Challenges with clinical trial participants in studies with classical psychedelics: A position statement from the National Network of Depression Centers’ task group on psychedelics and related compounds

Abstract

Rationale:

Classical psychedelics—a broad class of compounds that include psilocybin, lysergic acid diethylamide, dimethyltryptamine, and mescaline—have shown significant promise for the treatment of mental health conditions in recent clinical trials. Organizations such as the National Network of Depression Centers (NNDCs) can play a pivotal role in uniting researchers and clinicians working in this field to explore and synthesize existing evidence as well as characterize emerging challenges.

Objectives:

We outline several categories of challenges that have emerged in the context of clinical trials with psychedelic drugs, drawing from our collective empirical observations as well as the extant literature. While these challenges have been presented in the context of clinical trial environments, many of them are likely to persist if and when psychedelic treatments become approved and are implemented in psychiatric clinical practice.

Results:

We describe four categories of challenges in the context of clinical trial participants—(1) treatment nonresponse, (2) expectancy effects and functional unblinding, (3) post-session psychological difficulties, and (4) contagion effects—and provide management strategies for study teams to mitigate associated risks.

Conclusions:

Classical psychedelics show therapeutic promise as mental health treatments. Studying them properly presents unique and unprecedented challenges that require researchers to develop sophisticated strategies to navigate nonresponse, expectancy effects, functional unblinding, post-session psychological issues, and possible contagion effects to responsibly advance this field. The NNDC and similar organizations are well-positioned to guide best practices and ensure the responsible advancement of this promising field.

Introduction

Classical psychedelics are a broad class of compounds that include psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine, and mescaline. At therapeutic doses, these agents produce robust subjective effects that are described as substantially altered states of consciousness mediated by their action on the serotonin 2A receptor (5HT2AR). Clinical research with classical psychedelics for the treatment of mental health conditions is progressing rapidly, spanning potential indications for major depressive disorder (MDD), treatment-resistant depression (TRD), generalized anxiety disorder (GAD), postpartum depression, substance use disorders, and adjustment disorders secondary to serious medical illness (Andersen et al., 2021; Borgogna et al., 2025; Correa Da Costa et al., 2025; Dos Santos et al., 2018; Schipper et al., 2024; Yao et al., 2024). Phase 3 trials are currently underway for psilocybin (TRD and MDD) and LSD (GAD and MDD). While firm conclusions regarding the efficacy of this pharmacological class depend on outcomes from these larger trials, evidence from the clinical trials conducted to date has demonstrated an acceptable safety profile and promising preliminary evidence of sustained efficacy following 1–3 doses accompanying multiple study visits that may or may not include formal psychotherapy. However, additional and more definitive clinical trials are still needed to replicate and fully characterize potential adverse events (AEs) as well as the prevalence of short- and longer-term risks—such as the rare but concerning increase in suicidal ideation observed in TRD patients receiving an ostensibly psychoactive dose. (Goodwin et al., 2022; Gukasyan, 2023).

Organizations such as the National Network of Depression Centers (NNDCs) can play a pivotal role in uniting researchers and clinicians working in this field to explore and synthesize existing evidence as well as characterize emerging challenges. Here, we outline several categories of challenges that have emerged in the context of clinical trials with psychedelic drugs, drawing from our collective empirical observations as well as the extant literature. While these challenges are presented within the context of clinical trial environments, many of them are likely to persist if psychedelic treatments become approved and are implemented in psychiatric clinical practice.

We present key categories of challenges present in the context of clinical trial participants: (1) treatment nonresponse, (2) functional unblinding and expectancy effects, (3) post-session psychological difficulties, and (4) contagion effects. We also provide management strategies for study teams to mitigate risks associated with each category of challenge. We recognize the early stage of the science for many of these recommendations, and that there is a multiplicity of strategies that might be employed in addressing these challenges. As such, we have kept our recommendations general and oriented toward suggestions that might be useful for study teams.

Methods

The NNDC is a collaboration among 27 leading academic medical centers across the United States, with 11 task groups dedicated to focused areas of interest. The NNDC Task Group on Psychedelics and Related Compounds is comprised of psychiatrists, psychologists, neuroscientists, psychedelic researchers, and leaders in healthcare consulting and includes approximately 50 active members who are representatives of their institutions with specific expertise in psychedelics. All task group members were invited to contribute to the report. No ethics committee approval was required for the writing of this article. The group achieved consensus on the categories of clinical trial challenges through collaborative monthly discussions, literature review, and iterative drafting in the same fashion as our earlier consensus statement regarding integrating psilocybin interventions into clinical care (Hosein et al., 2025). While meeting attendees all contributed to the discussion, the current authorship reflects contributors to the article. Study participants were not directly included in the conceptualization, but relevant literature as to participant experience and perspectives is cited. While the NNDC is focused primarily on improving the lives of those affected by depression and related mood disorders, our analysis is focused more broadly on psychedelic clinical trials across a range of indications, recognizing that a majority of this work is focused on the treatment of depressive disorders.

