Psychedelics in Psychiatry: Oh, What A Trip!

Thirty years after publication of the first peer-reviewed studies of the effects of dimethyltryptamine in healthy volunteers (1, 2) and nearly 20 years after publication of the first study of psilocybin administration to individuals with obsessive-compulsive disorder in the modern post-prohibition era (3), we are delighted to introduce this special issue of the American Journal of Psychiatry on psychedelics. This marks a moment of legitimacy for what was once considered a fringe, fledgling movement driven solely by a select group of zealously dedicated scientists and clinicians (4). In contrast to this early nascent period, the enthusiasm, interest, and pursuit of scientific and medical research on the psychiatric applications of psychedelic compounds has exploded in recent years, leading to the declaration of the current phase as a “renaissance” period for psychedelic research (5). There is objective data to support this view. The combined sample size across all modern-era published clinical trials evaluating a psychedelic compound for treatment of one or more mental health conditions now exceeds 1,000 (with the largest representation, by far, being those participating in psilocybin studies), and commercial investments in psychedelic drug development now number in the billions of dollars (6). Psychedelic clinical trials are now routinely published in very high-tier biomedical journals, including the New England Journal of Medicine (7, 8) and Nature Medicine (9, 10). However, despite these markers of the field’s transition to a greater state of maturity, fundamental questions and methodological challenges remain unanswered and in critical need of additional research. Sufficiently addressing and answering these scientific and clinical questions will be critical for the future clinical success of these agents.

This issue of the Journal addresses many of the ongoing challenges and looming questions in the field of psychiatric psychedelic research and treatment. These include issues relevant to basic pharmacology and effects on neural circuits, evidence of clinical efficacy, methodological challenges/limitations of existing research, and contextualizing factors pertaining to public health and policy considerations. A review by McIntyre et al. (11) addresses general methodological considerations that impact the interpretation of existing psychedelic clinical trial data and provides recommendations to address fundamental unanswered questions regarding durability of effects, safety, dosing, and cost-effectiveness. Ramaekers et al. (12) then review existing evidence for clinical efficacy of ultra-fast, short-acting psychedelic compounds (dimethyltryptamine and 5-methoxy-dimethyltryptamine) in the treatment of depression and discuss the potential future flexibility in clinical care delivery models afforded by such short-acting compounds in a post-approval landscape. Ghaznavi et al. (13) review the critically important but often overlooked element of potential harms associated with psychedelic treatments, which range from common mild adverse events to rare but potentially serious psychiatric decompensation and life-threatening cardiac effects. In the first of two drug-specific deep-dives, Fonzo et al. (14) provide a systematic review of the evidence base for psilocybin in the treatment of psychiatric disorders and identifies major depression as the indication with the strongest evidence base. The authors emphasize that conclusions from the studies must be tempered by key limitations such as insufficient blinding, large variability in dosing and psychological procedures, threats to generalizability, and possibly large expectancy effects. Wolfgang et al. (15) provide a similar in-depth review of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy, highlighting distinctions in scientific and clinical findings of recreational MDMA use versus therapeutic MDMA use while underscoring the importance of not conflating the two separate use cases for risk/benefit analysis.

In the first of a series of commentaries, Mian et al. (16) propose a three-dimensional public policy framework for assessing psychedelic use, with potential implications for future models of access and delivery in a rapidly shifting U.S. legal framework. This framework currently spans strict illegality to managed systems for religious and recreational use. Olson (17) addresses the translational gap associated with measuring psychedelic-induced increases in neuroplasticity in humans using a novel radioligand for synaptic vesicle 2A with noninvasive brain imaging. This method may provide a key translational bridge from in vitro (18, 19) and animal model findings (20, 21) of psychedelic mechanisms of neuroplasticity to assessing presence and therapeutic contribution of similar ostensible effects in human clinical studies. O’Donnell et al. (22) then tackle the longstanding division between scientists/researchers and clinicians in postulating and conceptualizing therapeutic mechanisms of action, calling for an attitude of humility to facilitate greater crosstalk and collaboration as well as multidisciplinary measurement approaches incorporating not only basic and clinical neuroscience but also potential effects of idiosyncratic patient-therapist dyadic relationships. Wolfgang et al. (23) provide a brief and informative summary of outcomes and initiatives emerging from a recent Department of Veterans Affairs State of the Art Conference on Psychedelic Treatments for Mental Health Conditions. This meeting established a research framework to understand mechanisms of action, safety, and efficacy of psychedelic therapies as well as a clinical implementation framework to potentially scale up this treatment modality (pending possible future FDA approval) in Veterans Affairs hospitals.

