Ketamine is the one member of the psychedelic-adjacent group with regulatory approval, and it works differently from the classic psychedelics: it blocks the NMDA glutamate receptor rather than acting on serotonin. Its refined form, esketamine nasal spray, is FDA-approved for treatment-resistant depression and is given in a certified clinic under monitoring, and intravenous racemic ketamine is used off-label for the same purpose. The antidepressant effect is fast and real. In a phase 3 trial, esketamine plus a new oral antidepressant lowered depression scores 4.0 points more than the antidepressant alone by day 28 on the 0 to 60 MADRS scale, and a meta-analysis of intravenous ketamine found a large effect within hours that peaked at 24 hours.
It also cuts suicidal thoughts within a day. The clear limit is durability: the effect fades within days to weeks unless the treatment is repeated, which is why it is given as a course and then maintained. This page describes what the research shows, where the law stands, and the risks, including the bladder damage seen with frequent high-dose use. It is not a guide to sourcing.
Findings & Outcomes
What It Is
Ketamine is an anesthetic first approved in the 1970s that turns out to lift mood quickly at doses well below the ones used for surgery. It is the one compound in the wider psychedelic conversation with a settled regulatory position, and it is not a classic psychedelic. It acts on the NMDA glutamate receptor, produces dissociation rather than the serotonin-driven experience of psilocybin or MDMA, and its antidepressant effect comes on within hours instead of the weeks a standard antidepressant takes.
Two forms are used for depression. Esketamine is the S-enantiomer, one of the two mirror-image halves of the ketamine molecule, delivered as a nasal spray and FDA-approved for treatment-resistant depression. Racemic ketamine, the original mixture of both halves, is given as an intravenous infusion off-label for the same purpose. Both are administered in a clinic with monitoring, because the acute effects need supervision. This page describes the research, the law, and the risks. It carries no dosing and no sourcing.
What It Does
The findings are graded claim by claim in the research section below. The approved use is the anchor. In a phase 3 trial in treatment-resistant depression, switching to esketamine nasal spray plus a newly started oral antidepressant lowered depression scores by 4.0 points more than a newly started antidepressant plus a placebo spray at day 28, measured on the MADRS scale, which runs from 0 to 60. That is the trial behind the approval, and it used an active comparator rather than an inert placebo, which is a stronger test than most of this field manages.
Intravenous racemic ketamine points the same way and faster. A meta-analysis of randomized placebo-controlled trials found that a single infusion raised the odds of remission roughly sevenfold at 24 hours, with a number needed to treat of about 5, and produced a large drop in depression scores within a day. A separate meta-analysis in treatment-resistant depression found a strong effect within 4 hours that peaked at 24 hours and was still present, though diminished, at 7 days, with repeated infusions extending it. Ketamine also lowers suicidal thoughts quickly: an individual-participant meta-analysis found a single dose reduced suicidal ideation within one day, with a moderate-to-large effect that held for up to a week, and the effect was partly separate from the change in overall mood.
The antidepressant effect is rapid and real, and it fades within days to weeks unless the treatment is repeated, which is why it is given as a course and then maintained rather than as a single event.
That durability limit sits at the center of the picture. In the relapse-prevention trial behind the approval, people who had reached stable remission on esketamine and then kept taking it relapsed far less often than people switched to placebo spray: 26.7% against 45.3%, a 51% lower risk of relapse. The benefit depends on continued dosing. The reduction in suicidal thoughts is likewise measured over days to a week, not as a durable cure, and in the esketamine study of patients at imminent suicide risk the separation from placebo was clear at 4 and 24 hours but no longer significant by day 25. Ketamine is a fast and repeatable treatment, not a one-time fix.
The Research & Studies
Everything here is based on the research we have collected and checked, sorted into groups and ordered with the strongest evidence first. Click any claim to open the studies behind it.