Challenge 1: Treatment nonresponse

While classical psychedelic interventions have shown large effect sizes following both single and repeated treatments, a substantial portion of individuals who experience subjective drug effects but do not experience a therapeutic response. There are several forms of nonresponse worth mentioning: (a) absence of significant clinical improvement at any time point, (b) significant improvement that is short-lived; that is, lack of durable response, and (c) not having an expected psychoactive experience with the study drug (which may or may not correlate with lack of symptomatic improvement). While acute experiential effects of classical psychedelics have been shown to correlate with therapeutic outcomes, there remain many questions as to the nature of this relationship and its consistency and therapeutic relevance (Goodwin et al., 2025; Ko et al., 2022; Olson, 2021; Yaden and Griffiths, 2021). Although the science of predicting treatment response to psychedelics is in its infancy, it is reasonable to assert that a host of biological, psychological, social, and contextual reasons may account for a lack of actual or perceived response (Gukasyan, 2023). In addition, it may be possible that previous exposure to serotonergic antidepressants as a class or specific compounds within this class—which are generally, but not always, tapered off in the context of clinical trials—may blunt therapeutic response to classical psychedelics—affecting not only experiential elements but possibly limiting therapeutic effect. However, evidence is somewhat contradictory on this point (Goodwin et al., 2022; Gukasyan et al., 2023; Marwood et al., 2024).

While all clinical drug trials contend with nonresponse, there are unique aspects of this phenomenon that manifest in psychedelic studies. For instance, pre-treatment expectations with psychedelic interventions can be heavily influenced by media and online platforms, associated with exaggerated hopes and over-promising outcomes. This has been termed “The Pollan effect,” in reference to Michael Pollan’s 2018 book How To Change Your Mind, which had a disproportionate effect on public conceptions of psychedelic drugs (Noorani, 2020b; Pollan, 2019). The changing legislative landscape and associated advocacy efforts, particularly at the state and local levels, provides a level of legitimization, normalization, and institutional acceptance of psychedelic use that also influence the likelihood of unrealistically high expectations for these treatments, which can then set up study participants for crushing disappointment when they do not experience the effects or benefits they anticipated, particularly when participants have already attempted and not experienced benefit from a number of approved antidepressant and other psychiatric interventions.

Challenges arise when study participants have an initial treatment response that does not prove durable, such that effects wane and symptoms return. While these issues are again present in many investigational drug trials, the legal landscape with psychedelics introduces additional issues or risks for study participants. In most cases, it is not possible to access re-treatment with the psychedelic in a legal, medically supportive, and psychologically safe setting. In this instance, some participants may be inclined to seek out psychedelics through underground means, or in jurisdictions with either legalization measures in place (e.g., Oregon, Colorado, and Portugal) or an accepted market for psychedelic availability (e.g., Costa Rica and Jamaica). This raises additional ethical issues with regard to preventing future harms from a potentially poorly delivered re-treatment effort with substances of unknown purity and composition, and with potentially unskilled or inadequately trained, prepared, or resourced facilitators. The possible efficacy of such re-treatments following relapse also remains poorly understood from a scientific and medical perspective, especially when delivered outside the context of highly controlled research settings where outcomes (both therapeutic and harmful) are not being systematically tracked and reported.

Risks of negative outcomes following non-response may be elevated in more vulnerable psychiatric populations. For instance, in the Phase 2b study of psilocybin for TRD, sponsored by COMPASS Pathways, suicidal ideation and behavior were observed in several study participants (1.9% of 154 who received psilocybin at 10 or 25 mg), representing a concerning early risk signal. All three participants were noted to be non-responders at 3 weeks post-treatment (Goodwin et al., 2022), and all of whom received an ostensibly psychoactive dose (10 or 25 mg). A TRD population is predisposed to a greater risk of suicidal ideation, and it is worth noting that these initial signals of suicidal ideation from the COMPASS Pathways trials remain low, relative to population reports of suicidal ideation in TRD (Kern et al., 2023) and completed suicide in patients with TRD. It is estimated that 30% of patients with TRD will attempt suicide at least once in their lifetime (Bergfeld et al., 2018), and prior studies have shown a 7.3% prevalence of past-year suicide attempts in this population (Rhee et al., 2024). Thus, it may be that this population may be especially vulnerable to the risk of suicidal ideation after non-response to a psychedelic intervention.