As for the original research presented in this issue, Aaronson et al. (24) describe positive findings from an open-label trial of psilocybin treatment in individuals with severe treatment-resistant depression, i.e., documented failures of five or more treatments. Pagni et al. (25) provide a secondary analysis of a previously published randomized clinical trial of psilocybin versus diphenhydramine for alcohol use disorder (26), showing that psilocybin promotes long-term changes in key personality characteristics that are theoretically and empirically related to psychiatric disorder development and treatment. This special issue concludes with an in-depth description of the theory, development, implementation, and fidelity assessment of the psychological support model (27) developed by COMPASS Pathways for their phase two and three studies of COMP360 (synthetic psilocybin). This was developed with the regulatory approval-motivated intent to ensure participant safety with minimal contribution of the psychological component to therapeutic drug effects.

A survey of this issue’s Table of Contents impresses upon the reader the highly multifaceted and interdisciplinary scope of inquiry required to sufficiently characterize the basic, clinical, and public health facets of psychedelic therapeutics. This diverse approach brings together scientists and clinicians of various professional backgrounds with sometimes disparate views on mechanism of action, role of drug versus therapy in centrality of therapeutic benefits, and various other considerations with a common goal of addressing these critical questions. However, there is considerable agreement that the unanswered questions are numerous, critically important to the evolution of the field, and can only be addressed with the continued generation of high-quality clinical and scientific data with clever study designs aimed at providing much-needed answers.

There are key challenges inherent to psychedelic research that remain to be addressed (28), as exemplified by issues recently raised at the FDA Psychopharmacologic Drugs Advisory Committee hearing for the approval package submitted for midomafetamine (MDMA) by Lykos Therapeutics. There was an overwhelming negative vote by the panel regarding both demonstration of efficacy (nine against vs. two for) for the treatment of PTSD and favorable risk/benefit ratio (10 against vs. one for). This decision foreshadowed an eventual rejection of the Lykos Therapeutics application by the FDA 2 months later in the form of a Complete Response Letter (CRL), which has not been made publicly available at the time that this commentary was written. Key methodological issues raised included possibly large expectancy effects and functional unblinding (exacerbated by the high percentage of participants in these trials with prior MDMA experience), both of which present ongoing challenges in conducting adequate and well-controlled studies of psychedelic compounds (29–31). Another key issue was related to the short- and long-term safety and efficacy of the treatment approach, which was compounded by a lack of rigorous safety data collection and toxicity testing and insufficient long-term monitoring of therapeutic benefits. As echoed in the Advisory Committee, another important consideration for future efforts at regulatory approval and clinical trial design will be the role of the drug (regulated by the FDA) versus the psychological support/therapy component (likely not to be FDA-regulated) versus the interaction of the two in promoting therapeutic effects, a question which has generated much debate (32, 33) but which remains to be teased apart empirically. This is not only an important scientific question to guide clinical implementation (34) but is especially noteworthy in the context of recent FDA guidance calling for measurement of how the psychological component of psychedelic treatments contributes to therapeutic effects, expectancy, and performance biases (35). The field will need to creatively contend with these design issues as more studies are designed and launched, more high-quality data accumulates, and more compounds reach the potential cusp of FDA approval.

