Ketamine and esketamine explained

What ketamine and esketamine are

Ketamine has been used since the 1960s as a general anesthetic. Its antidepressant potential was noticed at psychiatric doses that are much lower than anesthesia doses, and the story of ketamine as an antidepressant has moved from research to clinical use over the last twenty years.

Ketamine is a racemic mixture, meaning it contains equal parts of two mirror-image molecules called R-ketamine and S-ketamine. S-ketamine, called esketamine, is the more potent NMDA antagonist of the two. In 2019, the FDA approved esketamine as a nasal spray (Spravato) for treatment-resistant depression when combined with an oral antidepressant, and in 2020 for major depressive disorder with acute suicidal ideation or behavior. Racemic IV ketamine remains off-label for depression but is widely used at ketamine clinics.

Auvelity, a combination of dextromethorphan and bupropion, is included in this discussion because dextromethorphan acts on the NMDA receptor and adds a related mechanism to a standard antidepressant. Auvelity is FDA-approved for major depressive disorder and represents a related, if less potent, NMDA-based approach.

The medications covered here are esketamine nasal spray (Spravato), racemic ketamine IV (off-label for depression), and dextromethorphan-bupropion (Auvelity).

How they work

Most antidepressants work through the monoamine systems (serotonin, norepinephrine, dopamine). Ketamine works through glutamate, the main excitatory chemical messenger in the brain.

Ketamine is an antagonist at the NMDA glutamate receptor. It blocks the receptor at rest and when it's briefly active. The immediate result is a reduction in NMDA-mediated signaling. But the interesting effect happens downstream. Blocking NMDA receptors, particularly on certain inhibitory interneurons, disinhibits a burst of glutamate release. That glutamate acts on a different receptor called AMPA, and the AMPA activation triggers a cascade that includes brain-derived neurotrophic factor (BDNF) release and activation of the mTOR pathway. The net result over the following hours is rapid growth of dendritic spines, which are the connection points between neurons. That structural change is thought to be part of why ketamine works fast when it works.

The clinical implication. Standard antidepressants take four to six weeks to work because their effects on serotonin and norepinephrine set off slower adaptations. Ketamine, by acting on a different system, can produce mood improvement within hours to a day or two. The effect from a single dose isn't permanent. Repeated dosing is standard.

Esketamine is the S-enantiomer of ketamine and is the more potent NMDA antagonist. It's delivered by nasal spray, which produces plasma levels lower and more variable than IV administration. Dextromethorphan, the common cough suppressant, is a weak NMDA antagonist, and its combination with bupropion (Auvelity) uses bupropion's inhibition of dextromethorphan metabolism (via CYP2D6) to keep dextromethorphan levels higher and add an NMDA-based effect to a standard antidepressant.

How the class developed

Ketamine was synthesized in 1962 by Calvin Stevens at Parke-Davis. It was developed as a safer anesthetic than phencyclidine (PCP), and it became widely used for surgery, in emergency medicine, and on the battlefield. Ketamine also became a drug of misuse in some settings.

The observation that ketamine could rapidly lift mood came from anesthesia and pain medicine literature in the 1990s and from a landmark trial by Berman and colleagues at Yale in 2000, which showed that a single IV infusion produced rapid improvement in depression. Follow-up trials through the 2000s and 2010s built the evidence base for treatment-resistant depression. Off-label ketamine infusion clinics started opening in the 2010s.

Esketamine (Spravato) was developed by Johnson and Johnson and received FDA approval in 2019 for treatment-resistant depression and in 2020 for major depressive disorder with acute suicidal ideation or behavior. It came with a Risk Evaluation and Mitigation Strategy (REMS) program, which requires certified healthcare settings, direct observation during and after dosing, and no driving that day.

Dextromethorphan-bupropion (Auvelity) was approved in 2022 for major depressive disorder. It's an oral once- or twice-daily medication and doesn't require a REMS program or observation.

The regulatory status of ketamine in the U.S. is worth noting. Ketamine is a DEA Schedule III controlled substance. Esketamine is Schedule III as well. Both carry misuse potential.