Mood & stress
Esketamine nasal spray plus a new oral antidepressant eased treatment-resistant depression 4.0 points more than the antidepressant alone by day 28
Adding esketamine nasal spray to a newly started antidepressant eased treatment-resistant depression more than the antidepressant alone after four weeks.
The phase 3 TRANSFORM-2 trial (Popova et al., Am J Psychiatry 2019) randomized 227 adults with treatment-resistant depression, defined as nonresponse to at least two antidepressants in the current episode, to esketamine nasal spray plus a newly initiated oral antidepressant or to a newly initiated antidepressant plus placebo nasal spray. The primary endpoint, change in MADRS score from baseline to day 28, favored esketamine by 4.0 points (95% CI -7.31 to -0.64). Dissociation, nausea, vertigo, dysgeusia, and dizziness were more common with esketamine and generally appeared shortly after dosing and resolved within about 1.5 hours.
The study · 1
Popova et al., efficacy and safety of flexibly dosed esketamine nasal spray in treatment-resistant depression · Am J Psychiatry 2019;176:428-438
A single intravenous ketamine infusion raised remission odds roughly sevenfold at 24 hours in a meta-analysis of randomized trials
Pooling the controlled trials, a single dose of intravenous ketamine improved depression sharply within a day, far faster than a standard antidepressant.
McGirr et al. (Psychol Med 2015) pooled seven intravenous and one intranasal randomized controlled trial (73 subjects in parallel arms and 110 in crossover designs; 149 with major depressive disorder and 34 with bipolar disorder). Against saline or midazolam controls, ketamine raised remission at 24 hours (OR 7.06, NNT 5), 3 days (OR 3.86), and 7 days (OR 4.00), with a standardized mean difference of 0.90 at 24 hours and greater efficacy in unipolar depression (SMD 1.07) than bipolar (0.68). Transient psychotomimetic effects occurred, but no persistent psychosis or affective switch.
The study · 1
McGirr et al., systematic review and meta-analysis of ketamine in the rapid treatment of major depressive episodes · Psychol Med 2015;45:693-704
The antidepressant effect of a single ketamine infusion peaks at 24 hours and is diminished by 7 days, with repeated infusions extending it
The lift from one ketamine infusion is strongest at a day and starts fading within a week, so it is given as a series of infusions rather than once.
Marcantoni et al. (J Affect Disord 2020) synthesized 28 studies across 35 publications on sub-anesthetic intravenous ketamine in treatment-resistant depression, examining outcomes at 4 hours, 24 hours, and 7 days. A strong ketamine effect appeared within 4 hours and peaked at 24 hours; it remained present but diminished at 7 days. Multiple infusions produced an enhanced and prolonged effect. The authors noted that long-term safety and efficacy of extended ketamine use remain to be established.
The study · 1
Marcantoni et al., meta-analysis of intravenous ketamine infusion for treatment resistant depression · J Affect Disord 2020;277:831-841
A single intravenous ketamine dose reduced suicidal ideation within one day, with the effect holding for up to a week
In pooled trials, one dose of intravenous ketamine cut suicidal thoughts within a day, and the drop lasted up to about a week.
Wilkinson et al. (Am J Psychiatry 2018) obtained individual participant data from 10 of 11 identified trials that used saline or midazolam as a control, analyzing the 167 participants who had suicidal ideation at baseline. Ketamine reduced suicidal ideation within one day on both clinician-rated and self-report measures, with effect sizes of Cohen's d 0.48 to 0.85 sustained to one week, and the benefit remained after adjusting for changes in depression severity.
The study · 1
Wilkinson et al., effect of a single dose of intravenous ketamine on suicidal ideation, an individual participant data meta-analysis · Am J Psychiatry 2018;175:150-158
Continuing esketamine after remission cut the relapse rate about in half, so the benefit depends on ongoing dosing
People who kept taking esketamine after getting well stayed well far more often than those who stopped, which shows the benefit has to be maintained.