There are no clear or readily apparent options for how to maintain blinding in a safe and effective manner in the absence of inducing active comparator-specific side effects or unintended therapeutic benefits beyond the pure placebo effect, as might occur with low doses of active compounds or other active comparators. The question regarding short- and long-term safety of psychedelic compounds continues to loom large given state and locale-specific relaxation of legal prohibitions (36, 37), which allow for use that is largely removed from the medical safeguards that are in place in clinical trials. Coinciding with the loosening of legal prohibitions in certain localities is a prominent increase in rates of nonmedical/non-research psychedelic usage in both adolescents and adults (38, 39), along with increasing awareness of the potential severity and extent of harms associated with psychedelic use. These can range from common transient challenging psychological experiences (40) to, in rarer cases, mania/psychosis (41, 42), distressing persistent perceptual alterations (43), and adverse effects on the cardiovascular system, particularly in the case of chronic dosing (44). Relatedly, knowledge and evidence for presence or absence of drug-drug interactions continues to grow but remains underdeveloped (45–49), particularly in the context of efforts to seek regulatory approval in treatment-resistant populations that are likely to already be taking one or more psychiatric medications.

A hotly debated argument concerns the need for the psychedelic experience per se to promote therapeutic benefit (50, 51), with both preclinical evidence (52) and a fortuitously informative case report (53) suggesting that therapeutic effects may occur in the absence of the altered state commonly known as the “psychedelic experience.” These and other data have led to the undertaking of clever study designs in patient populations to block the psychedelic effect using targeted pharmacology in the hopes that therapeutic effects persist (54). There are also ongoing efforts to better characterize the safety and potential clinical benefits of chronic low-dosing (“microdosing”) of psychedelic compounds (55–57), which may offer another avenue toward harnessing therapeutic properties in the absence of the profound alterations in consciousness promoted by the moderate-to-high doses that have demonstrated the most convincing therapeutic effects. Other efforts, based upon drug development and preclinical findings (58, 59), are targeted toward bringing to human testing novel psychedelic derivative compounds that promote neuroplasticity (and ostensible therapeutic effects) in the absence of subjective consciousness-altering effects. The ability to decouple the powerful, typically long-lasting subjective effects from therapeutic benefits that are promoted by psychedelic compounds would be a potential game-changing development. This could obviate the need for the complicated, time-intensive delivery paradigms that are currently the mainstay of psychedelic treatments and spare some individuals the discomfort of challenging psychedelic experiences and associated adverse effects. Relatedly, a modified approach that maintains the psychedelic experience but improves upon the current time-intensive delivery paradigm employs rapid-acting, short-duration compounds such as dimethyltryptamine (60–62) and 5-methoxy-dimethyltryptamine (63–65). Both compounds are currently being investigated in clinical studies, and both have substantially shorter durations of subjective effect (∼90 min). However, the key question is how effective these short-acting treatments are compared with the more tried-and-true classical psychedelic administration with the accompanying hours-long subjective “trip.” The field awaits the data that will resolve this ongoing controversy.

There are additional ethical issues with which to contend. Given the unique, powerful, and unpredictable effects of psychedelics, a heightened degree of participant vulnerability to abuses of power or coercion can occur. The nature of the psychedelic experience, given the unpredictability of effects, is also difficult—if not impossible—to adequately convey in words during informed consent of trial participants. Standards in procedures and professional behavior will have to be established in training individuals to work with trial participants in altered states of consciousness (66, 67). Concerns have also been raised regarding the promotion of health equity in a post-approval landscape (68), which is a very realistic concern given the existing inequities that largely plague psychedelic and other forms of biomedical research (limited sociodemographic and ethnic diversity) and which may be exacerbated by the extremely high projected costs of such treatments once FDA-approved.

There is clearly no shortage of issues with which researchers and clinicians must contend in pushing forward psychedelic science to optimally benefit patients in desperate need of additional safe, rapid-acting, and durable psychiatric treatment options. In addition to the numerous unanswered questions and a desire for greater clarity, most would agree that the traditional federal funding mechanisms (the National Institutes of Health and National Science Foundation) need to increase support for critical studies that are necessary to generate data to address many of the questions presented here (69).

The potential for therapeutic strategies utilizing psychedelic drugs is exciting and yet there is a long path ahead toward clinical success. We believe that it is important to honor the journey to this point, spanning multiple generations, several decades, and countless hours of work by numerous individuals. In this spirit, we hope this special issue of the American Journal of Psychiatry on psychedelics will be the first of many more to come over the next decades and generations.