Psychedelic Therapies: One Drug, Multiple Treatments: Reply to Modesto-Lowe et al

David A. Bender, MD; Sandeep M. Nayak, MD; Joshua S. Siegel, MD, PhD; David J. Hellerstein, MD; Baris C. Ercal, MD, PhD; Eric J. Lenze, MD

J Clin Psychiatry 2025;86(4):25lr15978a

See letter by Modesto-Lowe et al and article by Bender et al

To the Editor: We appreciate the thoughtful letter to the editor by Modesto-Lowe et al¹regarding the contribution of psychosocial interventions to psychedelic drug treatments. As they emphasized, the context of drug administration is widely believed to influence the psychological effects of classical psychedelic drugs, which have been characterized as nonspecific amplifiers of consciousness²and meaning- response magnifiers.³There is substantive neurophysiologic evidence that suggests this psychological property may be mediated through serotonergic receptor modulation of the dopamine release.⁴Thus, providers’ beliefs about these compounds could impact patients due to variation in study protocols and provider behaviors, which may in turn affect treatment efficacy.⁵Neuromodulatory approaches to psychedelic treatments—which emphasize pharmacological drug effects as the primary therapeutic mechanism—may carry different risk- benefit profiles relative to emotive approaches,⁶such as integration within group psychotherapy.

Although there is substantial evidence supporting a key role for set and setting in influencing the effects of classical psychedelic drugs,⁵there is not high-quality evidence that clearly demonstrates the superiority of specific psychological support approaches for particular psychiatric conditions. Historically, prominent 20th century researchers from the Spring Grove Hospital Center felt strongly about the importance of intensive preparatory psychotherapy and settings intended to promote mystical experiences in the clinical use of lysergic acid diethylamide (LSD),^2,7,8and many current researchers also emphasize the importance of psychotherapy to treatment outcomes.^9–13Clinically significant 20th century research results suggested that superior outcomes were achieved in the treatment of alcohol use disorder (AUD) with LSD through psychotherapy-intensive methods employed at Spring Grove,^7,8,14,15a pattern in many ways consistent with recent results of psilocybin trials for AUD.^16,17However, randomized controlled trials have not established the superiority of specific psychological support approaches for any disorder. Factorial studies conducted in the treatment of AUD with LSD during the 20th century had significant design limitations,^7,18–20and no such studies have been published in the 21st century. Psychotherapy itself is an intervention that carries its own complexities and unique risks, which may be amplified in the setting of psychedelic drug administration.^21,22

In their letter, Modesto-Lowe et al¹discuss the potential of group settings for psychedelic treatments. The perceived effectiveness of integrating psychedelics within group settings was among the most agreed upon survey items for our respondents⁶despite the fact that the research supporting this approach is limited.²³This common belief might be explained by the fact that historically, various cultures with approved uses of psychedelic plants or fungi have taken them in ceremonial group settings,^24,25and they continue to be used in these settings today.²⁶Group administration of high-dose psychedelics has previously been considered challenging by researchers, in part due to difficulties in maintaining group cohesion during peak drug effects.²Recent research applying this model has most often used individual dosing combined with group psychotherapy pursued outside of peak drug effects,^27,28though other practitioners have pursued group administration in clinical settings.²⁹Group approaches may offer distinct benefits, such as making treatment more accessible and harnessing group support to improve the quality of the experience. However, group approaches will likely carry their own unique complexities and risks.

Several pharmaceutical companies advancing psychedelic treatments have emphasized their use of drug-focused models which minimize the role of psychotherapy,^30–32decisions that likely relate in part to the goal of expeditious regulatory approval. However, such approaches may not be optimal methods for implementing psychedelic compounds as psychiatric treatments, and the data generated from these studies should not be fully extrapolated to represent the safety and efficacy of psychedelic drugs administered with more extensive psychological support models. Investigator-initiated research and public funding will be key to enable the evidence-based expansion of psychedelic treatments alongside a variety of psychological support models.

Article Information

Published Online: September 1, 2025. https://doi.org/10.4088/JCP.25lr15978a
© 2025 Physicians Postgraduate Press, Inc.
J Clin Psychiatry 2025;86(4):25lr15978a
To Cite: Bender DA, Nayak SM, Siegel JS, et al. Psychedelic therapies: one drug, multiple treatments: reply to Modesto-Lowe et al. J Clin Psychiatry 2025;86(4):25lr15978a.
Author Affiliations: The University of Texas at Austin Dell Medical School, Austin, Texas (Bender); Washington University School of Medicine, Saint Louis, Missouri (Bender, Siegel, Ercal, Lenze); The Johns Hopkins University School of Medicine, Baltimore, Maryland (Nayak); NYU Langone Center for Psychedelic Medicine, Department of Psychiatry, New York University Grossman School of Medicine, New York, New York (Siegel); Columbia University Vagelos College of Physicians and Surgeons, New York, New York (Hellerstein); New York State Psychiatric Institute, New York, New York (Hellerstein).
Corresponding Author: David A. Bender, MD, The University of Texas at Austin Dell Medical School, Department of Psychiatry, 1501 Red River Street, Austin, TX 78712 ([email protected]).
Relevant Financial Relationships: Relevant financial relationships are listed in the article discussed in this letter [J Clin Psychiatry;86(1):24m15521].
Funding/Support: None.
ORCID: David A. Bender: https://orcid.org/0000-0001-9842-2110

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