Drug: Kétamine et eskétamine

What It Is

Ketamine is an anesthetic first approved in the 1970s that lifts mood quickly at doses well below the ones used for surgery. It acts on the NMDA glutamate receptor and produces dissociation. Its antidepressant effect arrives within hours, where a standard antidepressant takes weeks.

Two forms are used for depression. Esketamine is the S-enantiomer, one of the two mirror-image halves of the ketamine molecule, made into a nasal spray and FDA-approved for treatment-resistant depression. Racemic ketamine, the original 1-to-1 mixture of both halves, is given as an intravenous infusion off-label for the same purpose. Both are delivered in a supervised clinic.

What It Does

In the phase 3 trial behind the approval, patients with treatment-resistant depression switched to esketamine nasal spray plus a newly started oral antidepressant. By day 28 their depression scores fell 4.0 points further than the group given a placebo spray plus a new antidepressant, on the 0-to-60 MADRS scale. The control group got a real antidepressant, not a sugar pill, so the 4.0-point gap survives a harder test.

Intravenous racemic ketamine shows the same effect, and faster. A meta-analysis of randomized placebo-controlled trials found a single infusion raised the odds of remission roughly sevenfold at 24 hours, with a number needed to treat of about 5. It also produced a large drop in depression scores within a day.

A separate meta-analysis in treatment-resistant depression traced the timing. The effect was strong within 4 hours, peaked at 24 hours, and was still present, though smaller, at 7 days. Repeated infusions extended it.

In the relapse-prevention trial behind the approval, patients reached stable remission on esketamine and then kept taking it. They relapsed far less often than the group moved to a placebo spray: 26.7% versus 45.3%, a 51% lower risk of relapse.

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 28Moderate

In plain terms

Adding esketamine nasal spray to a newly started antidepressant eased treatment-resistant depression more than the antidepressant alone after four weeks.

In detail

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 trialsModerate

In plain terms

Pooling the controlled trials, a single dose of intravenous ketamine improved depression sharply within a day, far faster than a standard antidepressant.

In detail

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 itModerate

In plain terms

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, not once.

In detail

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 weekModerate

In plain terms

In pooled trials, one dose of intravenous ketamine cut suicidal thoughts within a day, and the drop lasted up to about a week.

In detail

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 dosingModerate

In plain terms

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.

In detail

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 25Emerging

In plain terms

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.

In detail

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 antidepressantsModerate · mixed

In plain terms

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.

In detail

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 works by blocking the NMDA glutamate receptor, and that single action starts a cascade the older antidepressants never trigger. 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 the classic psychedelics act on, which is why ketamine is grouped with the dissociatives instead of 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. Blood pressure and heart rate rise transiently, and there is sometimes nausea. These acute effects are why the dose is given in a clinic with monitoring, and they settle within 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 new synaptic connections 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. The benefit lasts only while dosing continues; a single dose does not reset the depression.

The Legal Position

In law, ketamine splits into its two forms, and the two are treated very differently 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 stops short of a formal approval for depression.
• Esketamine nasal spray is 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.

Both forms are legitimate, regulated treatments, reachable through a psychiatrist or a certified clinic, and the risks 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. The classical tradition treats such disturbance as something to calm and anchor. The bias of the medicine is toward grounding: settling the Shen and harmonizing the Heart and Liver. A scattered mind is rooted back in the body through stillness, breath, and regular life.

In this frame, ketamine's dissociation reads as a deliberate loosening of the Shen from its anchor. The tradition would approach that with care, especially in someone already depleted, agitated, or unsettled, and most of all outside a calm, supervised setting. In the tradition's own terms, this matches what the trials show: a strong effect, a short-lived one, tied to setting and supervision. The wider preventive tradition of Yang Sheng, nourishing life, puts self-directed daily practices first and treats potent, mind-altering interventions as a last, carefully-set step.

Cautions For This Practice

Extra restraint

Everything 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. It also raises blood pressure and heart rate briefly, and can bring nausea, vertigo, or an altered sense of taste. These are the reason the treatment is given in a clinic with monitoring. 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 in heavy recreational use, can cause a severe bladder-wall inflammation called ketamine cystitis. Symptoms are painful, frequent, urgent urination and blood in the urine; in the worst cases the bladder damage lasts. 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

Ketamine carries potential for misuse and psychological dependence. That is why it is a controlled substance and why clinic use is monitored. A history of substance use disorder is a reason for particular care. Separately, the long-term safety of extended maintenance is not yet fully mapped.

Who should be especially careful

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. There is no dosing or sourcing here; the pathway that has been studied is a dose-controlled, supervised one.

Ketamine and esketamine are real, clinically used treatments for depression. The antidepressant effect is fast and repeatable. The risk turns on the setting: it is far lower in a dose-controlled, supervised course than in frequent, unsupervised high-dose use. For anything touching your own care, work with a qualified clinician.

Common Questions

Does ketamine work for depression?

Yes. But it is studied mainly in treatment-resistant depression, so it is a later-line option, used after other antidepressants have failed.

What is the difference between ketamine and esketamine?

The difference that matters is regulatory. Esketamine has the FDA label and a defined dosing program; intravenous ketamine has the larger body of trial evidence for a rapid effect.

Does it help with suicidal thoughts?

Yes, fast and for a limited window. An individual-participant meta-analysis found a single dose of intravenous ketamine cut suicidal thinking within one day. The moderate-to-large effect held for up to a week and ran partly separate from the change in overall mood. An esketamine trial in people at imminent suicide risk showed clear improvement at 4 and 24 hours, but the separation was no longer significant by day 25. The effect is rapid but time-limited, which is why it runs alongside continuing care.

Is ketamine safe, and is it addictive?

The risks are real and rise with dose and frequency. The heavy recreational pattern, high doses taken often and unsupervised, is where the serious bladder damage and the dependence concentrate. The clinic version uses controlled doses on a set schedule, so the same molecule carries far less of that risk. Whether it is "safe" depends almost entirely on which of those two settings you mean.

Go Deeper

• Psychedelics in mental health: the wider field, where ketamine sits beside psilocybin for depression and MDMA-assisted therapy for post-traumatic stress. The blinding problem and the law are laid out there.
• 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.