Psychedelic drug trial guidance: Commenters see vital role for psychotherapy

Commenters on the US Food and Drug Administration’s (FDA) first guidance on clinical investigations and drug development programs for psychedelic drugs raised concerns about decoupling drug administration from psychotherapy support, the proposed credentials for lead safety monitors and the agency’s characterization of the abuse potential of psychedelic drugs.

The draft guidance, issued in June 2023, outlines the nonclinical, clinical, and safety considerations of conducting trials for classic psychedelic agents, which include 5-HT2 agonists such as psilocybin and lysergic acid diethylamide (LSD) and methylenedioxymethamphetamine (MDMA). The guidance applies to trials conducted under an investigational new drug application (IND), including academic studies that are not designed to support marketing applications (RELATED: FDA issues first psychedelic drug trial guidance, Regulatory Focus 28 June 2023).

Incorporating psychotherapy support

In the guidance, the FDA wrote that sponsors should plan to “justify the inclusion of a psychotherapy component” in trials of psychedelics because of the potential to create bias in the assessment of effectiveness and to complicate future product labeling. Several commenters objected to the agency’s language, noting the importance of providing therapeutic support for safety reasons.

The Johns Hopkins Center for Psychedelic and Consciousness Research wrote that while psychotherapy can complicate the effectiveness assessment, the FDA’s language implies that there is a preference for excluding psychotherapy that will deter researchers from incorporating psychotherapeutic elements. “Because psychotherapy may be necessary for patient safety under certain conditions (e.g., trauma-focused therapy skills in the context of drug-related reexposure), we invite the FDA to consider modifying their language,” wrote members of the Center.

Researchers at The Ohio State University noted that the current body of evidence supports the inclusion of psychotherapy and current trials of psychedelic drugs typically include preparation sessions, drug sessions, and integration sessions. Therapy practices in psychedelic research are understudied and more research is needed but “it is alarming to think that the response to this gap in the literature is to assume at the start that these treatments are drugs alone and that the therapeutic component is an accessory rather than necessity,” the Ohio State researchers wrote.

Researchers in the Translational Psychedelic Research (TrPR) Program at the University of California, San Francisco took a strong stand in favor of the use of psychotherapy, comparing the importance of pairing of psychotherapy and psychedelic drug use to physical therapy following cardiac stenting.

“Efficacy is intrinsically related to the processes of preparation, appropriate setting, and integration for the safety and optimization of the dosing intervention. Future product labeling should follow FDA guidelines of Ketamine lozenges, advising its use accompanied by psychotherapeutic support only. In addition to ketamine, it should be noted that there have been analogous concerns about the implementation of other kinds of psychiatric interventions that have included some form of specialized monitoring (e.g., brexanolone, suboxone); therefore, this is not an altogether novel consideration for psychedelic medicines,” the TrPR researchers wrote.

Continuity of care

The Psychedelic Medicine Coalition (PMC), an industry-led coalition that is focused on research and development of psychedelic therapies, questioned FDA’s recommendation that studies not use the same therapist to provide in-session monitoring and post-session psychotherapy. In the guidance, FDA asserted that the therapist’s knowledge of the treatment could bias their delivery of the subsequent therapy. However, the PMC wrote that following this advice could complicate risk reduction measures for sponsors because continuity of care and trust establishment are relevant to the patient’s overall experience.

“PMC encourages FDA consider additional guidance and future data/suggestions to ensure continuity of care, such as introduction of post-therapy practitioners to trial participants during the pre-trial stage,” the group wrote.

The International Society for CNS Clinical Trials and Methodology also objected to interfering with continuity of clinician support, which it said is an important element of psychological support. Instead, the group suggested that in-session monitors not be involved in efficacy ratings or assessments.

Safety monitoring

Several commenters also expressed concerns about FDA’s proposed professional credentials for the lead monitors during treatment sessions. In the draft guidance, FDA recommends that the lead monitor have graduate-level professional training and clinical experience in psychotherapy and be licensed to practice independently. The guidance provides several examples of appropriate credentials including clinical or counseling psychologist, psychiatrist or other physician, Master of Social Work, licensed clinical professional counselor, licensed marriage and family therapy or psychiatric nurse practitioner.

In joint comments, the American Association of Nurse Anesthesiology and the American Nurses Association wrote that certified registered nurse anesthetists (CRNAs) should be included among the provider types that are eligible to be lead monitors for psychedelic drug trials. “Restricting access to a broad scope of nurses is a disservice to patients to access these treatments. CRNAs play a critical role by ensuring proper anesthesia services management which can make a tremendous difference in terms of improving patient flow, patient safety, and cost savings,” the groups wrote.

The American Psychedelic Practitioners Association, which is an accreditation body in the field, also requested that FDA broaden its list of recommended professional credentials for lead monitors to include psychiatric nurse practitioners and other advanced practice registered nurses.

Abuse potential

The American Psychedelic Practitioners Association also objected to FDA’s definition of “abuse,” noting that it is different from the clinical definition, which describes excessive or compulsive use of a drug in a way that is harmful. “Research increasingly shows that certain psychedelic compounds, when used without a prescription, do not necessarily present the hallmarks of substance abuse and, in some cases, have reduced symptoms of drug abuse,” the group wrote. It urged FDA to revise the guidance to ensure it does not equate use of psychedelics without a prescription to abuse of the drugs.

Public comments on Psychedelic drugs guidance

Psychedelic drug trial guidance: Commenters see vital role for psychotherapy

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