What they treat

• Treatment-resistant depression. Depression that hasn't responded to two or more antidepressant trials at adequate dose and duration. Esketamine plus an oral antidepressant is FDA-approved for this. Racemic IV ketamine is used off-label with substantial evidence for the same population.
• Major depressive disorder with acute suicidal ideation or behavior. Esketamine is FDA-approved specifically for this, with rapid effect being the practical value.
• Major depressive disorder more broadly. Dextromethorphan-bupropion (Auvelity) is FDA-approved for MDD without the treatment-resistance requirement.
• Bipolar depression. Off-label use of ketamine has some evidence, though the concern about triggering mania keeps the picture more cautious.

Racemic IV ketamine is also used at some clinics for chronic pain, PTSD, OCD, and other conditions, but the evidence base and regulatory picture for those uses are outside this class page's scope.

Individual medications in this class

• Esketamine nasal spray (Spravato). S-enantiomer of ketamine delivered as a nasal spray. FDA-approved for treatment-resistant depression and for major depressive disorder with acute suicidal ideation or behavior, in both cases used with an oral antidepressant. Delivered under a REMS program requiring in-clinic administration and 2-hour post-dose observation.
• Racemic ketamine IV (off-label for depression). Standard ketamine (mixture of R and S) given IV, typically at 0.5 mg/kg over 40 minutes. Widely used at ketamine clinics for treatment-resistant depression, PTSD, and other conditions off-label. Not FDA-approved for depression.
• Dextromethorphan-bupropion (Auvelity). Oral combination that uses bupropion to raise dextromethorphan levels. FDA-approved for major depressive disorder. Not delivered under REMS.

Common side effects across the class

Ketamine and esketamine share a set of effects that come from the acute drug effect during and shortly after dosing.

• Dissociation. This is a shift in perception during dosing, ranging from mild spaciness or feeling detached from surroundings, to more pronounced experiences of distortion of time, distance, or body perception. Dissociation typically peaks 20 to 60 minutes after dosing and resolves within an hour or two. For most people it's tolerable, and some find it neutral or even pleasant. For some it's distressing.
• Sedation and drowsiness during and after dosing.
• Increased heart rate.
• Transient rise in blood pressure. The BP effect typically peaks 30 to 60 minutes after dosing and resolves within an hour or two. This is why blood pressure is monitored during and after.
• Nausea. Sometimes managed with an antinausea medication before dosing.
• Dizziness.
• Headache.
• Anxiety during dosing.
• Taste disturbance (esketamine nasal spray).

Dextromethorphan-bupropion (Auvelity) has a different side-effect profile because it's taken orally and doesn't produce the same peak-drug-level dissociation.

• Dizziness.
• Headache.
• Diarrhea.
• Nausea.
• Dry mouth.
• Insomnia.
• Increased sweating.
• The bupropion component brings its own side-effect and interaction picture, including seizure risk at higher doses.

Serious warnings across the class

Boxed warning for esketamine (Spravato) regarding sedation, dissociation, misuse and abuse potential, and suicidal thoughts and behavior. This is the reason for the REMS program.

REMS program. Spravato is only administered in certified healthcare settings where the patient is monitored for at least two hours after dosing. Patients cannot drive that day and must arrange transportation home. Home administration isn't allowed. This isn't optional, and it shapes how Spravato is delivered.

Hemodynamic effects. Both ketamine and esketamine raise heart rate and blood pressure acutely. This is monitored during and after dosing. Uncontrolled hypertension, unstable coronary artery disease, aneurysmal vascular disease, and recent stroke or intracerebral hemorrhage are cautions or contraindications.

Misuse and dependence. Ketamine and esketamine both have misuse potential. Ketamine can produce dependence with heavy long-term use, and there are patterns of misuse where daily or near-daily unsupervised use causes serious problems. Bladder toxicity (see below) is one of the most concerning consequences of heavy ketamine misuse.

Ketamine bladder syndrome (uropathy). Heavy, long-term ketamine misuse can cause severe bladder inflammation, ulceration, and scarring, sometimes requiring bladder removal. This is a real problem in the ketamine-using population who use daily or heavily. Occasional therapeutic dosing has not been clearly linked to bladder problems, but the concern is why long-term monitored use is different from unmonitored heavy use.

Cognitive effects with heavy long-term use. Chronic recreational ketamine users have shown cognitive changes, especially in memory. Therapeutic dosing at clinic intervals doesn't appear to produce this, but the concern factors into how ketamine treatment is structured.

Antidepressant boxed warning about suicidal thoughts in people under 25 applies to esketamine and dextromethorphan-bupropion as antidepressants.

