Reply to "Capturing Synergy Holistically in Psychedelic Clinical Trials".

The authors respond to commentary on their article about synergy in clinical trials of psychedelics combined with psychotherapy. They maintain that synergy is properly defined as the whole being greater than the sum of its parts, determined by effects on quantitative outcomes, not as a process. They argue that once synergy is demonstrated, examining its mechanisms becomes important. They propose that psychedelics and psychotherapy may mutually reinforce each other through increased neuroplasticity and psychosocial processes like openness to change. They emphasize three principles for designing informative, unbiased, and reproducible psychedelic trials, warning against hype and uninformative results.

Study at a glance

Abstract

We appreciate the opportunity to respond to the comments1 on our article2 and discuss the argument that “synergy is not just an outcome; it is also a process, and focusing just on outcomes may risk detracting from a holistic, accurate assessment of synergistic phenomena.”1 As defined in dictionaries and in the clinical and statistical literatures, synergy is considered present when the “whole is greater than the sum of its parts.” This determination is based on the effects of treatments or other variables on a quantitative assessment of outcome. The comments on our article did not provide an alternative definition of synergy as a process or an example of such so-called synergy.1 Indeed, those comments1 reference articles that emphasize “potential” synergy in their titles, and that appear to consider this synergy as overlapping or interacting processes, which is very different from our standard approach to this concept. It is therefore difficult for us to know how our focus on evaluating whether outcomes providing evidence of synergy might detract from holistic assessments of synergistic phenomena. Nevertheless, we believe that once the presence of synergy has been demonstrated in clinical trials of psychedelics combined with psychotherapy, examining the putative processes or mechanisms accounting for such synergy will become an important research objective. The pharmacologic effects of psychedelics may be enhanced by the set and setting provided by psychotherapy and the therapeutic benefits of psychotherapy may be augmented by the cognitive and affective effects of psychedelics. Indeed, both psychedelics and psychotherapy may increase neuroplasticity as well as psychosocial processes, such as openness to experience and readiness to change. It is therefore possible that such mutually reinforcing processes could explain why the benefits of a psychedelic combined with psychotherapy might be superior to the sum of the effects of each of these treatments administered alone. For this reason, studies designed to determine the mechanisms that explain any such synergistic effects on outcomes will be critical to identify optimal approaches to providing psychedelics combined with psychotherapy. We conclude by emphasizing three important principles that should guide the design, execution, analysis, and interpretation of clinical trials of psychedelics, including 2 × 2 factorial trials of synergy. As recently emphasized, uninformative trials provide “results that are not of meaningful use for a patient, clinician, researcher, or policy maker (and) present a challenge to ethics, science, and medical practice.”3 It is therefore imperative that the design and analysis of psychedelic trials be as informative and free of bias as possible, and that the interpretation of these trials be free of hype.4 During the past decade, increasing attention has been devoted to concerns about the reproducibility of scientific research. An overview of these concerns is provided in Figure 1,5 and careful attention to these threats would increase the reproducibility of psychedelic clinical trials. Preparation of these comments was supported by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks and Pediatric Anesthesia Safety Initiative (ACTTION/PASI) public-private partnership with the US Food and Drug Administration (FDA), which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, philanthropy, royalties, and other sources (a list of industry sponsors can be found at https://www.acttion.org/partners). R.H.D. has received in the past 5 years research grants and contracts from the US Food and Drug Administration and the US National Institutes of Health, and compensation for serving on advisory boards or consulting on clinical trial methods from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, Beckley, Biogen, Biohaven, Biosplice, Boston Scientific, Braeburn, Cardialen, Centrexion, Chiesi, Chromocell, Clexio, Collegium, CoimbiGene, Confo, Decibel, Editas, Eli Lilly, Endo, Ethismos (equity), Eupraxia, Exicure, GlaxoSmithKline, Glenmark, Gloriana, Hope, Juca, Kriya, Lotus, Mainstay, Merck, Mind Medicine (also equity), Neumentum, Neurana, NeuroBo, Novaremed, Novartis, OliPass, Orion, Oxford Cannabinoid Technologies, Pfizer, Q-State, Reckitt Benckiser, Regenacy (also equity), Rho, Sangamo, Sanifit, Scilex, Semnur, SIMR Biotech, Sinfonia, SK Biopharmaceuticals, Sollis, SPM Therapeutics, SPRIM Health, Teva, Theranexus, Vertex, Vizuri, and WCG. M.P.M has received research funding from the National Institutes of Health, the US Food and Drug Administration, Cure SMA, and PTC Therapeutics. He has received consulting fees from NeuroDerm, Ltd. and Fulcrum Therapeutics, Inc. He has served on Data and Safety Monitoring Boards for the National Institutes of Health, Eli Lilly and Company, Catabasis Pharmaceuticals, Inc., Vaccinex, Inc., Neurocrine Biosciences, Inc., Voyager Therapeutics, Prilenia Therapeutics Development, Ltd., ReveraGen BioPharma, Inc., and NS Pharma, Inc. S.M.N is a co-investigator on a study of psilocybin for major depressive disorder funded by Usona Institute and has received funding via The Center for Psychedelic and Consciousness Research from the Steven and Alexandra Cohen Foundation, Tim Ferriss, Matt Mullenweg, Blake Mycoskie, and Craig Nerenberg. E.C.S. has consulted, done work for, received study support from, or served on advisory boards to the following organizations: Cerevel, Fast Track Drugs and Biologics, Masimo/Innovative Health Solutions, Otsuka, Pear Therapeutics, UpToDate, and Wolters Kluwer. The views expressed are those of the authors, and no endorsement by the FDA should be inferred. The organizations and individuals that have provided support for the ACTTION/PASI public-private partnership with the FDA had no role in the preparation of this article or in the decision to submit it for publication.