Despite reassurance and scientific and therapeutic equipoise, study participants may nonetheless feel that to some extent they have “let down” their study therapist or team, given the intensive, and even intimate, nature of the dosing and psychedelic processing and the psychological vulnerability that participants can experience during this process (Noorani, 2020a). Participants may also feel some degree of responsibility toward the broader efforts to mainstream psychedelic medicine and concomitant approval pathways (Labate et al., 2025; Schlag et al., 2022). This may be less prominent in pure pharmacological intervention studies (e.g., studies with no psychotherapeutic or interpersonal component) but may be more prominent in studies utilizing psychotherapy or intensive device-based intervention(s) necessitating frequent and/or prolonged contact with study personnel. In essence, strong interpersonal bond formation between the patient and research staff elevates the likelihood of negative demand characteristics.

Challenge 1. Management strategies

Study teams should emphasize the distinction between research and clinical environments and the distinction between pure, pharmaceutical-grade drugs (likely to be utilized in clinical trials) vs. natural products or illicit synthetic compounds (unlikely to be utilized in clinical trials, or to have the same expected risk or benefit profile as a pharmaceutical) in relation to psychedelic interventions. Study teams and investigators should also deliberately and repeatedly emphasize the preliminary nature of existing research and the evidence base. While positive expectancy may be a critical engagement piece, study participants should be reminded repeatedly of the possibility of minimal or no treatment response. This messaging can be framed in terms of scientific equipoise: all data obtained from the trial are not only useful, but essential, and these include nonresponse, disappointing/incomplete response, and AEs. Participants should be educated that it is through their openness and honesty that they contribute most to the psychedelic research effort. It may also be fruitful to counteract amplified expectations by having an open discussion with study participants about both media bias and therapeutic misconception. Emphasis that media coverage is often highly distilled and oversimplified may be helpful, pointing out that this can have both a positive (in cases of successful treatment outcome studies) and negative slant (in the cases of AEs or unintentional harms). Individuals can then be invited to join in the effort to counteract this type of information via their participation in scientific truth-seeking. Extending these conversations to educating participants about publication bias and the role that it may play in fueling sensationalized media claims of transformative and seemingly universal efficacy may prove beneficial when it comes to enlisting participants as stakeholders and advocates of rigorous, transparent science.

Study teams, and especially therapists, facilitators, or dosing session monitors, need to explore and discuss expectations and hopes that participants have for their study participation. In addition, we need to assess a participant’s prior knowledge and experience with psychedelic drugs to, if needed, provide targeted mitigation of therapeutic misconception(s). It is essential and helpful to pre-emptively identify how participants usually deal with disappointments in life and discuss how this may impact their subjective response to the treatment process and its outcome, which may help to flag potential hopelessness or even suicidal ideation for early identification or intervention.

Investigators need to remain conscious and vigilant that nonresponse may increase the likelihood of suicidal ideation or self-harm, as may have occurred in the previously mentioned study (Goodwin et al., 2022). Study teams, therefore, should perform rigorous, densely-sampled risk assessment immediately following dosing and for several weeks thereafter; if concerns or difficulties are post-dosing, study participants may be provided with enhanced psychotherapeutic support to the degree possible, that is, maintaining study integrity via similar face time with psychotherapists or other permitted study-related support processes. Study teams should maintain a list of referrals, crisis lines, and resources in case of psychiatric emergency that can be given to all participants at the start of the study, as well as reviewed at intervals through the study period. Risk protocols that have been employed by study teams have included maintaining current emergency contact information, routinely identifying a person’s location and callback number when communicating remotely, conducting a Columbia Suicide Severity Rating Scale and/or safety evaluation at each study visit, and escalating immediately to a licensed clinician if and when any risk increase arises.

Many of these procedures are standard operating procedures among many interventional and observational studies, both within and outside of psychedelic science; therefore, psychedelic trials have a wealth of established protocols to draw upon to facilitate the development of a standardized protocol across study centers and sites. Additional design methods may be helpful to guard against negative or life-threatening outcomes as a result of initial non-response, including the availability of open-label dosing portions following the primary comparison period (though this does not guarantee therapeutic response during the open-label dosing period), provision of other forms of treatment at low or no-cost to study participants after the primary comparison period, and/or adaptive clinical trial designs allowing for flexible modifications to improve safety or efficacy prior to full study completion. While including open-label dosing portions in a clinical trial may be seen as a threat to equipoise, there have been compelling ethical arguments that can be made for not withholding this component, given the evidence for a potential positive and transformational outcome of psychedelic experiences in both healthy and patient populations (Jacobs et al., 2023; Yaden et al., 2022a). Furthermore, some studies have facilitated ongoing integration groups or meetings with study participants that go beyond the study conclusion as a means of providing additional support.