Interactions. Combining ketamine with monoamine oxidase inhibitors is generally avoided. Combining with other CNS depressants (benzodiazepines, opioids, alcohol) raises sedation and respiratory depression risk.

What tips the choice within the class

Speed. When rapid effect matters (severe depression, acute suicidal ideation), the fast-acting options are esketamine or racemic IV ketamine. Standard antidepressants take weeks.

FDA approval versus off-label. Esketamine is FDA-approved and has a REMS program that structures its delivery. Racemic IV ketamine is off-label for depression but has more research support historically (many trials predate the esketamine approval) and is generally less expensive than Spravato, though not covered by insurance for depression at most clinics.

Delivery. Esketamine is a nasal spray delivered in a certified healthcare setting with 2-hour observation. IV ketamine is delivered as an infusion at a clinic. Auvelity is an oral pill taken at home.

Access and cost. Spravato has REMS-required in-clinic administration, is often covered by insurance for the FDA-approved indications, and requires a certified provider. IV ketamine is typically cash-pay at ketamine clinics and often ranges from $400 to $1000 per infusion. Auvelity is a standard prescription antidepressant delivered through pharmacies.

Structure and frequency. Standard induction protocols for esketamine involve twice-weekly dosing for four weeks, then once weekly for four weeks, then once every one to two weeks for maintenance. Racemic IV ketamine protocols vary but often involve six infusions over two to three weeks for induction, then maintenance infusions as needed. Auvelity is a daily oral medication.

Cardiovascular risk. In someone with uncontrolled hypertension or unstable heart disease, ketamine and esketamine are used with more caution or avoided. Auvelity doesn't share the same acute blood pressure spike.

Personal history of substance use. Ketamine and esketamine have misuse potential. History of substance use disorder isn't an automatic contraindication but factors into how treatment is structured and monitored.

Common questions

How fast does ketamine work for depression? Fast, when it works. Some people notice mood improvement within hours of a single dose. For most who respond, the effect is clearer by 24 to 72 hours after dosing. That speed is the main practical difference from standard antidepressants, which take four to six weeks. The effect from a single dose isn't permanent, and repeat dosing is standard. Response to a single dose predicts response to a course, but response to the first dose isn't universal.

What is dissociation like during a ketamine session? It varies a lot. For many people it's a mild, floating, spacey feeling with some distortion of time or body perception. For some it's more pronounced, including feelings of being outside the body, seeing patterns or colors, or a sense that surroundings look unreal. It typically peaks 20 to 60 minutes into or after dosing and resolves within an hour or two. Most people find it tolerable. Some find it distressing enough that ketamine isn't a good fit. Clinics often support the experience with a quiet room, an eye mask, and calm music.

Do I have to be off other antidepressants to start esketamine? No. Esketamine is FDA-approved specifically as an addition to an oral antidepressant, not as a replacement. Most people continue their existing antidepressant when starting Spravato. IV ketamine is used both alongside existing antidepressants and, in some clinic protocols, alone.

Is at-home ketamine (troche, lozenge, oral) as good as IV or nasal spray? The evidence is much weaker. IV ketamine and nasal spray esketamine have the most trial data. Oral and sublingual ketamine (compounded troches or lozenges) have less predictable absorption, lower peak levels, and less research support. Home-based ketamine services expanded rapidly in the 2020s. Whether they deliver the same benefit at the same safety as monitored clinic-based dosing is not well established, and home dosing removes the observation that catches problems in the two hours after administration.

Is ketamine addictive? It has misuse potential. In monitored therapeutic settings with weekly or less-frequent dosing, evidence of clinical addiction is limited. Heavy unmonitored use, especially daily or near-daily recreational use, can produce psychological dependence, bladder damage, and cognitive changes. The DEA classifies ketamine as Schedule III, meaning it has recognized medical use with a moderate to low potential for physical dependence and a moderate potential for psychological dependence. Personal history of substance use disorder factors into how treatment is structured, but it isn't an automatic exclusion.

Sources

This guide draws on current prescribing information and public health references. It's reviewed for clinical accuracy and updated as guidance changes. This is educational content and isn't medical advice.

1. U.S. Food and Drug Administration. Prescribing information for Spravato and Auvelity.
2. MedlinePlus, U.S. National Library of Medicine.
3. National Institute of Mental Health. Mental health medications.
4. American Psychiatric Association. Consensus statement on the use of ketamine in the treatment of mood disorders.
5. Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 2000.