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Psychedelics and Psychotherapy: Is the Whole Greater than the Sum of its Parts?

2023; Wiley; Volume: 114; Issue: 6 Linguagem: Inglês

10.1002/cpt.3050

1532-6535

Robert H. Dworkin, Michael McDermott, Sandeep M. Nayak, Eric C. Strain,

Neurotransmitter Receptor Influence on Behavior

Clinical trials of psychedelics have provided support for their potential efficacy and safety. Although most combined a psychedelic with psychological support akin to psychotherapy, providing psychotherapy is costlier and more difficult to scale than providing only support to reduce harms. Trials with factorial designs can evaluate the individual effects of a psychedelic and psychotherapy and any synergistic interaction between them. Such trials would provide an important evidence base for developing safe and cost-effective psychedelic treatments. Psychedelics, such as psilocybin, have received increasing attention over the past 2 decades as potential treatments for a variety of medical conditions, including depression, anxiety disorders, chronic pain, and migraine and cluster headache.1-5 This is undoubtedly a result of several factors, including promising results of early clinical trials, generally modest efficacy of existing treatments for these conditions, and provocative reports in the popular press. Despite this enthusiasm, critically important questions about psychedelics remain unanswered, especially confirmation of efficacy and safety in phase III trials as well as mechanisms of action, appropriate contexts of use, and methodologic challenges, including blinding integrity.3-5 In addition, future clinical trials will need to examine the potential roles of postdosing neuroplasticity from psychedelics6 and of home and other environmental factors7 in accounting for whether treatment benefits persist. In these comments, we focus on "classic" psychedelics administered as single doses that typically cause marked perceptual effects and alterations in consciousness (e.g., psilocybin, mescaline, and LSD) primarily via serotonin 2a agonism. These are distinct in mechanism from other agents with somewhat similar subjective effects (e.g., ketamine and MDMA). However, many of the issues we discuss are applicable to these other medications as well as to "microdosing."1 Clinical trials of classic psychedelics conducted during the past 2 decades have typically randomized patients to 1 or 2 doses of a psychedelic vs. an inert placebo or other treatment intended to make it more likely that patients and investigators will remain blinded to the treatment allocation (e.g., a stimulant, sedative-hypnotic, or lower psychedelic dose).3 In most of these trials, patients also received some type of psychotherapy or supportive counseling, with preparatory visits that began before the psychedelic was administered and that often continued for several weeks thereafter. The specific type of psychosocial support provided has been heterogeneous, including cognitive-behavioral, supportive, and motivational therapies. Although we acknowledge there can be debate about the precise nature of the psychological interventions offered in psychedelic trials,2 we argue that these frequently share such factors common to all psychotherapies as the importance of the therapeutic relationship, the healing setting, and an overarching therapeutic rationale.8 Thus, for the purposes of this paper, we refer to these psychological interventions as psychotherapy. Several different assumptions have been made about the benefits of combining psychedelics with support or therapy. Foremost among these is safety; even in the controlled environment of clinical trials, for some individuals, psychedelic experiences can be frightening, including anxiety, hallucinations, and paranoia.1 In addition, adverse cardiovascular events have been reported in individuals taking classic psychedelics.5 For these reasons, careful preparation of patients enrolled in clinical trials and the presence of trained monitors during the psychedelic session are considered essential to minimize harms.5 Many investigators also believe that providing psychotherapy in combination with a psychedelic enhances the magnitude and duration of the benefits of the psychedelic. For this reason, preparatory psychotherapy beginning before the psychedelic session, one or two therapists accompanying the patient during the session, and integrative psychotherapy following the session is a common approach, with the total number of pre- and post-treatment visits ranging widely.2 The combination of a psychedelic and time-limited psychotherapy to maximize treatment benefits must be distinguished from the combination of a psychedelic and the support required to reduce the risk of adverse events.4 These two broad approaches to psychedelic treatment require different resources, and providing even time-limited psychotherapy is more costly and more difficult to scale than only providing support to minimize harms. It has been suggested that the specific pharmacology of psychedelics works synergistically with the context in which they are administered, and that enriched contexts, such as psychotherapy, will be associated with greater benefits of the psychedelic.7 It is therefore possible that benefits of a psychedelic combined with psychotherapy could be substantially greater than the benefits of a psychedelic alone and that the increased costs and other challenges would be worthwhile. For this reason, informative evaluations of such synergies are needed to determine optimal approaches to providing psychedelic treatment and their benefits, risks, and cost-effectiveness. This information will be critically important to patients, clinicians, regulatory agencies, and the government and other organizations