Challenge 2. Functional unblinding and expectancy effects

Functional unblinding and expectancy effects are interacting but conceptually distinct methodological challenges in psychedelic clinical trials (Muthukumaraswamy et al., 2021; Szigeti and Heifets, 2024). Functional unblinding occurs when participants can correctly guess their treatment assignment based on noticeable physical or psychological effects of an otherwise presumably “blinded” intervention, thereby undermining the intended masking integrity of randomized controlled study designs. Expectancy effects refer to changes in outcomes based on participants’ beliefs about the anticipated benefits or harms of treatment, independent of accuracy or relationship to treatment arm assignment. Whereas expectancy effects reflect belief-driven placebo or nocebo responses, functional unblinding introduces differential response bias that may amplify expectancy in that participants who correctly identify active treatment assignment may report greater improvement, whereas those who suspect placebo assignment may disengage or report reduced benefit.

The double-blind randomized controlled trial has been upheld as a standard of rigor in evidence-based medicine. The use of a placebo condition and blinding to study arm allocation is intended to maximize internal validity to strengthen causal inferences about active drug effects. Even though this study design is not without criticism (Cartwright, 2007, 2010; Deaton and Cartwright, 2018), it remains the gold standard for clinical drug trials moving through FDA approval pathways (Ioannidis, 2018). This presents significant challenges for clinical trials of compounds that reliably occasion very remarkable and unique subjective effects that are not easily replicated by other compounds with no expected therapeutic effects. These issues are not unique to psychedelic clinical trials, as they are challenges faced in all randomized clinical trials (Fergusson et al., 2004; Schenberg, 2024). For instance, in an older randomized controlled trials (RCT) of phenelzine versus imipramine versus placebo in the treatment of depression, 78% of participants and 87% of study clinicians could correctly identify who received active drug versus who received placebo (Rabkin et al., 1986). Regardless, this has become a central criticism of the psychedelics field and was included as one of the multiple critiques raised at the recent Food and Drug Administration (FDA) advisory committee meeting for 3,4-Methylenedioxymethamphetamine (MDMA)-assisted therapy in the treatment of post-traumatic stress disorder (Flameling et al., 2023; Roseman, 2024).

These concerns are also not new for the field as they presented significant challenges with the first wave of research into these drugs (Hall, 2022), particularly following the passage of the Kefauver–Harris amendments to the Federal Food, Drug, and Cosmetics Act which specified that the FDA could require proof of efficacy (instead of simply safety) for new drug approval, with an emphasis on randomized controlled trials and the establishment of phased clinical trials (Greene and Podolsky, 2012). This significantly constrained study design for psychedelic trials at the time and contributed to the waning research interest in this class of compounds (Oram, 2014, 2018). It has also likely contributed to a devaluation of more pragmatic and “real-world” study designs that could add to the psychedelic knowledge base (Carhart-Harris et al., 2022).

To address these study design challenges, modern studies have employed a range of “active placebo” controls acting on several alternative pharmacological mechanisms have been employed to mimic some of the acute effects of the intervention, including stimulants (methylphenidate and others), N-methyl-D-asparate (glutamate) receptor antagonists (dextromethorphan and ketamine), historical controls that elicit strong discomfort (high-dose niacin), and drugs that cause drowsiness (diphenhydramine; Colloca and Fava, 2024; Gukasyan, 2023; Gukasyan and Nayak, 2021; Hovmand et al., 2023; Muthukumaraswamy et al., 2021; Schenberg, 2024). Low-to-moderate dose psilocybin has also been used as a minimal treatment control to mimic the psychoactive effects in a sub-therapeutic range. Present-day strategies again accord with earlier clinical research in the field, which employed a range of active placebo strategies, including amphetamines and niacin (Cohen and Ditman, 1962; Oram, 2014; Smart et al., 1966). However, with the exception of different doses of the same active compound (for which the blinding efficacy remains unknown), these strategies have been largely ineffective in reducing functional unblinding, with a majority of participants correctly identifying the study arm they were randomly assigned to following dosing (Aday et al., 2025; Bogenschutz et al., 2022; Butler et al., 2022; Muthukumaraswamy, 2023; Muthukumaraswamy et al., 2021). Blinding study therapists and personnel presents another set of challenges, given the possibilities of different styles of engagement with participants depending on perceptions of active drug versus placebo assignment. Currently, the most conventional method to guard against functional unblinding entails a double-blind design with primary endpoints assessed by blinded, centralized raters that have no other contact with study participants (Hovmand et al., 2023).

