A new systematic review in Clinical Psychology Review offers the most comprehensive overview to date of studies combining ketamine with psychotherapy across psychiatric indications. The findings are promising, but they also expose just how much we still don’t know about whether and how psychotherapy adds value to ketamine treatment.
The review, led by researchers Jolien Veraart, Nina Schimmers, and including Breeksema and colleagues at the University Medical Center Groningen (UMCG) and PsyQ, examined 64 articles reporting on 72 studies published up to 2025. It is the first to systematically categorise the psychotherapeutic approaches used alongside ketamine into their overarching psychological paradigms, and to trace the historical development of ketamine-assisted psychotherapy (KAP) from its earliest roots to the present day.
A Long and Varied History
Ketamine’s potential as a therapeutic catalyst is not new. The compound was first used in a psychotherapeutic context in the 1960s and 70s, initially as an abreactive agent and later within psychodynamic group therapy frameworks. Throughout the following decades, researchers and clinicians explored its use within a range of therapeutic traditions, from psychoanalytic and humanistic approaches to cognitive-behavioural and integrative models.
What makes this review particularly valuable is the way it maps this diversity. The authors sorted psychotherapeutic approaches into six overarching paradigms:
- Psychoanalytic and psychodynamic,
- Behavioural,
- Humanistic,
- Cognitive-behavioural,
- Integrative/holistic,
- A residual “other” category.
Strikingly, the largest group of studies (n = 24) fell into the “other” category, reflecting the fact that many treatment protocols don’t fit neatly into established therapeutic traditions. This heterogeneity is part of the story: there is no consensus on what KAP should look like in practice.
Transdiagnostic Promise
Across the included studies, KAP was applied to a wide range of psychiatric conditions, including major depressive disorder, posttraumatic stress disorder, obsessive-compulsive disorder, substance use disorders, and eating disorders. Results were generally positive, but since most studies lacked control conditions, it’s not possible to draw any firm conclusions. Compared with psychotherapy alone, KAP appeared to strengthen treatment engagement, produce greater symptom reduction, and extend the duration of therapeutic gains. These are meaningful clinical outcomes, particularly for populations that have often proved resistant to conventional treatment.
The review also highlights some proposed mechanisms by which the combination might work. Ketamine’s rapid pharmacological effects, including NMDA receptor antagonism and increased neuroplasticity, may open a window during which patients become more receptive to therapeutic processes. The altered states of consciousness that ketamine can produce may facilitate emotional processing, shift rigid patterns of thought, and support deeper engagement with psychotherapeutic work. These ideas are compelling, but they remain largely theoretical and may depend on the psychotherapeutic framework within which they’re applied.
The Evidence Gap
This is where the review becomes most sobering. Of the 72 studies included, only 11 were randomised controlled trials. The vast majority relied on open-label, observational, or case-based designs. This matters because without proper controls, it is difficult to determine whether the positive outcomes reported are due to the combination of ketamine and psychotherapy, or simply to the pharmacological effects of ketamine itself.
Only two studies in the entire review actually randomised the psychotherapy component in the context of ketamine treatment. Neither found a clear added benefit from psychotherapy. One of those studies also randomised ketamine and did not find a significant interaction effect between the drug and the therapy. This doesn’t prove that psychotherapy adds nothing to ketamine treatment, but it does mean the field cannot yet claim, based on controlled evidence, that combining the two produces genuinely synergistic effects.
The authors are careful to note that methodological heterogeneity and the small number of trials with psychotherapy control groups limit the ability to draw definitive conclusions. Many studies used different ketamine formulations (intravenous, intramuscular, intranasal, sublingual), different doses, different timing of therapeutic interventions, and different outcome measures. This makes it hard to compare across studies and nearly impossible to identify optimal protocols.
Common Therapeutic Elements
Despite the wide variation in approaches, the review identifies several elements that appeared consistently across KAP protocols:
- Structured preparation before ketamine administration,
- Attentive supervision during the ketamine experience,
- Post-ketamine integration work.