Daly et al. (JAMA Psychiatry 2019) enrolled 705 adults with treatment-resistant depression; 297 who reached stable remission or stable response after an induction and optimization course of esketamine plus an oral antidepressant were randomized to continue esketamine or switch to placebo nasal spray, with the oral antidepressant continued in both arms. Among the 176 stable remitters, relapse occurred in 26.7% on continued esketamine versus 45.3% on placebo (log-rank P = .003, NNT 6); among stable responders, 25.8% versus 57.6% (NNT 4).
The study · 1
Daly et al., efficacy of esketamine nasal spray for relapse prevention in treatment-resistant depression · JAMA Psychiatry 2019;76:893-903
Esketamine improved depressive symptoms at 4 and 24 hours in patients at imminent suicide risk, but the separation from placebo was gone by day 25
Adding esketamine to standard care helped depressed patients at high suicide risk within hours, but its edge over placebo had faded by around three and a half weeks.
Canuso et al. (Am J Psychiatry 2018) randomized 68 participants at imminent suicide risk to esketamine 84 mg or placebo twice weekly for four weeks, alongside comprehensive standard-of-care treatment. The primary endpoint, MADRS change at 4 hours, favored esketamine (effect size 0.61), as did the 24-hour timepoint (0.65), but not day 25 (0.35). The MADRS suicidal-thoughts item improved at 4 hours only, and clinician global judgment of suicide risk did not differ significantly between groups at any timepoint.
The study · 1
Canuso et al., intranasal esketamine for rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide · Am J Psychiatry 2018;175:620-630
How it works
Ketamine works by blocking the NMDA glutamate receptor and increasing connections between neurons, a mechanism distinct from serotonin-based antidepressants
Ketamine blocks a glutamate receptor and rapidly strengthens connections between brain cells, which is a different route to lifting mood than serotonin-based antidepressants take.
As reviewed by Zanos and Gould (Mol Psychiatry 2018), ketamine's antidepressant action begins with NMDA receptor antagonism, which produces a glutamate surge and downstream signaling that increases synaptogenesis in mood-regulating circuits over hours. The review also notes that several mechanisms, including actions of ketamine metabolites, remain under investigation, so the account of how the acute pharmacology produces a lasting mood change is not fully settled.
The study · 1
Zanos and Gould, mechanisms of ketamine action as an antidepressant · Mol Psychiatry 2018;23:801-811
How It Works
Ketamine blocks the NMDA glutamate receptor, and that single action starts a cascade that the classic antidepressants do not. Standard drugs raise serotonin or noradrenaline and take weeks to change mood. Ketamine instead produces a rapid surge of glutamate signaling and, over the hours that follow, an increase in the connections between neurons in mood-regulating circuits. This is a different mechanism from the serotonin 5-HT2A receptor that the classic psychedelics act on, which is why ketamine is grouped with the dissociatives rather than with psilocybin.
What Happens Across a Course of Treatment
1The single dose
Ketamine blocks NMDA receptors and triggers a brief rise in glutamate signaling. During the dose the person experiences dissociation, a sense of detachment from the body and surroundings, along with a transient rise in blood pressure and heart rate and sometimes nausea. These acute effects are why the dose is given in a clinic with monitoring, and they settle within a couple of hours.
2The hours after
Over the hours following the dose, mood often lifts and suicidal thoughts often ease, faster than any standard antidepressant acts. The proposed mechanism is a short window of increased connections between neurons in mood-regulating circuits, driven by the glutamate surge the block sets off. Mechanism alone does not establish clinical benefit, and the size of the lasting effect is still being worked out.
3Days to weeks, and maintenance
The effect of a single dose fades within days to weeks. This is why intravenous ketamine is given as a series of infusions and esketamine as an induction course followed by maintenance dosing. In the relapse-prevention trial, continued esketamine kept people well; stopping it raised the relapse rate. The treatment holds mood up while it is given, rather than resetting it once.