Regarding the related but distinct phenomenon of expectancy, these effects can be heavily influenced by the degree of media attention to psychedelic therapies and their associated sensationalism (Noorani, 2020b, 2021; Yaden et al., 2022c) as well as prior experience with psychedelic substances. Study participants may approach their involvement in psychedelic clinical trials with unrealistic expectations, both about the nature of the engendered experience and the durability of therapeutic effects (Aday et al., 2023). Expectancy effects are theoretically heightened by the limitations of current pharmacological treatments for many psychiatric conditions and the perception among many study participants that psychedelic interventions are a potential panacea, or miracle cure. Expectancy may also be driven by instructions and both implicit and explicit signals of expectations communicated by study team members. Clear and unbiased education about the potential effects of psychedelics (both positive and adverse) and maintenance of scientific equipoise by the study team can help to counteract expectancy that might be communicated, implicitly or explicitly, by the team, and such education, as previously indicated, can also serve to counteract expectancy driven by popular media.

There remain larger questions as to the relationship between expectancy and therapeutic outcomes, particularly given the context-dependent actions of psychedelic drugs, which are heavily influenced by “set” (expectancy) and “setting” (context; Gukasyan and Nayak, 2021; Noorani, 2021; Szigeti and Heifets, 2024). There are also aspects of the RCT design that are not necessarily therapeutically neutral and encourage a degree of uncertainty and doubt that may have significant effects on how a study participant engages with the treatment. That is to say, preoccupation and uncertainty as to receiving a placebo versus an active drug may interact with the powerful subjective effects of psychedelics to have significant effects on the occasioned experience—and how a participant engages with that experience—given the outsized effects that set and setting have on psychedelic interventions (Gukasyan and Nayak, 2021; Schenberg, 2024). This introduces an additional element that is often not an issue in other placebo-controlled drug trials, that is, the uncertainty and often resulting increased anxiety at the beginning of the administration day, of not knowing what to expect from taking the pill. This includes not only randomization, which, of course, is characteristic of all randomized controlled trials; it also pertains to the potential of so-called “bad trips” in recreational settings, especially in psychedelic-naive participants. This creates challenges for study personnel, given that cultivating positive expectations may not be entirely disentangled from achieving optimal therapeutic outcomes (Aday et al., 2022). However, there is the simultaneous motivation to maintain realistic expectations, given the possibility of being randomized to a placebo or of having a disappointing response to the active drug.

The nocebo effect, a qualitatively different but related phenomenon, describes situations where negative expectations and beliefs surrounding an intervention can cause harm. A common example of this is that expectations for a high side effect burden of a given treatment may result in greater side effects even in participants assigned to the inactive comparator condition. Given elevated expectations surrounding psychedelic drugs, study participants—upon discovering or suspecting they have received a placebo condition given the absence of significant or expected alterations to consciousness—may mount an exaggerated response due to disappointment with resultant worsening of mental health symptoms (Bălăeţ, 2024; Hieronymus et al., 2025). This is a typical negative manifestation of functional unblinding that can result in not only a lack of benefit but also potential worsening of symptoms. As such, estimations of the difference between active drug and placebo comparators may be potentially exaggerated, given expectancy amplifications that increase the difference between participants who experience strong psychoactive effects and participants who experience nocebo effects when encountering the comparator condition.

The set and setting elements of psychedelic trials carry implicit cultural connotations (Noorani, 2021). Primary among these are the kind of psychological support and psychotherapy that is provided as a component of psychedelic clinical trials, and the question of whether any framing or point of reference during the study includes a spiritual aspect (which is found in many non-research or non-medical settings, but which may often be contrary to research and medical settings). Psychedelic clinical trials to date have included study participants who are majority white, with Western cultural backgrounds, and higher resourced (Hughes and Garcia-Romeu, 2024). Despite calls for increased diversity, there is ongoing underrepresentation of minority populations, and little attention, if any, has been paid to the importance of pairing therapists and/or session facilitators with patients or participants in a culturally sensitive manner. This also raises the question of matching participants and therapists/dosing session monitors in cultural and other background characteristics, and the potential role of having interpreter services available. These issues limit the generalizability of study findings but are also significant in relation to different therapeutic preferences, spiritual attitudes and beliefs, and sense of safety with medical research. More work is needed to understand the impact of alignment or misalignment of individual study participants’ therapeutic needs with the cultural sensitivity of the study team and study therapists and the way those domains impact expectancy (Neitzke-Spruill, 2020; Williams et al., 2020).

