Walk through any major US city and you'll see ads for ketamine clinics. The drug has gone from anaesthetic to club drug to FDA-approved depression treatment (in the form of esketamine, Spravato) within a generation. For people with severe treatment-resistant depression, it can be genuinely life-changing.
For people with schizophrenia, the same drug has the opposite reputation. It is one of the few medications that researchers deliberately give to healthy volunteers to induce a temporary state that resembles psychosis. That is not an accident — it tells us something important about how schizophrenia might work, and why ketamine is not on the menu for most people with the diagnosis.
Ketamine and esketamine are generally contraindicated or used only with extreme caution in people with schizophrenia, schizoaffective disorder, or any active psychotic illness, because they can transiently worsen or precipitate psychotic symptoms.
Why ketamine is on the radar at all
Ketamine works by blocking the NMDA glutamate receptor. Unlike antidepressants that take weeks, a single dose can produce antidepressant effects within hours that last days. The FDA approved esketamine (the S-isomer of ketamine, marketed as Spravato) as a nasal spray for treatment-resistant depression in 2019, and later for depressive symptoms in adults with major depression and acute suicidal ideation.
The NMDA hypothesis of schizophrenia
One of the most important findings in psychiatry from the 1990s was that ketamine, given to healthy people, reliably produces a brief experience that closely resembles schizophrenia: thought disorder, perceptual changes, a feeling that thoughts are being inserted, and disorganisation. This led to the NMDA hypofunction hypothesis of schizophrenia — the idea that reduced glutamate signalling at NMDA receptors is part of what produces psychotic symptoms.
Several large reviews, including work by Krystal and colleagues at Yale, document how predictable this effect is. It is one of the cleanest "drug models" of psychiatric illness in the literature.
Why this matters for schizophrenia
If a single dose of ketamine can produce psychosis-like experiences in healthy people, it stands to reason that the same drug given to someone with an underlying psychotic illness can:
- Worsen current positive symptoms (voices, paranoia, thought disorder)
- Precipitate a relapse of psychosis in someone currently stable
- Trigger a longer-lasting psychotic episode in vulnerable people
This is not theoretical. Multiple case reports and small studies describe psychotic exacerbations after ketamine in schizophrenia. The Spravato US prescribing information specifically lists psychosis as a reason to use the drug only with extreme caution and ongoing monitoring.
What about depression in someone with schizophrenia?
Depression is common in schizophrenia, particularly during recovery and in chronic phases. It is a serious problem and frequently undertreated. The question is fair: if my main symptoms are depressive, can I use ketamine?
The honest answer is: usually not as a first option. Standard treatments include:
- Optimising the antipsychotic regimen (some antipsychotics, like aripiprazole or cariprazine, have antidepressant effects)
- Adding an antidepressant (with attention to interactions)
- CBTp focused on hopelessness and post-psychotic depression
- Treating sleep, exercise, and substance use, all of which heavily affect mood
- For severe, refractory cases, ECT is sometimes used
Ketamine or esketamine in this population is generally avoided unless other options have failed and the team can monitor closely for psychotic worsening.
What about schizoaffective disorder?
Same caution applies. People with schizoaffective disorder have psychotic symptoms by definition; the depression component does not erase the risk of ketamine destabilising the psychosis.
Recreational ketamine and psychosis risk
Recreational ketamine use carries the same theoretical risk plus the additional issues of dose unpredictability, contamination, and bladder damage from chronic use. For people with schizophrenia or a strong family history of psychotic illness, recreational ketamine is one of the higher-risk substances to use, alongside cannabis and stimulants.
Tell every clinic and prescriber about the schizophrenia diagnosis up front. Many clinics screen out patients with psychotic disorders and will decline treatment. This is the right and protective response.
What's actually being researched
Some research is investigating whether NMDA-targeting drugs other than ketamine could treat rather than worsen schizophrenia. Glycine-site agonists, D-serine, and selective NMDA modulators have been studied. Results so far have been disappointing, but the line of research continues. The arrival of xanomeline-trospium (Cobenfy) shows that non-D2 mechanisms can in fact treat schizophrenia, even if NMDA-direct approaches haven't worked yet.
The bottom line
Ketamine is a powerful tool used carefully. For people with schizophrenia, the same pharmacology that makes it effective in depression makes it risky. If a clinician is considering it for you despite a psychotic disorder diagnosis, that conversation needs to be detailed, conservative, and close-monitored — not a walk-in at a wellness clinic.
This article is for educational purposes only and is not medical advice, diagnosis, or treatment. Always consult a qualified mental health professional. If you or someone you know is in crisis, call or text 988 in the US, or your local emergency number.