The Legal Position
Ketamine sits apart from the classic psychedelics in law as well as in pharmacology. In the United States:
- Racemic ketamine is a Schedule III controlled substance, FDA-approved as an anesthetic. Its use for depression is off-label, given as an intravenous infusion in a clinic. Off-label prescribing of an approved drug is legal and common, but it is not the same as an approval for depression.
- Esketamine nasal spray is FDA-approved for treatment-resistant depression and, separately, for depressive symptoms with suicidal thoughts. It is dispensed only through a restricted program in certified healthcare settings, where the patient is monitored for about two hours after each dose.
- Neither is available by ordinary prescription to take at home, and both are given under supervision because of the acute dissociation and blood-pressure rise.
This is a real, regulated treatment, reachable through a psychiatrist or a clinic, not an investigational compound. None of this page is a route to obtaining ketamine outside that setting, and the risks below attach mainly to frequent, high-dose, or unsupervised use.
The Chinese Medicine View
Chinese medicine has a long-standing frame for altered states of mind, and it leans toward caution. The Heart is said to house the Shen, the spirit or consciousness, and clear thought, steady emotion, and restful sleep are read as signs of a settled Shen. A mind flooded, disoriented, or thrown into fear or agitation is described as a disturbance of the Shen, and the classical tradition treats such disturbance as something to calm and anchor. The bias of the medicine is toward grounding: settling the Shen, harmonizing the Heart and Liver, and rooting a scattered mind back in the body through stillness, breath, and regular life.
Read through that lens, the dissociation ketamine produces is not neutral. It could be seen as a deliberate loosening of the Shen from its anchor, which the tradition would approach with care, especially in someone already depleted, agitated, or unsettled, and especially outside a calm, supervised setting. This is an interpretation, not a verdict, and not a claim that the tradition anticipated modern trials. It lines up, in its own language, with what the clinical evidence keeps showing: that the effect is powerful, that it is transient, and that setting and supervision matter. The wider preventive tradition of Yang Sheng, nourishing life, would place the emphasis on grounding practices first, and would read a fast, potent intervention as something for a serious, supervised situation rather than a first move.
Cautions For This Practice
Extra restraintEverything to be aware of is here, in one place. This practice suits most healthy people; a few situations call for real care.
Frequent high-dose ketamine use can cause severe ulcerative cystitis, a painful and sometimes lasting bladder injury
Shahani et al. (Urology 2007) described nine daily ketamine users with severe dysuria, urinary frequency, urgency, and gross hematuria. Urine cultures were sterile; CT showed marked bladder-wall thickening, small capacity, and perivesicular stranding; cystoscopy showed severe ulcerative cystitis, and biopsies showed epithelial denudation and inflammation. Stopping ketamine, with pentosan polysulfate, gave some symptomatic relief. Later reports confirmed the syndrome and its dose-and-frequency dependence.Shahani et al., ketamine-associated ulcerative cystitis, a new clinical entity
The acute effects need supervision
Every dose causes dissociation, a sense of detachment that can be disorienting, along with a transient rise in blood pressure and heart rate and sometimes nausea, vertigo, and an altered sense of taste. These are the reason the treatment is given in a clinic with monitoring for a couple of hours afterward. Anyone with uncontrolled high blood pressure, unstable heart disease, or an aneurysm is at higher risk from the blood-pressure rise and should raise it with the prescribing clinician.
Bladder and urinary toxicity with frequent high-dose use
Frequent, high-dose ketamine, the pattern seen in heavy recreational use rather than in monitored treatment, can cause a severe inflammation of the bladder wall called ketamine cystitis, with painful, frequent, urgent urination and blood in the urine, and in the worst cases lasting bladder damage. This risk rises with dose and frequency. It is one of the strongest reasons the treatment is dose-controlled and supervised, and one of the clearest harms of unsupervised use.