Challenge 2. Management strategies

Functional unblinding and expectancy effects are related but distinct phenomena and require independent assessment and mitigation in psychedelic clinical trials. Acknowledging the challenges of expectancy up front in a transparent fashion with study participants can be helpful. A significant proportion of modern psychological support protocols for psychedelic drug administration should devote time during the pre-dosing preparation period to addressing the possibility of disappointing, challenging, or unexpected subjective experiences during the dosing session. Such discussion may help to limit the maladaptive impact of potential disappointment and maintain engagement with the study regardless of the presence or perceived strength/quality of effects that are encountered by a given participant. Exploration of how the individual usually deals with disappointment is also paramount, as well as their coping strategies and social support network outside of the study. These discussions should also emphasize the wide variability in strength and quality of subjective effects that a participant may experience from a given dose of a psychedelic compound, such that it is possible for someone to feel very little on a high dose of a psychedelic, and for someone else to have a very powerful experience on low doses. While some data exist suggesting that the quality/intensity of the drug experience is linked to therapeutic outcome, this has by no means been definitively established. Therefore, the participant should be educated that they might do better, worse, or the same regardless of how intense their dosing experience was. This amounts to another psychoeducational method that may help to mitigate some of the potential detrimental effects of functional unblinding. Overall, these discussions help to maintain transparency, build rapport, and provide a platform for discussing the challenges inherent in the delivery of psychedelics for therapeutic purposes, and they may help to establish a reasonable middle ground for engagement. Having a balanced conversation surrounding expectations and strategies for managing expectations while still engaging in the therapeutic process can help participants navigate some of these challenges. Other strategies worth exploring include the use of placebo response mitigation scripts that involve reminding participants about the double-blind nature of the study, structuring eligibility criteria to minimize prior psychedelic experience among study participants, minimizing expectation on behalf of study personnel, and the scientific uncertainty surrounding the actual benefits of the active drug at this stage of testing. The use of external outcome assessors and the incorporation of expectancy measures such as the Credibility and Expectancy Questionnaire (Devilly and Borkovec, 2000) may also mitigate the effects of suboptimal blinding in this field and better characterize these effects.

Study teams should take steps to not only enhance inclusivity and diversity of study populations through recruiting strategies but also actively address culturally attuned aspects of setting, preparation, and integration, therapist assignment, and cultural background, language, music choice, and spiritual preferences for participants. Rigorous reporting of set and setting variables can significantly improve not only the rigor of research but also help improve the quality of care delivery across diverse populations. The Reporting of Setting in Psychedelic Clinical Trials (ReSPCTs) guidelines represent the outcomes of a global Delphi consensus study on extra-pharmacological variables that should be reported in clinical trials (Pronovost-Morgan et al., 2025a).

Innovative study designs that diverge from standard RCT formats may help isolate treatment effects from expectancies. These include factorial design studies that rely on deception (though there are associated ethical issues in relation to the use of deception in psychedelic trials that need to be carefully weighed). Studies that investigate dose response and durability of effects provide another avenue for accounting for and mitigating the effects of functional unblinding and expectancy (Goodwin et al., 2022; Robison et al., 2025). Other strategies that have been employed include the use of general anesthesia concurrent with drug administration. For instance, Lii et al. (2023) found large treatment effects for both ketamine and placebo when administered under general anesthesia. There remain conceptual challenges with this approach, however, as well as uncertainty about how to interpret these study outcomes given concomitant neurobiological changes implicit in the simultaneous administration of a general anesthetic. The use of biomarker analyses in prospective studies is another promising avenue that avoids issues related to unblinding (Muthukumaraswamy, 2023) and facilitates causal understanding of drug effects that is not fully reliant on subjective first-person reports and theoretically less influenced by effects of unblinding. A limitation of biomarker analyses is that a sole reliance on these techniques presumes the primacy of biological mechanisms underlying psychedelic therapeutic effects, and may inherently discount or ignore the potential contribution of subjective effects to therapeutic outcomes. AI techniques of analyzing phenotypic characteristics (language, speech patterns, facial expression) present another set of strategies to develop objective measures that can be correlated with clinical outcomes (Kargbo, 2023). Such phenotypic measures may allow for rein-corporation of elements of subjective experience in the assessment of psychedelic therapeutic effects.

Challenge 3. Post-session psychological difficulties

Some participants in clinical trials encounter significant psychological difficulties during and after their dosing session that may require careful consideration of how these difficulties should be addressed within the confines of a study protocol (Hinkle et al., 2024; Palitsky et al., 2023). This can relate to challenging psychological material, questions, or confusion about the experience itself, uncertainties about how to integrate aspects of the experience into daily living, existential or spiritual questions that have surfaced, questions about personal identity or life choices, or a perceived lack of any meaningful experience.

A range of background personal and/or culturally held ideas related to psychedelic therapies may contribute to the subjective distress and difficulties post-session. An individual with an internal locus of control may attribute “a failed treatment” internally (e.g., inadequate engagement with the treatment, personal weakness) or to poor luck (e.g., “I always draw the short straw”). Such maladaptive cognitions may result in worsening of underlying disorders. By contrast, an individual with an external locus of control may attribute externally (e.g., “The setting was too clinical, it should have been in nature”; “The clinic team did not prepare me or inform me sufficiently about what to expect”). There are patients who may not be good candidates for a psychedelic intervention despite meeting diagnostic criteria for enrollment (with MDD, for instance), or who may be more likely to have difficult experiences given high trait neuroticism (Barrett et al., 2017), high pre-session emotional excitability, dysregulated mood, and poor rapport (Studerus et al., 2012) or pre-existing medical and psychiatric comorbidities that present risk (Hosein et al., 2025; Johnson et al., 2008). However, the field has not yet clearly identified those who may or may not be good candidates a priori.

