Ketamine-Assisted Psychotherapy

Ketamine before psychiatric use

The Royal Australian and New Zealand College of Psychiatrists (RANZCP) guideline states that ketamine has been used for almost 50 years, mainly as a general anesthetic and short-acting analgesic, and that antidepressant effects were reported in placebo-controlled trials more than two decades ago. The same guideline notes that the drug's dissociative effects have also led to illicit recreational use. The 2019 US label for the nasal spray gives 1970 as the year of initial US approval for ketamine.

Early psychotherapy research in alcohol dependence

Krupitsky and Grinenko reviewed ten years of work at a regional center for alcoholism and drug addiction therapy in Leningrad, in which ketamine was used to induce a psychedelic experience within psychotherapy, a method they called ketamine psychedelic therapy. They reported that 73 of 111 patients (65.8%) in the ketamine group were abstinent for more than a year, against 24 of 100 (24%) given conventional treatment. This is the developers' own review, its abstract does not say how participants were allocated, and the sources reviewed here include no independent replication.

Esketamine approval and clinic-based use

The nasal spray label revised in March 2019 records US approval of esketamine, used with an oral antidepressant, for adults with treatment-resistant depression. The RANZCP guideline says approvals of the spray in Australia and New Zealand increased interest among clinicians and the public. An American Psychiatric Association (APA) task force had noted in 2017 that small studies already led to increased off-label use of ketamine for mood and other psychiatric disorders. A clinic group describes the spray as a patented preparation that reached the market in 2019, while racemic ketamine stays in off-label psychiatric use.

Ketamine, esketamine and racemic ketamine

Ketamine exists as two mirror-image forms, S and R. The mixture used in anesthetic practice and in most off-label psychiatric use contains both. Esketamine is the S form alone, and the FDA label calls it the S-enantiomer of ketamine, with ketamine itself the racemic mixture of arketamine and esketamine. The nasal spray contains esketamine only, so findings about the spray should not be carried over to racemic ketamine, nor the reverse.

What the term ketamine-assisted psychotherapy covers

The RANZCP guideline defines ketamine-assisted psychotherapy (KAP) as dosing with ketamine to induce a trance-like state that facilitates therapy, using a model akin to psychedelic-assisted therapy, and says there is no consensus on the best way to combine ketamine with therapy. A 2026 review by authors at Yale separates KAP, which treats the consciousness-altering experience as integral, from approaches that give cognitive-behavioral therapy (CBT) after ketamine to use a window of cognitive flexibility. Usage is looser in practice: a 2026 Brazilian trial applies the label to structured psychotherapeutic support alongside esketamine sessions, and the earlier Russian program used the name ketamine psychedelic therapy.

A clinic-described KAP model

One US clinic group describes KAP as preparation, a ketamine session and later integration sessions, with a therapist present throughout a session of about three hours; for adolescents and young adults it uses a family therapy format. This is one provider's account and not a standard. The RANZCP guideline notes that other studies delivered therapy after ketamine treatment and advises that, when therapy is combined with ketamine, the type of therapy and boundaries around touch need attention.

Esketamine nasal spray under supervision

The 2019 US label states that the spray is given under direct observation of a healthcare provider in a certified healthcare setting, that patients are monitored for at least two hours, and that an assessment follows before the patient leaves. It is available only through a restricted program because of the risks of sedation, dissociation, and abuse and misuse. The indication wording refers to an oral antidepressant and not to psychotherapy.

Off-label ketamine in psychiatric practice

The RANZCP guideline states that racemic ketamine for mental disorders is off-label, that treatment should start after assessment by a psychiatrist with relevant expertise, and that a follow-up plan is necessary because the risk of relapse after stopping is high. It calls for monitoring for two hours after treatment and for processes to manage sharp blood pressure rises and severe psychological effects. These are one professional body's statements for one region and are not a protocol.

The approved use of esketamine

The 2019 label indicates the nasal spray, with an oral antidepressant, for treatment-resistant depression (TRD) in adults. The RANZCP guideline says only patients with TRD should receive ketamine therapy in routine clinical practice, and that other indications belong in research or approved evaluation programs. The label read for this page dates from 2019, and later label changes were not reviewed.

Uses studied or promoted with psychotherapy

Reports of ketamine combined with psychotherapy span several conditions. A systematic review pooled studies in adults with posttraumatic stress disorder (PTSD), a pilot trial combined ketamine infusions with psychotherapy for chronic neuropathic pain, a clinic group reports on adolescents and young adults with mixed emotional difficulties, and the older Russian program addressed alcohol dependence. Clinic descriptions say therapy supports the ketamine experience; that is a claim about purpose and not a tested effect.

Proposed mechanism

Proponents propose that ketamine produces a transient state of enhanced neuroplasticity after dosing, during which people may be more open to therapy. The Yale review frames this as a theoretical rationale, and the RANZCP guideline states that the precise mechanism of antidepressant action is not fully understood. The idea has not been shown to explain any clinical difference between ketamine with and without psychotherapy.