Abuse and dependence potential, and the durability limit
Ketamine carries potential for misuse and psychological dependence, which is why it is a controlled substance and why clinic use is structured and monitored. A history of substance use disorder is a reason for particular care. Separately, the antidepressant benefit fades without repeated dosing, so the treatment is a course to be maintained, not a single cure, and the long-term safety of extended maintenance is not yet fully mapped.
Who should be especially careful, and this is not a guide to sourcing
A personal or family history of psychosis is an important reason for caution, because dissociatives can worsen psychotic symptoms. Pregnancy, uncontrolled hypertension, and active substance use disorder all change whether and how the treatment should be used. This page carries no dosing and no sourcing; the safe and studied route is a psychiatrist or a certified clinic, where the drug is dose-controlled and the person is monitored.
Ketamine and esketamine are real, approved or clinically used treatments for depression, with a fast and repeatable antidepressant effect and a clear set of risks that rise with unsupervised, high-dose use. The stance here is to inform: read the evidence at its true strength, take the durability limit and the bladder and dependence risks seriously, and, for anything touching your own care, work with a qualified clinician.
Common Questions
Does ketamine work for depression?
Yes, quickly, and the effect is short-lived without repeated dosing. In the phase 3 trial behind the approval, esketamine nasal spray plus a new oral antidepressant lowered depression scores 4.0 points more than the antidepressant alone by day 28 on the 0 to 60 MADRS scale. A meta-analysis of intravenous ketamine found a single infusion raised remission odds about sevenfold at 24 hours. It is the fastest antidepressant effect measured, and it fades within days to weeks unless the treatment is repeated.
What is the difference between ketamine and esketamine?
They are closely related. Racemic ketamine is the original molecule, a mixture of two mirror-image halves, given as an intravenous infusion off-label for depression. Esketamine is one of those halves, the S-enantiomer, made into a nasal spray and FDA-approved for treatment-resistant depression and for depression with suicidal thoughts. Esketamine is the version with a formal approval and a defined dosing program; intravenous ketamine is the version with the longer and larger body of trial evidence for a rapid effect.
Does it help with suicidal thoughts?
There is fast evidence that it does, measured over days rather than as a cure. An individual-participant meta-analysis found a single dose of intravenous ketamine reduced suicidal ideation within one day, with a moderate-to-large effect that held for up to a week and was partly separate from its effect on overall mood. An esketamine trial in people at imminent suicide risk found a clear improvement at 4 and 24 hours. The effect is rapid and time-limited, which is why it is used alongside ongoing care rather than on its own.
Is ketamine safe, and is it addictive?
It carries real risks that rise with dose and frequency, which is why treatment is supervised. Every dose causes dissociation and a transient rise in blood pressure and heart rate. Frequent, high-dose use, the recreational pattern, can cause severe bladder damage known as ketamine cystitis. It also carries potential for misuse and psychological dependence, so it is a controlled substance and a history of substance use disorder calls for extra care. In the monitored, dose-controlled clinical setting these risks are far lower than in unsupervised use.
Go Deeper
- Psychedelics in mental health: the wider field, where ketamine sits beside psilocybin for depression, MDMA-assisted therapy for PTSD, the blinding problem, and where the law stands. Ketamine is the one member of that group with regulatory approval.
- Depression: what actually helps: the full range of treatments for depression, and where a fast-acting option like ketamine sits among the ones with a longer track record.
Explore Related
Other pages this one connects to, by the evidence they share, the outcomes they touch, and the ground they cover.
All 8 sources on this page independently checked and cross-referenced.
Thomas Dehli, Founder & Editor, Sacred Lotus
Sacred Lotus has published Chinese medicine reference material since 2001. Integrative pages are held to the same standard as the herb and formula library: cite the source, grade the claim at its real strength, and say where the research has not looked. This page is educational and it is not medical advice. Last reviewed and updated August 10, 2026.
Evidence strength
How confidently the research supports a claim. Strength describes the evidence, not our endorsement.