Lessons learned from the regulatory alignment in ketamine, esketamine and arketamine clinical trials: A cross-sectional analysis of protocols from ClinicalTrials.gov.

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.