that would cover the costs of such treatment. But what exactly is meant by synergy and how can it be evaluated? True synergy is present when the effect of a combination treatment is superior to the sum of the effects of its individual components, or as attributed to Aristotle, "the whole is greater than the sum of its parts." In contrast, additivity is present when the effect of the combination equals the sum of the effects of its components, and subadditivity is present when the effect of the combination is less than the sum of the component effects.9, 10 A combination effect that is subadditive but greater than the effect of each of its components can be considered "favorable" subadditivity, whereas a combination effect that is less than (or equal to) the effect of each of its components can be considered "adverse" subadditivity. Randomized clinical trials with factorial designs make it possible to evaluate the individual effects of two (or more) treatments as well as any synergistic or subadditive interaction between them in a single trial. In a 2 × 2 factorial trial of a psychedelic and time-limited psychotherapy, patients would be randomized to four different groups (see Figure 1): (i) double placebo condition (placebo drug plus psychotherapy control); (ii) psychotherapy alone (placebo drug plus psychotherapy); (iii) psychedelic alone (psychedelic plus psychotherapy control); and (iv) combination treatment (psychedelic and psychotherapy). In such a trial, we assume that steps would be required for all groups to reduce the risk of adverse events, such as patient education and a low threshold to pharmacologically abort drug effects in the event of marked distress. These steps would ideally be designed to limit as much as possible the characteristics of the psychotherapy that are hypothesized to synergize with the psychedelic. In addition, careful consideration would need to be given to the psychotherapy control, including the extent to which nonspecific factors, such as expectations and re-assurance, can be addressed. As emphasized by the US Food and Drug Administration (FDA) in a recent draft guidance on psychedelics, a factorial design makes it possible to evaluate "the separate contributions of drug and psychotherapy to any observed treatment response."5 Importantly, the data from a factorial trial also make it possible to test the hypothesis that the combination of a psychedelic and psychotherapy is truly synergistic, with its benefit exceeding the sum of the benefits of each of these treatments administered alone. Although synergy may be rare for medical treatments, it is a plausible hypothesis that the benefits of combining a psychedelic with psychotherapy will show synergy. First, it is possible that the psychedelic itself exerts therapeutic effects by a psychotherapeutic mechanism, namely via affective and cognitive effects. Second, psychedelics may acutely increase neuroplasticity, which could facilitate change from ongoing psychotherapy. The psychedelic session could also enhance the benefits of psychotherapy by increasing openness to experience, readiness to change, and other factors associated with psychotherapeutic improvement.7, 8 These are not mutually exclusive mechanisms, and, for many years, the predominant orientation of psychedelic-assisted psychotherapy has involved such mutually reinforcing processes. In conducting a standard 2 × 2 factorial trial to evaluate the magnitude or duration of therapeutic benefit of a combination treatment, the dosages or number of therapy visits of the component treatments would be kept the same in all conditions, that is, whether the treatment is administered in combination with the other active treatment or with its control. This design can be contrasted with other approaches that would examine whether the benefits of combination treatment could involve lower dosages of one or more of the components compared with dosages used for monotherapy.10 In addition, other combinations could be intended to decrease risks, as noted above (e.g., providing just support with psychedelics to minimize harms), or to enhance compliance with one or more components (e.g., by increasing tolerability or convenience). Depending on the specific clinical trial design, such benefits may not demonstrate true synergy, nor would studies showing that combination treatments are superior to one of more of their components. These can all be important research objectives, but it is beyond our scope to discuss the clinical trial designs that would evaluate such benefits of psychedelic treatment. We conclude by emphasizing the critical importance of conducting informative clinical trials with factorial designs of psychedelics and psychotherapy. Although there are many examples of uninformative clinical trials, one common problem arises from inadequate sample sizes and statistical power. Factorial trials of combination treatments need large sample sizes to detect even moderate interactions with adequate power, and must consider the impact of missing data and treatment noncompliance.9 Such trials require considerable resources, but they can provide informative evaluations of treatment efficacy (including synergy) and safety. There is a substantial public health burden of psychiatric disorders, chronic pain, and other conditions that can have adverse effects on quality of life. If clinical trials demonstrate that the benefits of combining psychedelics and psychotherapy are truly synergistic, this treatment approach has the potential to improve the well-being of large numbers of patients around the world. Preparation of this article 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 FDA 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 FDA, 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.