Ketamine-Assisted Psychotherapy (KAP) for Depression and PTSD

Ketamine-assisted psychotherapy (KAP) has gained increasing attention as a novel approach to treating treatment-resistant depression (TRD) and post-traumatic stress disorder (PTSD). The model combines the biological effects of ketamine with structured psychological therapy, with the aim of enhancing and consolidating treatment outcomes.

While early clinical experience has been encouraging, the emerging research presents a more nuanced picture. Understanding what KAP can — and cannot — offer is essential for patients and clinicians considering this approach.

What is ketamine-assisted psychotherapy?

Ketamine-assisted psychotherapy involves the use of ketamine in conjunction with psychological therapy. Typically, this includes:

• Preparation sessions prior to treatment
• Therapeutic support during or shortly after ketamine administration
• Integration sessions to process the experience

The rationale is that ketamine may create a temporary state of increased psychological flexibility, allowing patients to engage more deeply with therapeutic processes.

Why combine ketamine with psychotherapy?

Ketamine has well-established effects on the brain, including modulation of glutamate signalling and rapid enhancement of neuroplasticity. These changes are thought to create a window during which entrenched patterns of thinking and emotional responses may become more accessible to change.

In PTSD, this may involve:

• Reduced emotional reactivity to trauma memories
• Enhanced extinction learning
• Greater openness to revisiting and processing traumatic experiences

A pilot study combining ketamine with brief exposure therapy following trauma memory retrieval demonstrated reduced reactivation of key brain regions involved in fear processing, including the amygdala and hippocampus, suggesting a potential role in modifying traumatic memory circuits (Duek et al., 2023). However, this remains preliminary and requires further replication.

What does the evidence show?

Despite strong theoretical rationale and positive clinical reports, the highest-quality evidence to date does not clearly demonstrate that psychotherapy adds benefit when combined with ketamine.

A 2026 systematic review of ketamine-assisted psychotherapy for treatment-resistant depression found that while all included studies showed meaningful reductions in depressive symptoms lasting up to six months, controlled trials did not show a significant advantage of KAP over ketamine alone (Simpson & Juruena, 2026).

This finding is consistent with other research. A large real-world analysis of 624 patients found no significant difference in symptom trajectories between ketamine alone and ketamine combined with psychotherapy over a follow-up period of 30 to 180 days (Moore et al., 2025).

Importantly, only a small number of randomised controlled trials have directly tested the addition of psychotherapy within ketamine treatment, and none have demonstrated a clear additive effect to date (Veraart et al., 2026).

Why do clinical outcomes still appear positive?

Despite the lack of clear superiority in controlled trials, real-world studies and case series often report strong outcomes with KAP.

For example, observational data combining ketamine with psychodynamic psychotherapy has reported response rates of 67% and remission rates of 58%, with approximately half of patients maintaining remission at one year (Cohen et al., 2025).

Several factors may explain this discrepancy.

First, ketamine itself is a highly effective treatment for depression and PTSD, and improvements may be attributed primarily to its pharmacological effects rather than the addition of psychotherapy.

Second, psychotherapy may still play an important role in supporting and stabilising gains, even if it does not significantly enhance short-term symptom reduction.

Third, subjective experiences during ketamine treatment may be relevant. Studies have shown that mystical-type or ego-dissolution experiences correlate with greater symptom improvement, suggesting that the psychological context of treatment may influence outcomes in more subtle ways (Cohen et al., 2025; Greenway et al., 2025).

What about PTSD specifically?

Ketamine has demonstrated efficacy as a treatment for PTSD in its own right. Randomised controlled trials have shown that repeated ketamine administration can significantly reduce PTSD symptoms (Feder et al., 2021), and systematic reviews confirm its therapeutic potential (Yin et al., 2025).

The role of psychotherapy in this context remains less clear. While there is a strong theoretical basis for combining ketamine with trauma-focused therapies, particularly in enhancing extinction learning, robust clinical evidence supporting this combined approach is still limited.

What does this mean for patients?

Ketamine-assisted psychotherapy is a promising model, but it is important to approach it with realistic expectations.

Current evidence suggests that:

• Ketamine itself is the primary driver of symptom improvement
• Psychotherapy may provide supportive or integrative benefits
• The combination does not yet demonstrate clear superiority over ketamine alone in controlled trials

This does not mean psychotherapy is unnecessary. Rather, it highlights that its role may be more about consolidating and maintaining change, rather than enhancing the acute antidepressant effect.

The future of ketamine-assisted care

As research continues, the role of psychotherapy in ketamine treatment is likely to become more clearly defined. Future studies may identify:

• Which patients benefit most from combined approaches
• Optimal timing and type of psychotherapy
• How to leverage ketamine’s effects on neuroplasticity more effectively

For now, the focus remains on delivering ketamine safely and effectively, while integrating psychological care in a way that supports long-term outcomes.

Key takeaway

Ketamine-assisted psychotherapy represents an evolving area of treatment for depression and PTSD. While clinical experience is encouraging, current evidence suggests that ketamine alone accounts for most of the therapeutic effect, with psychotherapy playing a supportive but not clearly additive role.

As with all emerging treatments, careful patient selection, clinical expertise, and ongoing research will be key to refining its use. 

References

Simpson RJ, Juruena MF. Effectiveness of ketamine-assisted psychotherapy as a treatment for treatment-resistant depression: A systematic review. Psychopharmacology. 2026.

Veraart JKE, Schimmers N, Breeksema JJ, et al. Ketamine-assisted psychotherapies for mental disorders: A historical overview and systematic review. Clinical Psychology Review. 2026.

Moore TM, Walker K, Tung E, et al. Combined ketamine and psychotherapy provide no additional benefit beyond ketamine alone in treating depression or PTSD. Journal of Affective Disorders. 2025.

Cohen R, Bastos J, Cunha C, et al. Ketamine combined with psychotherapy for treatment-resistant depression: Real-world outcomes and the role of subjective experience. General Hospital Psychiatry. 2025.

Greenway KT, Garel N, Dinh-Williams LL, et al. The Music for Subanesthetic Infusions of Ketamine Randomised Clinical Trial: Ketamine as a psychedelic treatment for highly refractory depression. British Journal of Psychiatry. 2025.

Feder A, Costi S, Rutter SB, et al. A randomized controlled trial of repeated ketamine administration for chronic posttraumatic stress disorder. American Journal of Psychiatry. 2021.

Yin L, Lu A, Le GH, et al. Effects of intravenous ketamine on posttraumatic stress disorder: A systematic review. Acta Psychiatrica Scandinavica. 2025.

Duek O, Korem N, Li Y, et al. Long-term structural and functional neural changes following a single infusion of ketamine in PTSD. Neuropsychopharmacology. 2023.

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