.jnj.com/media-center/press-releases/janssen-announces-u-s-fda-approval-of-spravato-esketamine-ciii-nasal-spray-to-treat-depressive-symptoms-in-adults-with-major-depressive-disorder-with-acute-suicidal-ideation-or-behavior
Johnson & Johnson press release — Spravato approved as the first and only monotherapy for adults with treatment-resistant depression, January 21, 2025. TRD4005: remission 22.5% vs 7.6% on placebo at week 4 (figures via AJMC coverage of the same approval). Accessed 2026-08-17. https://www.jnj.com/media-center/press-releases/spravato-esketamine-approved-in-the-u-s-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression
FDA — warning to patients and healthcare providers about potential risks associated with compounded ketamine products, including at-home use, October 10, 2023. Accessed 2026-08-17. https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine
Popova V, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study (TRANSFORM-2). Am J Psychiatry 2019. PMID 31109201. n=227; NCT02418585. Funding statement not readable without subscription — recorded UNKNOWN rather than inferred. Accessed 2026-08-17. https://doi.org/10.1176/appi.ajp.2019.19020172 read our summary of this study →
Daly EJ, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial (SUSTAIN-1). JAMA Psychiatry 2019. PMID 31166571. n=297; funded by Janssen Research & Development LLC. Accessed 2026-08-17. https://doi.org/10.1001/jamapsychiatry.2019.1189 read our summary of this study →
Anand A, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression (ELEKT-D). N Engl J Med 2023. PMID 37224232. n=403; funded by the Patient-Centered Outcomes Research Institute; NCT03113968. Accessed 2026-08-17. https://doi.org/10.1056/NEJMoa2302399 read our summary of this study →
Bahji A, et al. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord 2021. PMID 33022440. 24 trials, 1,877 participants; "this study was not funded". An erratum was issued in 2021 — checked, not a retraction. Accessed 2026-08-17. https://doi.org/10.1016/j.jad.2020.09.071 read our summary of this study →
Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000. PMID 10686270. n=7; historical anchor only. Accessed 2026-08-17. https://doi.org/10.1016/s0006-3223(99)00230-9