Measures of AE collection for psychedelic trials may be inadequate for accounting for the wide range of challenges that can emerge (Evans et al., 2023, 2025; Palitsky et al., 2023). Similarly, psychedelic compounds may occasion experiences that are characterized by mystical or spiritual elements (Garcia-Romeu et al., 2014; Griffiths et al., 2008, 2011, 2018; Ko et al., 2022). The latter may present unique challenges and questions for the participant that do not fit cleanly into the kinds of data collection afforded in the context of a clinical trial. This also can depend on the background of the study participant and pre-existing spiritual inclinations. These concerns related to experiential elements of psychedelic drug administration are particularly relevant for the field, given accumulated evidence of the relationship of subjective experience measures to therapeutic outcomes (Hovmand et al., 2024; Kangaslampi, 2023; Ko et al., 2022). However, it should be noted that the aspects of subjective experience typically measured and associated with clinical outcomes may be a proxy measure for another underlying process or experiential component of the psychedelic experience. Thus, the causal relationship between subjective experience and therapeutic response remains to be demonstrated or fully understood.

There is also the question of what post-session psychological support or engagement entails, and how it is optimally delivered. There is no current consensus on this front (Aday et al., 2023; Brennan and Belser, 2022; Cavarra et al., 2022; Earleywine et al., 2022; Goodwin et al., 2024; Psychiatrist.com, n.d.). This uncertainty is amplified by limited reporting to date by study teams characterizing the associated psychological interventions in their clinical trials (Brennan et al., 2023). There is a precedent in current models of psychedelic delivery in industry-sponsored trials moving through Phases 2 and 3 to frame the intervention as not including any psychotherapy (Goodwin et al., 2022, 2024; Robison et al., 2025). Recognizing that FDA approval pathways may be complicated by incorporating non-standardized psychotherapeutic interventions and the inherent challenges of studying combination interventions, these recent trials with psilocybin and LSD have framed the psychedelic intervention around “session monitors” (Robison et al., 2025) or “psychological support” (Goodwin et al., 2022; Kirlić et al., 2025). There have also been calls for more rigorous incorporation of evidence-based psychotherapies with a cognitive behavioral emphasis, which have clearly established effect sizes to better characterize these respective contributions to efficacy (Yaden et al., 2022b). A recent meta-analysis did not show any clear relationship between treatment outcomes and the number of therapy hours in psychedelic clinical trials (Hultgren et al., 2025); however, this analysis was limited by non-standardized reporting practices across constituent studies.

Post-session “integration” of the psychedelic experience has been conceptualized as a self-guided, autonomous process of the individual that is supported by the therapist, facilitator, or dosing session monitor. However, the FDA requires that psychedelic drug administration sessions include at least one monitor or facilitator who is an independently licensed mental health practitioner, and unless explicitly stated and carefully controlled within a given protocol, these facilitators may occasionally or regularly engage participants in therapeutic processes before and after experimental drug administration sessions, though the degree to which this occurs has not been well-characterized. Furthermore, for some participants, integration-related activities such as meditation, yoga, journaling, painting, self-reflection, and other self-care activities might already be within their repertoire of potential resources or come naturally to them, whereas for others, they might need more support and encouragement to identify and try activities that allow them to integrate and learn from their experience.

Challenge 3. Management strategies

Study teams can consider incorporating a broader range of AE assessment tools along the lines suggested by Palitsky et al. (2024) that can better account for the sociocultural, interpersonal, psychospiritual, behavioral, psychotherapy-related, affective, and perceptual AEs in addition to standard physical and psychiatric AEs typically collected.

There may be good reasons to consider the incorporation of spiritual health practitioners on study teams for guidance and consultation on how to approach psychospiritual or existential challenges that arise for study participants (Palitsky et al., 2023; Peacock et al., 2024), as these issues may be inadequately addressed with standard mental health approaches. However, it may be critical to take an ecumenical or otherwise inclusive approach to spiritual care in this case, to avoid the imposition of any particular faith tradition or interpretive framework (Johnson, 2021).

As described above, current Phase 3 trials have emphasized “psychological support” as opposed to intensive psychotherapeutic engagement (Kirlić et al., 2025). To enhance research standardization and improve treatment outcomes, study teams should carefully characterize associated psychotherapeutic interventions utilized in clinical trials with psychedelic interventions. There remain critical questions for the field in terms of the relative contribution of psychotherapy and other components, which are only answerable with careful, thoughtful study design, and these issues and improved reporting practices surrounding the intervention and larger trials as outlined by the ReSPCTs (model) discussed above (Pronovost-Morgan et al., 2025b).

