Expectations and Motivations for Participation in Clinical Trials Utilizing Psychedelics for Treatment-Resistant Depression: A Qualitative Study

Psychedelic trials are difficult to interpret because participants’ expectations can shape both the subjective experience and treatment outcomes, and the obvious effects of these drugs often make blinding weak. The paper notes that expectancy is usually treated as part of the placebo effect, but it may also contribute to therapeutic change itself. Although quantitative expectancy scales exist, the authors argue that they may not capture the complexity of expectations in psychedelic research, particularly for people with treatment-resistant depression (TRD), whose chronic illness and repeated treatment failures may create a distinctive mix of hope, desperation, scepticism, and prior psychedelic experience. Poppe and colleagues therefore set out to explore, in depth, the motivations and expectations of individuals with TRD who were considering participation in psychedelic clinical trials. The study aimed to examine these issues both before trial screening and, for a small number of participants, retrospectively after participation, in order to understand how expectations are articulated and how they may change over time. The authors present the work as filling a gap in qualitative research on expectancy in TRD populations.

The study used a qualitative, exploratory design and followed the COREQ-32 reporting checklist. Participants were recruited by purposive sampling from people who had expressed interest in two clinical trials for TRD at a German university hospital. One trial involved a single dose of 5-MeO-DMT and the other involved low, medium, and high doses of psilocybin. In both trials, psychological support was provided throughout, and both included an open-label extension so that participants could receive the psychedelic substance regardless of randomisation. The researchers conducted semistructured interviews before screening for the trials. Seventeen pre-trial interviews were completed between May 2024 and May 2025. Two of these participants later took part in psychedelic trials and were re-interviewed afterwards, allowing a small retrospective within-case analysis of how expectations were remembered and reinterpreted after participation. The pre-trial interviews were brief, with a mean duration of 13 minutes, while the post-trial interviews averaged 37.5 minutes. Interviews were audio-recorded and transcribed verbatim; automated transcription was checked and corrected by research assistants and then reviewed in depth by the first author. Analysis used reflexive thematic analysis. One author coded the transcripts inductively in MAXQDA, producing 137 initial codes, which were then reviewed by a second author. Through discussion, these were condensed into 39 higher-level codes and organised into categories, which were then grouped into the study themes. The authors report that later interviews did not generate substantially new codes or categories, suggesting sufficient depth for the study aims. Reflexivity was addressed through discussion of possible role conflicts, since some interviewers were also involved in screening, and participants were informed that their interview responses would be confidential and would not affect trial eligibility.

The analysis produced two main themes: motivations for psychedelic trial participation and expectations for psychedelic trials. Within motivations, the authors identified four subthemes: hope, demoralisation, previous psychedelic experiences, and social motivation. Hope was an important driver of interest in the trials. Participants often described the trials as a last resort after many unsuccessful treatments, and some viewed psychedelics as a more natural or potentially more effective alternative to antidepressants, particularly because they hoped to escape emotional blunting and anhedonia. Demoralisation was strongly linked to chronic suffering, repeated treatment failures, side effects, and increasing hopelessness over time. Previous psychedelic experiences also mattered: some participants were motivated by earlier recreational or self-directed use, while a few who had previously been in psilocybin trials reported disappointment with outcomes or follow-up care. Social encouragement from family or friends supported participation for some, although others encountered scepticism or stigma. For expectations, the authors identified four subthemes: symptom reduction, mechanism of change in the psychedelic experience, therapists and setting, and expectations in retrospect. Participants generally hoped for symptom relief, but many did not expect straightforward improvement; instead, they anticipated small changes, a breakthrough, a fundamental shift, or, in some cases, an outright cure. To protect themselves from disappointment, several described deliberately lowering their expectations. Participants also described varied theories about how psychedelics might help, including neurobiological explanations such as increased brain connectivity, psychological processes such as ego dissolution or trauma processing, and more existential changes such as feeling more connected. Expectations about setting were strong: participants wanted a professional, safe, supportive context, with trust in therapists seen as especially important. One participant suggested that therapists with their own psychedelic experience might better understand the altered state, but this view was rare. The two follow-up interviews suggested that expectations may be reinterpreted after the trial. In both cases, participants had initially described limited expectations or mainly hoped simply to have the experience, but later reflected that stronger hopes for benefit had probably been present all along. The authors present these cases as illustrative rather than representative.

The authors interpret the findings as showing that participants with TRD approached psychedelic trials from a context of demoralisation but also renewed hope. They argue that expectations were not simple or uniform: rather than imagining a ‘magic pill’, participants tended to think in terms of a process of change, with different personal theories about how that change might occur. These theories ranged from neurobiological to psychological and existential explanations, which the authors suggest supports a flexible, patient-centred therapeutic stance in preparation sessions rather than imposing one fixed model of action. The discussion emphasises the importance of set and setting. The authors note that participants understood setting both as the safety of a reputable clinical environment and as trust in therapists, which they present as a relational prerequisite for navigating potentially challenging psychedelic experiences. They also suggest that the rare preference for therapists with personal psychedelic experience may have implications for therapist training, although they acknowledge ethical concerns around this. In relation to earlier research, the authors state that their findings are consistent with work on demoralisation and with previous studies showing that participants can hold specific theories of change and may manage or downplay their expectations. They also connect their findings to the limited quantitative expectancy literature, which has used very few expectancy measures in psychedelic trials and suggests that expectancy may not operate in the same way across different treatments. The authors highlight several limitations. The interviews were short, which may have limited depth; the study was conducted at a single German university hospital; self-selection may have favoured more optimistic participants; and the presence of a screening clinician in some interviews may have encouraged socially desirable responses. Most importantly, only two participants completed post-trial interviews, so the longitudinal findings are explicitly presented as illustrative. The study also did not assess whether pre-trial expectations influenced clinical outcomes. The authors conclude that future research should examine whether specific expectations, or the match between expectation and experience, relate to outcomes, and they argue for the development of a purpose-built expectancy measure for psychedelic trial populations.