Psychedelic Drugs:
Considerations for Clinical Investigations

The history of psychedelic drugs in the United States is marked by a complex relationship between public perception, scientific research, legal status, and recent developments. These substances, such as LSD (lysergic acid diethylamide) and psilocybin (found in certain mushrooms), rose to prominence in the mid-20th century, capturing the imaginations of individuals who sought expanded states of perception and spiritual experiences.

Introduction

As the recreational use of psychedelics increased, concerns about their safety and potential for abuse grew, leading to a backlash and subsequent criminalization. In 1970, the U.S. government classified psychedelics as Schedule I drugs, placing them in the most restrictive category of controlled substances. Consequently, psychedelic research suffered from severe limitations for several decades, with stringent regulations and societal stigma hindering scientific exploration.

However, recent years have witnessed a resurgence of interest in the therapeutic potential of psychedelics. Promising studies have emerged, demonstrating their efficacy in treating mental health conditions such as depression, post-traumatic stress disorder (PTSD), and addiction. As a result, recent years have witnessed a remarkable shift in the perception of psychedelics, driven by emerging evidence of their therapeutic potential.

This shift in public perception has also led to a growing recognition of the need for rigorous scientific investigation and balanced regulatory frameworks. As the understanding of psychedelics' therapeutic benefits has deepened, legal status and regulatory attitudes have begun to evolve. In fact, some jurisdictions, including Oregon and Washington, D.C., have taken steps to decriminalize or reduce penalties associated with psychedelic substances. These changes reflect the shifting tides of public opinion and an acknowledgement of the potential value that psychedelics hold.

In this vein, the U.S. Food and Drug Administration (FDA) has played a pivotal role by granting breakthrough therapy designations for psilocybin-assisted therapy for depression. This designation expedites the development and review processes, underscoring the FDA's recognition of the therapeutic potential of psychedelic substances.

Additionally, in an exciting development on June 23, 2023, the FDA released a draft guidance for industry titled "Psychedelic Drugs: Considerations for Clinical Investigations." This draft guidance serves as a response to the growing interest in the therapeutic potential of psychedelics and the unique challenges encountered in designing clinical trials to evaluate these compounds. This draft guidance is geared towards sponsors and provides guidance to researchers, sponsors, and regulatory authorities in designing and implementing scientifically rigorous investigations to evaluate the potential therapeutic benefits of psychedelic drugs. In the guidance document, the term psychedelic is used as shorthand to include classic psychedelics, typically understood to be 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD), as well as entactogens or empathogens such as methylenedioxymethamphetamine (MDMA). As with all guidance documents, legally enforceable responsibilities are not being established. The FDA is providing their current thinking and recommendations for conducting clinical trials involving psychedelic substances.

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The guidance encompasses various crucial aspects, with a special focus on five items: (1) Chemistry, Manufacturing, and Controls, (2) Nonclinical programs, (3) Clinical Pharmacology, (4) Abuse Potential Assessment, and (5) Clinical considerations.

With regards to chemistry, manufacturing, and controls, detailed information must be provided by the sponsor when conducting clinical trials with psychedelic drugs. This ensures that the drug is properly identified, high quality, pure, and of the appropriate strength. For the submission of chemistry data sponsors can either provide their own data or incorporate previously submitted information. The Agency notes that some investigational psychedelic drugs may be considered a botanical. Regardless, the manufacturing of the drugs must comply with current good manufacturing practice (CGMP) regulations to facilitate quality control
Nonclinical studies play an essential role in establishing the safety of psychedelic drugs. Even when extensive human exposure and previous studies show no safety concerns, nonclinical studies should still be conducted after the initiation of an Investigational New Drug (IND) application. Special attention should be given to the evaluation of binding to serotonin (5-HT) receptor subtypes, particularly 5-HT2B, due to its association with heart valvulopathy. Thorough microscopic heart evaluations should be carried out to assess the potential thickening of heart valves in repeat-dose toxicity studies.
A comprehensive understanding of the pharmacokinetics and pharmacodynamics of psychedelic drugs is crucial for their development. Sponsors should investigate factors such as the impact of a high-fat meal on oral psychedelic drug absorption and potential drug interactions. Furthermore, for drugs affecting the 5-HT2B receptor, cardiac assessments may be necessary to evaluate their long-term effects on cardiac valve stiffness. It is essential to prioritize understanding the dose-response relationship for both efficacy and safety of these drugs.
Assessing the abuse potential of psychedelic drugs is an important aspect of their evaluation. This involves determining the drug's scheduling under the Controlled Substances Act and is an integral part of the new drug application. Compliance with Drug Enforcement Administration regulations is necessary for conducting investigations under an IND application. The inclusion of validated subjective scales and monitoring of abuse-related adverse events are critical during clinical studies. Moreover, potential physical dependence and risks of substance use disorder should be evaluated based on the proposed conditions of use.
Establishing the effectiveness of psychedelic drugs requires substantial evidence, similar to other drugs. However, designing adequate and well-controlled clinical studies for psychedelics presents unique challenges. Traditional placebos may be problematic due to perceptual disturbances and nocebo effects, necessitating alternative approaches such as subperceptual doses or other psychoactive drugs. Measures to minimize bias, such as blinding questionnaires and central raters, should be considered. Combining dose-response assessment and safety characterization in complementary trial designs during phases 2 and 3 can help overcome these challenges. The inclusion of psychological support or psychotherapy further complicates efficacy assessment and labeling, necessitating clarification of their impact and justification. Safety monitoring during treatment sessions is crucial, with involvement from licensed healthcare providers. Informed consent should highlight potential prolonged changes in perception and increased vulnerability. Evaluating the dose-response relationship, durability of response, and repeat dosing is essential, while mitigating adverse events and addressing public health effects.

In conclusion, the history of psychedelic drugs in the United States reflects a dynamic interplay between public perception, scientific research, legal status, and recent developments. From their initial popularity and subsequent criminalization to the recent resurgence of interest in their therapeutic potential, psychedelics have undergone a remarkable transformation. The positive shift in public perception, coupled with promising research findings, has led to changes in legal status and regulatory attitudes. The recently released FDA draft guidance for industry on psychedelic drugs further emphasizes the need for rigorous scientific investigation and comprehensive evaluation of these substances. As psychedelics are increasingly recognized as valuable tools for treating mental health conditions, the evolving landscape offers hope for further exploration, integration, and advancement in their therapeutic use.