It remains to be seen whether post-session therapeutic engagement should be best conceptualized as a patient-guided process or one that is either therapist-directed or collaborative between patient and therapist, and whether this process should differ from structured or unstructured psychotherapeutic support.

Challenge 4. Contagion effects

In clinical trials, it is of utmost importance to maintain and protect participant privacy and confidentiality in clinical trials. However, participants can sometimes report feeling uncomfortable discussing their experiences with other people who may not understand them (i.e., others who have not had a psychedelic experience). These individuals may seek out more information, especially through local or online psychedelic communities. In parallel, a growing number of studies are incorporating group therapy approaches to preparation, dosing, and integration (Agrawal et al., 2024.; Anderson et al., 2020; Gasser, 2022; Lewis et al., 2023a, 2023b, 2025). Structured group therapy approaches may provide an effective support network for some patients in therapeutic clinical trials, especially in the case of such potentially disruptive and impactful interventions as psychedelic therapies. Group therapy approaches may mitigate uncontrolled harm that could come from participants seeking psychedelic communities outside of study participation.

Study designs incorporating group therapy approaches may further provide logistical efficiencies to the study team while also testing the utilization of an approach that may increase the scalability and real-world viability of psychedelic therapy approaches. There are multiple parallels in place for group therapy in other therapeutic contexts, including group therapy support for patients with substance use disorders, cancer, and other chronic illnesses. However, community-seeking and group therapy may present additional unique challenges to psychedelic clinical trials. Researchers have recently outlined a number of ways in which participants in psychedelic trials may subsequently engage in forms of sociality (termed “chemosociality,” referring to how psychoactive substances can shape social meaning, identity, and shared interpretation through interpersonal processes) with other participants, or a community, with possible feedback effects on trial outcomes (Noorani et al., 2023). This can involve deep connections and relationships that participants can form with each other, or with study therapists, as well as engagement with psychedelic communities more broadly. It can also involve comparisons that study participants engage in related to their experiences with the study drug, if they are in communication with each other. Analogous to the discussion in Challenge 2 as to the impact of study team instructions as elements of set and setting, other forms of possible contagion effects include the possibility of implicit therapist or study team biases, personal beliefs, philosophies, or ethos surrounding psychedelic compounds or spirituality in general and the possible effects this positioning has on participant experiences and possible downstream belief change (Johnson, 2021; Kious et al., 2022; Langlitz, 2023). When present, contagion effects could have a significant influence on participant perceptions regarding the intervention and may represent alterations to ongoing engagement around psychedelics that are not necessarily separate from the therapeutic effects being measured longitudinally (Noorani, 2021). While possible in the context of individual format studies, these downstream effects may be particularly pronounced in group-format interventions where study participants are engaging in a collaborative group process through preparation sessions, dosing sessions, and integration sessions. Noorani identifies several strategies for approaching these effects, including “chemosocial minimization” (where there are rigorous attempts made to minimize feedback and contagion effects) “chemosocial description” (where attempts are made the characterize the kinds of possible dark loop effects engendered by the trial) and “chemosocial valorization” (where these feedback effects are seen as a feature, not a bug, for instance, group cohesion effects).

Challenge 4. Management strategies

Under certain conditions, psychedelic clinical trials, at least at their current stages, have the potential to present unique challenges related to interactive feedback effects and contagion. While study teams may not be able to predict or mitigate all the downstream effects or issues that can arise with “dark loop” or contagion-effect phenomena, this should be carefully considered during study design, and subsequently discussed and reviewed with the team at study commencement and at intervals through the study process to encourage awareness as to these effects and their possible impact. While these effects may not be fully preventable, rigorous incorporation of qualitative data gathering and anthropological expertise may help characterize and understand the relative contributions of these variables on study participants and study outcomes.

Study teams should maintain ongoing dialogue with ethics committees and Institutional Review Boards in relation to situations arising that may present concerns for boundary violations. Professional organizations and national workgroups (such as the NNDC task groups) provide a venue for discussion of these issues with other researchers. Harmonization of study processes and methodologies across psychedelic research groups may also mitigate some of the less predictable outcomes with these effects.

Conclusion

While classical psychedelics show potentially extraordinary therapeutic promise, studying them properly presents unprecedented challenges, requiring researchers to develop sophisticated strategies to navigate nonresponse, expectancy effects, and functional unblinding, post-session psychological issues, and possible contagion effects to responsibly advance this field. The NNDC and similar organizations are well-positioned to guide best practices and ensure the responsible advancement of this promising field.