The World Health Organization (WHO) identifies depression as a prominent contributor to disability, while suicide ranks as the fourth leading cause of death among individuals aged 15 to 29. Moreover, individuals with severe mental health conditions often experience a significant reduction in life expectancy, with some losing up to two decades of life prematurely. In recent times, there has been a notable resurgence of interest in exploring psychedelics as potential therapies for a range of mental health conditions. Psychedelics - such as psilocybin and lysergic acid diethylamide (LSD), as well as empathogens such as methylenedioxymethamphetamine (MDMA) - are substances that induce profound alterations in perception, cognition, and mood.
While there might be compelling reasons to explore the potential therapeutic effects of psychedelics, safety concerns arise with larger doses and uncontrolled use. Conducting clinical investigations with psychedelic drugs poses unique challenges, prompting the US Food and Drug Administration to release a draft guidance document. This document provides industry experts with recommendations for designing clinical trials involving psychedelics, covering a range of topics, including chemistry, manufacturing, and controls; nonclinical studies; clinical pharmacology; abuse potential assessment; and clinical investigations.
Unique Pharmacology and Abuse Potential
Psychedelic drugs appear to produce their effects on thought, mood and perception by primarily targeting the serotonin 2A receptor. However, their precise mechanisms of action remain unclear. Considering their history of recreational use, the FDA advises sponsors to conduct abuse potential assessments early in the drug development process.
Clinical Investigation Design and Conduct
One of the challenges of conducting clinical investigations with psychedelic drugs is the need to provide a supportive and safe environment for study participants. Psychedelic drugs can produce intense and sometimes challenging experiences, and it is important to ensure that participants are adequately prepared and supported throughout the study.
The guidance document provides recommendations for the ethical conduct of clinical investigations, including the need to obtain informed consent from study participants that clearly outline that the patient may experience changes in perception, cognition and judgement for several hours, as well as increased vulnerability and suggestibility during the treatment session.
Also, given that subjects receiving active treatment with psychedelic drugs remain in a vulnerable state for as long as 12 hours, the guidelines recommend strict safety-monitoring by a licensed healthcare provider as well as an assistant monitor with at least one year of clinical experience in a licensed mental healthcare setting.
The draft guidance not only covers the significance of safety monitoring, but also addresses the role of psychotherapy in psychedelic drug development, understanding dose-response relationships, and assessing the long-term treatment effects.
While there is still much to learn about the potential therapeutic benefits and risks of these substances, the guidance document provides a framework for conducting clinical investigations that can help to ensure that these drugs are developed in a safe and effective manner. As research in this area continues to evolve, it will be important to continue to monitor the safety and efficacy of these drugs and to refine our understanding of their potential therapeutic benefits.
>> FDA News Release
>> FDA Draft Guidance Document