Ketamine Therapy: What the Research Shows

Ketamine has gone from an operating-room anesthetic to one of the most talked-about treatments in psychiatry. Some people describe it as a breakthrough after years of failed antidepressants. Others see clinics popping up everywhere and wonder if it is the next wellness fad.

The evidence supports a middle position. Ketamine can work quickly for some people with hard-to-treat depression, and a large 2023 trial found it held its own against electroconvulsive therapy (ECT). But the benefit often fades without repeat treatment, long-term data are thin, and not every trial has been positive. It is a serious medical treatment, not a spa service.

This article explains the difference between ketamine and Spravato, what the major studies found, how many sessions they used, the real risks, and who may be a candidate.

If you are in crisis or thinking about suicide, call or text 988 (the Suicide & Crisis Lifeline) or call 911 now. Ketamine is not an emergency treatment.

Table of Contents

Ketamine vs. Spravato: not the same thing

People use "ketamine therapy" to mean two different things.

Ketamine (racemic ketamine) is FDA-approved as an injectable anesthetic. When clinicians give it at lower, "subanesthetic" doses for depression, usually as an IV infusion, that is off-label use. The FDA states plainly that ketamine "is not FDA approved for the treatment of any psychiatric disorder."

Spravato (esketamine) is a nasal spray containing one half of the ketamine molecule. It is FDA-approved for depression:

• March 2019: treatment-resistant depression (TRD) in adults, with an oral antidepressant.
• July 2020: depressive symptoms in adults with major depressive disorder and acute suicidal thoughts or behavior, with an oral antidepressant.
• January 2025: the TRD indication was expanded to include use on its own (monotherapy).

Spravato is only available through a restricted safety program called a REMS. It must be given in a certified health care setting, the patient never takes it home, and patients are monitored for at least two hours after each dose, including blood pressure checks.

Neither is "better" in a blanket sense. Spravato has the stronger regulatory backing. IV ketamine has a large body of research and allows precise, weight-based dosing. This article discusses Spravato for context; it is not a description of Rejuv's services.

How ketamine may work

Most antidepressants act on serotonin, norepinephrine or dopamine, and they usually take weeks. Ketamine works on a different system. It blocks the NMDA receptor, part of the brain's glutamate signaling. The prevailing view, as the expert panel below describes it, is that this triggers a brief glutamate surge and a signaling cascade that helps brain cells form and strengthen connections. That may explain why some people feel better within hours rather than weeks.

An international expert panel writing in the American Journal of Psychiatry called ketamine and esketamine "the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder." The exact mechanism is still being studied.

What the research shows

A single infusion: fast, but short-lived

A 2020 meta-analysis of 28 studies of IV ketamine for treatment-resistant depression found a strong effect within 4 hours of a single infusion, peaking at 24 hours. The effect was "still present, yet somewhat diminished" at 7 days. Multiple infusions produced a stronger and longer-lasting effect. The authors noted that long-term safety and efficacy had not been established.

A series of infusions

In an often-cited open-label study, 24 people with treatment-resistant depression received up to six IV infusions over 12 days. About 71% (70.8%) met response criteria at the end. Among responders, the median time to relapse after the last infusion was 18 days. That is the core challenge with ketamine: response can be fast, and so can relapse.

Ketamine vs. ECT (ELEKT-D, 2023)

The biggest head-to-head test was published in the New England Journal of Medicine in 2023. Researchers randomized 403 people with treatment-resistant depression without psychosis, all referred for ECT, to either ECT three times a week or IV ketamine (0.5 mg/kg over 40 minutes) twice a week for three weeks.

• Response: 55.4% with ketamine vs. 41.2% with ECT. Ketamine met the test for being "noninferior."
• Memory: ECT was associated with a drop in memory recall after three weeks, with gradual recovery. Ketamine was not.
• Side effects: ECT was associated with musculoskeletal effects; ketamine with dissociation.

Two caveats matter. The trial was open-label (patients knew which treatment they got), and it enrolled people without psychosis. ECT remains a highly effective treatment, especially for severe or psychotic depression.

Esketamine trials

In the ESCAPE-TRD trial (NEJM, 2023), 676 people with treatment-resistant depression received either Spravato or extended-release quetiapine, each added to an SSRI or SNRI. At week 8, 27.1% of the esketamine group were in remission, compared with 17.6% of the quetiapine group. Through week 32, 21.7% vs. 14.1% had remitted without relapse. The trial was open-label with blinded raters and was funded by the manufacturer.

For the 2025 monotherapy approval, the manufacturer reported remission at week 4 in 22.5% of patients on Spravato alone vs. 7.6% on placebo.

