Lessons learned from the regulatory alignment in ketamine, esketamine and arketamine clinical trials: A cross-sectional analysis of protocols from ClinicalTrials.gov.
Damian Swieczkowski, Aleksander Kwaśny, Krzysztof Sadko, Michal Pruc, Zuzanna Gaca, Lukasz Szarpak, Wiesław Jerzy Cubała
Psychiatry Research August 1, 2025 DOI: 10.1016/j.psychres.2025.116559 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Cross-sectional study Peer reviewed |
|---|---|
| Sample size | 40 |
| Population | Clinical trials listed on ClinicalTrials.gov |
| Topics | Esketamine Ketamine |
| Keywords | Clinical trials Ketamine-assisted therapy Research protocols Study design Mental health disorders Psychiatric conditions Medication trials Psychoph Mood disorders depression |
| Citations | 5 |
| Key findings | Methodological inconsistencies, particularly in blinding, placebo response management, and safety monitoring, are prevalent across ketamine and enantiomer trials for treatment-resistant depression. |
Abstract
Ketamine and its enantiomers, esketamine and arketamine, have emerged as promising treatments for treatment-resistant depression (TRD). This cross-sectional study evaluates the regulatory alignment of 40 clinical trials listed on ClinicalTrials.gov, focusing on the methodological challenges. The study highlights methodological inconsistencies, particularly around the challenges of functional unblinding caused by ketamine's dissociative effects, addressing expectancy bias, and the inadequate safety monitoring practices in many trials. A notable concern is the variability in blinding techniques, with many trials failing to adequately mask the perceptual effects of ketamine, potentially compromising outcome assessments. Furthermore, the placebo response, which accounts for a significant portion of treatment effects, was not consistently managed across trials, and safety strategies, particularly for monitoring adverse events such as dissociation and abuse potential, were not uniformly robust. Another critical issue is the lack of long-term follow-up in most trials, limiting the understanding of ketamine's safety profile over extended periods. The findings emphasize the need for harmonized and rigorous methodological frameworks to support the effective use of ketamine and its enantiomers in clinical practice. The potential lessons learned from these trials could be instrumental in guiding future research on other psychedelics currently under investigation for mental health disorders, such as psilocybin and DMT, ensuring both efficacy and safety in future therapeutic approaches. Such harmonization will be crucial to improve regulatory approval and achieve therapeutic success in real-world applications, making these treatments more accessible and reliable for patients with TRD.
Comparable studies
Other cross-sectional and survey studies on esketamine, most cited first.
Citations in the library
Cited by 3
- Beyond Efficacy Signals: Regulatory, Methodological, and Translational Challenges in Clinical Research on Ketamine and Psilocybin in Psychiatry Psychiatry International September 1, 2026
- The application of esketamine in cancer-related depressive states: attention from mechanisms to clinical translation Frontiers in Psychiatry July 30, 2026
- Protocol and pilot results for a double-blind randomized placebo-controlled trial of ketamine under propofol sedation for chronic pain and depression. Pain Management April 16, 2026
Cites 23
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Blinding and expectancy confounds in psychedelic randomized controlled trials Expert Review of Clinical Pharmacology May 26, 2021
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
and 18 more in the library