These three components mirror what is widely considered essential in psychedelic-assisted psychotherapy more broadly. They reflect an understanding that the value of a pharmacologically facilitated altered state depends, at least in part, on the relational and psychological context in which it occurs.
This is an important observation, because it suggests that even where specific psychotherapeutic modalities varied, a common therapeutic scaffolding was present. Whether this scaffolding drives the positive outcomes or simply reflects good clinical practice in any drug-assisted treatment remains an open question.
Why This Matters Now
Ketamine is increasingly available in psychiatric settings, and its use is growing faster than the evidence base for how best to deliver it. The FDA-approved model for intranasal esketamine (Spravato) in treatment-resistant depression, for example, does not explicitly require psychotherapeutic engagement in preparation or integration. Meanwhile, a growing number of private clinics and retreats offer KAP as a combined intervention, often drawing on psychedelic therapy frameworks without strong evidence that these frameworks improve outcomes beyond what ketamine does on its own.
This review serves as both a map of the field and a call to action. The authors argue for well-controlled trials that specifically test whether psychotherapy adds value to ketamine treatment and that investigate optimal timing, modality, and intensity of therapeutic support. Without such trials, the rationale for combining the two, however intuitively appealing, remains grounded more in theory and clinical observation than in rigorous evidence.
Looking Ahead
The broader question underlying this review is one that extends well beyond ketamine: when we combine a pharmacological agent with psychotherapy, are we creating something greater than the sum of its parts, or are we simply layering good practice on top of effective pharmacology? For psychedelic-assisted therapy, this question is very much alive at the moment. The field has long operated on the assumption that set, setting, and therapeutic support are not optional extras but essential ingredients. The evidence reviewed here suggests that this assumption, at least for ketamine, has not yet been convincingly shown.
As ketamine use expands and new psychedelic therapies move through the pipeline, understanding whether and how psychotherapy contributes to outcomes has direct implications for training, regulation, access, and the design of treatment protocols that will shape how these medicines are delivered for years to come.
The study, “Ketamine-assisted psychotherapies for mental disorders: A historical overview and systematic review,” was published open access in Clinical Psychology Review in February 2026.
On Monday, 2 March 2026, first author, psychiatrist Jolien Veraart will defend her thesis entitled ‘Ketamine for depression: moving from research to clinical practice’ at the University of Groningen in the Netherlands. The thesis covers a multitude of studies conducted within the UCP and in national collaborations in recent years.
A mini-symposium will be held at the UMCG prior to this event. In addition to the PhD candidate, several experts will present an overview of current approaches to treating depression with esketamine.
Contributions will be made by Rupert McShane, Jeanine Kamphuis, Eva Goedendorp, Robert Schoevers, and additional experts.
AUTHOR
Community builder & Writer with a longstanding involvement in the psychedelic research and policy space.
Gustaf’s professional engagement with psychedelics began at the Intercollegiate Psychedelics Network, where he served as Community Manager between 2020 and 2022. He went on to become a founding member and Communication and Community Lead at PsyDAO, an organization focused on the democratization of psychedelic research and development, where he conducted interviews with researchers and stakeholders and organized educational events on psychedelic science.
Gustaf has also worked as a Growth and Content Manager at Supermind, developing communications around psychedelic-assisted microdosing and mental health. His training includes a certification in Compassionate Inquiry, the trauma-informed therapeutic modality developed by Gabor Maté, as well as coursework in Music for Psychedelic Therapy through Wavepaths. He attended the Intelligence in Nature seminar at the Wasiwaska Research Center for Plants, Consciousness and Indigenous Spirituality.
Gustaf has training in ecovillage design, permaculture, and facilitation. He currently works as Chief Operations Officer at the Pond Foundation (Earthtrust), supporting global regenerative projects.
At the OPEN Foundation, Gustaf volunteers as a science communicator and newsletter contributor.