Where ketamine fell short

Not every trial is positive. In KARMA-Dep 2 (JAMA Psychiatry, 2025), 65 hospitalized adults with depression received up to eight twice-weekly infusions of either ketamine or midazolam (an active placebo that also causes sedation), on top of usual inpatient care. At the end of treatment, depression scores did not differ significantly between groups. Most patients and raters correctly guessed who got ketamine, a known challenge in ketamine research because its effects are hard to mask.

That result does not erase the positive trials. It does suggest ketamine may add less than hoped for some groups, and that expectation effects deserve attention.

PTSD and other uses

Evidence beyond depression is earlier. A small randomized trial in chronic PTSD (30 people, six infusions over two weeks) found 67% responded to ketamine vs. 20% to midazolam. Among ketamine responders, the median time to loss of response was 27.5 days. The expert panel describes evidence for PTSD, obsessive-compulsive disorder and bipolar depression as preliminary, from small controlled trials.

How many sessions do studies use?

There is no single standard, but research protocols cluster around a few patterns:

• IV ketamine (research): the trials described above used 6 to 8 infusions over 2 to 4 weeks, two or three per week, at 0.5 mg/kg. ELEKT-D used twice weekly for 3 weeks (40-minute infusions); the Murrough study used up to 6 over 12 days; KARMA-Dep 2 used up to 8, twice weekly.
• Checking for response: Expert guidance suggests reassessing after four to six infusions. Most responders improve after one or two. If there is minimal improvement (20% or less) after four to six, the person can be considered a non-responder, and continuing is generally not recommended.
• Spravato (FDA label): twice weekly for weeks 1–4, once weekly for weeks 5–8, then weekly or every two weeks. Benefit should be evaluated at the end of the 4-week induction phase.
• Maintenance: This is the biggest evidence gap for IV ketamine. Optimal maintenance schedules have not been established.

Risks and side effects

Ketamine's risks are real and mostly predictable, which is why monitoring matters.

• Dissociation: feeling detached from your body or surroundings, or a sense that time and space are distorted. It is very common: 61% to 84% of patients in Spravato studies had dissociative or perceptual changes. In those studies it was transient and occurred on the day of dosing.
• Sedation and dizziness, plus nausea and vomiting.
• Blood pressure and heart rate increases. The expert panel reports that in one community clinic, up to 20% of IV ketamine patients needed medication for ketamine-related high blood pressure (depending on clinic protocol). Spravato's label notes increases at all recommended doses.
• Breathing: Spravato's label includes a boxed warning for respiratory depression; certified settings must have pulse oximetry.
• Impaired judgment and coordination. Spravato's label says not to drive until the next day after a restful sleep. Plan a ride home after any ketamine session.
• Bladder problems. Among people who use ketamine recreationally, lower urinary tract symptoms affect roughly 20% to 40%. Most improve after stopping, but about 5% may persist or worsen. Spravato's label includes a warning about ulcerative or interstitial cystitis reported with long-term off-label ketamine use, and the FDA lists bladder symptoms among ketamine's known safety concerns.
• Misuse and dependence. Ketamine is a Schedule III controlled substance with real abuse potential. This is a major reason supervised, in-clinic dosing matters.
• Psychosis risk in people with a preexisting vulnerability.

Who may be a candidate, and who may not

The evidence is strongest for adults with treatment-resistant depression, commonly defined as not responding to at least two adequate antidepressant trials in the current episode.

Expert guidance and product labeling describe people who should not receive ketamine, or who need extra caution:

• uncontrolled high blood pressure, or anyone for whom a significant rise in blood pressure would be dangerous
• aneurysmal vascular disease, arteriovenous malformation or a history of bleeding in the brain (Spravato contraindications)
• a recent cardiovascular event such as a heart attack (within about 6 weeks), significant valve disease or advanced heart failure
• prior hypersensitivity to ketamine
• current or past psychosis, which should be ruled out or carefully weighed
• pregnancy (Spravato may cause fetal harm) and breastfeeding
• active substance use concerns, which require careful assessment

A good evaluation also looks for other contributors to low mood, such as sleep problems, thyroid or hormonal issues, and medication effects. Our articles on signs of hormonal imbalance and evening routines for better sleep touch on some of these overlaps. Ketamine is usually added to, not substituted for, ongoing mental health care.

The problem with unsupervised at-home ketamine

Online services selling compounded ketamine lozenges, tablets or nasal sprays for home use grew quickly. In October 2023, the FDA warned patients and providers about compounded ketamine products, including oral forms, for psychiatric conditions. Key points from that warning:

• Ketamine is not FDA-approved for any psychiatric disorder, and compounded products are not FDA-approved for anything.
• Using compounded ketamine without monitoring for sedation, dissociation, and changes in blood pressure and heart rate "may put patients at risk for serious adverse events."
• The FDA said it was not aware of evidence that compounded ketamine is "safer, is more effective, or works faster" than FDA-approved treatments.
• The agency described a report of a patient who had slowed breathing after taking compounded oral ketamine at home for PTSD, with a blood level about twice what is typical for anesthesia.