Esketamine nasal spray in treatment-resistant depression

A 2026 systematic review pooled six randomized trials (1,836 participants) of nasal esketamine plus a new oral antidepressant against placebo spray plus the same antidepressant. At day 28 in four induction trials (937 participants), the MADRS depression score difference was -2.99 points (95% confidence interval -5.10 to -0.89), with higher response (risk ratio 1.44) and remission (1.52). In two randomized-withdrawal trials (899 participants), continued esketamine was linked to fewer relapses among people who had already responded (hazard ratio 0.51). The authors call the acute benefit modest and note possible functional unblinding.

Off-label ketamine

The APA task force statement (2017) said studies showed rapid antidepressant effects in people with mood and anxiety disorders resistant to treatment, but with small samples, little longer-term efficacy data and limited safety data. The RANZCP guideline, approved in October 2024, recognizes a growing body of evidence, particularly for depression, while naming concerns about long-term efficacy, safety and patient selection. No pooled analysis of infusion trials was reviewed here, so no effect size is stated.

Ketamine-assisted psychotherapy: reviews and the one comparison with a control

The RANZCP guideline says observational reports suggest KAP may be useful but that it has not been studied in controlled designs. A 2026 individual participant data meta-analysis in PTSD included 12 studies (533 participants), nine of poor quality, most non-randomized, and analyzed only combined protocols, so it cannot separate the contribution of ketamine from that of therapy. In its quality-restricted analysis (63 participants), only baseline severity predicted improvement.

A nonrandomized, open-label Brazilian trial allocated 46 adults with TRD in sequence to esketamine alone or with KAP (23 each). Remission at completion was 34.8% against 78.3%, a significant difference, while response (52.2% against 78.3%) was not, and groups did not differ during six months of follow-up. Only the abstract was read.

Pilot, uncontrolled and sequential designs

A single-clinic series of 19 adolescents and young adults had no control group. A randomized pilot trial in chronic neuropathic pain assigned 30 adults to ketamine, psychotherapy or both, with feasibility as the primary outcome and pain changes exploratory. In a randomized trial of 28 responders to a ketamine course, CBT afterward gave a moderate MADRS effect size (0.65, interval -0.55 to 1.82) without a significant group-by-time effect; this is therapy after ketamine, not KAP.

Appraisal of the nasal spray in England

The National Institute for Health and Care Excellence (NICE) technology appraisal TA854 (December 2022) did not recommend the spray for TRD that had not responded to at least two antidepressants. It judged the clinical evidence uncertain because trials were short and excluded people with psychosis or recent suicidal ideation with intent, and found no reliable cost-effectiveness estimate. This is a judgment on NHS resource use as well as on evidence.

Limits of the KAP evidence

Most KAP reports are open-label, uncontrolled or pilot studies, and psychoactive effects make blinding hard. The adolescent series came from authors at a ketamine research foundation who declared no financial conflicts, and its authors say it supports designing controlled trials. The Brazilian comparison used sequential allocation and the PTSD meta-analysis treats associations as non-causal. No source reviewed compared KAP with ketamine alone in a randomized trial.

Searches run

A PubMed search for the phrase ketamine-assisted psychotherapy on 2026-10-11 returned 84 records. The records examined were small, uncontrolled, pilot, qualitative or case designs, but not every record was screened, so a randomized trial of KAP could exist that was not found. Searches for professional statements on KAP specifically found the RANZCP guideline but no separate position statement.

Acute effects

The 2019 label reports dissociative or perceptual changes in 61% to 75% of treated patients, and sedation is a boxed warning. A 2026 meta-analysis of esketamine found higher risk of dissociation (risk ratio 7.33) and raised blood pressure (3.96) than placebo spray, and more stopping because of adverse events (2.68). A second meta-analysis reported nausea, dizziness, vertigo and somnolence, with risks rising with dose. The RANZCP guideline adds that intense fear-of-death experiences can occur unexpectedly and may need close support.

Blood pressure, bladder and thinking

The label lists aneurysmal vascular disease and intracerebral hemorrhage as contraindications and warns of blood pressure increases. It reports ulcerative or interstitial cystitis in long-term off-label use or misuse of ketamine; with the spray, lower urinary tract symptoms were more frequent than with placebo, and no esketamine-related interstitial cystitis was seen in studies lasting up to a year. French urology guidelines call ketamine bladder disease a rising problem with limited, non-specific treatment. The RANZCP guideline links frequent non-medical use to cognitive dysfunction.

Misuse and dependence

The label warns of abuse and misuse and says people with a history of substance use disorder are at greater risk. A 2026 systematic review of 30 studies found minimal evidence of craving, dose escalation or misuse under clinical supervision, with misuse described mainly in case reports where monitoring was often absent. The RANZCP guideline says addiction risk has been low in formal trials but is less certain in clinical use, and recommends structured monitoring for craving.

Suitability, setting and care boundaries

The label says the spray is not approved for pediatric patients, may cause fetal harm, and calls for careful assessment of psychosis before use. The RANZCP guideline lists relative contraindications including severe cardiovascular disease, recent stroke and psychosis, does not support at-home use of compounded ketamine, and says only psychiatrists, or doctors they supervise, should prescribe. No KAP-specific training standard was found. This page is not a substitute for care, and necessary assessment or treatment should not be delayed.