Our view: ketamine belongs in a monitored medical setting with a clear plan, not in a delivery box.

What careful care looks like

Whatever clinic you consider, look for:

• A thorough evaluation of your diagnosis, prior treatments, medications, heart and blood pressure history, substance use and pregnancy status.
• Informed consent that covers off-label status, expected benefits, risks and costs.
• Monitoring during and after treatment, including blood pressure, with a defined recovery period and discharge criteria.
• A plan to measure response after a defined number of sessions, and to stop if it is not working.
• Coordination with your mental health care, including your therapist or psychiatrist.

Rejuv offers medically supervised ketamine therapy for appropriately selected patients after a clinical evaluation, with monitoring, in-clinic recovery and follow-up. A provider will tell you if ketamine is not a good fit.

Frequently asked questions

How many ketamine infusions do you need?

The major trials used about 6 to 8 infusions over 2 to 4 weeks. Expert guidance suggests reassessing after four to six; if there is minimal improvement by then, more infusions are unlikely to help. Maintenance needs vary and have not been well studied.

Ketamine infusion vs. Spravato: which is better?

They have not been directly compared in a large trial. Spravato is FDA-approved for depression and given under a strict REMS program. IV ketamine is off-label but has substantial research, including the ELEKT-D trial against ECT. The right choice depends on your history, access and a provider's assessment.

How long do the effects last?

After a single infusion, benefit typically fades over days to about a week. After a series, the studies above found median times to relapse or loss of response of a few weeks among responders. Some people need ongoing treatment.

Is ketamine therapy safe?

In monitored medical settings, short-term side effects such as dissociation and temporary blood pressure increases are common but usually manageable. Long-term safety is less well studied. Risks rise with unsupervised use, frequent or escalating use, and misuse.

Is ketamine covered by insurance?

Coverage varies by plan and by treatment. Spravato is an FDA-approved prescription drug, while ketamine for depression is off-label. Ask your insurer and the clinic about coverage and costs before starting. And if you are struggling right now, call or text 988 any time.

The bottom line

Ketamine is a legitimate option for some people with treatment-resistant depression. It can work fast, it outperformed expectations against ECT in a major trial, and esketamine has full FDA approval. It is not a cure, and it is not for everyone. Effects often fade without repeat treatment, maintenance is understudied, one well-designed inpatient trial found no added benefit, and the risks require real monitoring.

If standard treatments have not worked for you, a careful medical evaluation is the right next step. If you are in crisis, call or text 988, or call 911.

Related reading: NAD+ IV Drips: What the Evidence Really Shows · Fake Botox & Unlicensed Injectors: Red Flags

Sources

• SPRAVATO (esketamine) nasal spray, prescribing information (FDA, Drugs@FDA)
• Spravato NDA 211243 approval letter, March 5, 2019 (FDA)
• Spravato supplemental approval letter: MDD with acute suicidal ideation or behavior, July 31, 2020 (FDA)
• Spravato supplemental approval letter: TRD monotherapy, January 2025 (FDA)
• SPRAVATO approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression (Johnson & Johnson, January 21, 2025)
• FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders (FDA, October 10, 2023; archived)
• KETALAR (ketamine hydrochloride) injection, prescribing information (DailyMed)
• Anand A, Mathew SJ, Sanacora G, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. N Engl J Med. 2023;388(25):2315-2325. doi:10.1056/NEJMoa2302399
• Reif A, Bitter I, Buyze J, et al. Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression. N Engl J Med. 2023;389(14):1298-1309. doi:10.1056/NEJMoa2304145
• Jelovac A, McCaffrey C, Terao M, et al. Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial. JAMA Psychiatry. 2025;82(12):1216-1224. doi:10.1001/jamapsychiatry.2025.3019
• 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. doi:10.1176/appi.ajp.2020.20081251
• Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080
• Marcantoni WS, Akoumba BS, Wassef M, et al. A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 - January 2019. J Affect Disord. 2020;277:831-841. doi:10.1016/j.jad.2020.09.007
• Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-256. doi:10.1016/j.biopsych.2012.06.022
• Feder A, Costi S, Rutter SB, et al. A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. Am J Psychiatry. 2021;178(2):193-202. doi:10.1176/appi.ajp.2020.20050596
• 988 Suicide & Crisis Lifeline

This article is provided for general educational purposes and is not a substitute for individualized medical advice, diagnosis, or treatment. Do not start, stop or change any psychiatric medication without talking to your prescriber, and if you are in crisis, call or text 988 or call 911.

ASK OUR TEAM ABOUT KETAMINE THERAPY