A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research

David B Yaden; Marianna Graziosi; Alexa M Owen; Gabrielle Agin-Liebes; Scott T Aaronson; Katja Ehrmann Allen; Frederick S Barrett; Michael P Bogenschutz; Robin Carhart-Harris; Terence HW Ching; Mary P Cosimano; Alicia Danforth; Alan K Davis; Albert Garcia-Romeu; Roland Griffiths; Charles S Grob; Gerhard Gründer; Natalie Gukasyan; Keith G Heinzerling; Peter S Hendricks; Friederike Holze; David M Horton; Matthew W Johnson; Benjamin Kelmendi; Stephanie Knatz Peck; Michael Koslowski; Matthias E Liechti; Lea J Mertens; Francisco A Moreno; Sandeep M Nayak; Christopher R Nicholas; Katrin H Preller; Nathalie M Rieser; Stephen Ross; Karina Sergi; Jordan Sloshower; Lukasz Smigielski; Dea Siggaard Stenbæk; Franz X Vollenweider; Brandon Weiss; Max Wolff; Mary Elizabeth Yaden

doi:10.1089/psymed.2024.0019

. 2025 Feb 27;3(1):1–18. doi: 10.1089/psymed.2024.0019

A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research

David B Yaden ^1,^*, Marianna Graziosi ^1,², Alexa M Owen ³, Gabrielle Agin-Liebes ^4,⁵, Scott T Aaronson ^6,^7,^†, Katja Ehrmann Allen ^8,^†, Frederick S Barrett ^1,^9,^10,^†, Michael P Bogenschutz ^11,^†, Robin Carhart-Harris ^5,^†, Terence HW Ching ^12,^†, Mary P Cosimano ^13,^†, Alicia Danforth ^14,^†, Alan K Davis ^15,^1,^†, Albert Garcia-Romeu ^1,^†, Roland Griffiths ^1,^†, Charles S Grob ^14,^†, Gerhard Gründer ^16,^17,^†, Natalie Gukasyan ^18,^†, Keith G Heinzerling ^19,^†, Peter S Hendricks ^20,^†, Friederike Holze ^21,^22,^†, David M Horton ^23,^†, Matthew W Johnson ^24,^25,^†, Benjamin Kelmendi ^12,^†, Stephanie Knatz Peck ^26,^†, Michael Koslowski ^27,^28,^†, Matthias E Liechti ^21,^22,^†, Lea J Mertens ^16,^17,^†, Francisco A Moreno ^29,^†, Sandeep M Nayak ^1,^†, Christopher R Nicholas ^23,^†, Katrin H Preller ^30,^†, Nathalie M Rieser ^30,^†, Stephen Ross ^11,^†, Karina Sergi ^19,^†, Jordan Sloshower ^12,^†, Lukasz Smigielski ^31,^†, Dea Siggaard Stenbæk ^32,^33,^†, Franz X Vollenweider ^30,^†, Brandon Weiss ^1,^†, Max Wolff ^34,^27,^†, Mary Elizabeth Yaden ^1,^†

^¹Center for Psychedelic and Consciousness Research, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

^²Department of Clinical Psychology, Hofstra University, Hempstead, New York, USA.

^³Smith College School for Social Work, Northampton, Massachusetts, USA.

^⁴Department of Psychiatry, University of California, San Francisco, California, USA.

^⁵Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt, Towson, Maryland, USA.

^⁶University of Maryland School of Medicine, Baltimore, Maryland, USA.

^⁷University of Arizona, Tucson, Arizona, USA.

^⁸Department of Psychological & Brain Sciences, Krieger School of Arts & Sciences, Johns Hopkins University, Baltimore, Maryland, USA.

^⁹Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

^¹⁰Department of Psychiatry, NYU Langone Center for Psychedelic Medicine, NYU Grossman School of Medicine, New York, New York, USA.

^¹¹Department of Neurology, University of California San Francisco, San Francisco, California, USA.

^¹²Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.

^¹³Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

^¹⁴The Lundquist Institute at the Harbor-UCLA Medical Center, Torrance, California, USA.

^¹⁵Center for Psychedelic Drug Research and Education, College of Social Work, The Ohio State University, Columbus, Ohio, USA.

^¹⁶Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

^¹⁷German Center for Mental Health (DZPG), Partner Site Mannheim, Mannheim, Germany.

^¹⁸New York State Psychiatric Institute, Columbia University Medical Center, New York, New York, USA.

^¹⁹Treatment and Research In Psychedelics (TRIP) Center, Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California, USA.

^²⁰Department of Psychiatry and Behavioral Neurobiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

^²¹Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

^²²Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

^²³Department of Family Medicine and Community Health, University of Wisconsin, Madison, Wisconsin, USA.

^²⁴Center of Excellence for Psilocybin Research and Treatment, Sheppard Pratt, Townson, Maryland, USA.

^²⁵Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

^²⁶Department of Psychiatry, University of California San Diego, San Diego, California, USA.

^²⁷Department of Psychiatry and Psychotherapy, Charité CCM—Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

^²⁸Iméra Institute of Advanced Studies, Aix Marseille University, Marseille, France.

^²⁹College of Medicine Tucson, University of Arizona, Tucson, Arizona, USA.

^³⁰Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich, University of Zurich, Zurich, Switzerland.

^³¹Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital Zurich, University of Zurich, Zurich, Switzerland.

^³²Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark.

^³³Department of Psychology, Copenhagen University Clinic for Psychedelic Research, University of Copenhagen, Copenhagen, Denmark.

^³⁴MIND Foundation gGmbH, Berlin, Germany.

^{^†}

These authors contributed equally to this work.

^{^*}

Address correspondence to: David B. Yaden, PhD, Center for Psychedelic and Consciousness Research, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21205-2105, USA, dyaden1@jhmi.edu

ⁱORCID ID (https://orcid.org/0000-0002-9604-6227).

ⁱⁱORCID ID (https://orcid.org/0009-0001-3227-4925).

ⁱⁱⁱORCID ID (https://orcid.org/0000-0001-7616-8801).

^ivORCID ID (https://orcid.org/0000-0001-7443-3237).

^vORCID ID (https://orcid.org/0000-0001-5185-7854).

^viORCID ID (https://orcid.org/0000-0001-7068-0513).

^viiORCID ID (https://orcid.org/0000-0002-1765-9659).

^viiiORCID ID (https://orcid.org/0000-0002-0599-4046).

PMCID: PMC12060849 PMID: 40351554

Abstract

Introduction:

Serotonergic psychedelics, serotonin 2A receptor agonists such as psilocybin that can result in substantially altered states of consciousness, are used in recreational and research settings. The safety of psychedelic experiences in research settings is supported by controlled physical environments, presence of clinical and medical staff to address emergent issues, screening for personal and family history of potential contraindications, and psychoeducational preparation with psychological support. Research settings typically provide psychoeducation to participants verbally and in writing (e.g., informed consent), and such documents and conversations can provide safety-related information—but may also introduce a wide range of expectancies. Such expectancies might involve the specific character of the acute subjective effects of psychedelics, possible side effects, and anticipated outcomes.

Methods:

To better understand the content of this psychoeducation, we gathered study materials from many psilocybin studies conducted in the past two decades in healthy and therapeutic populations. We conducted a reflexive thematic analysis to better understand these documents.

Results:

While these documents varied substantially between studies, we identified themes intended to lower levels of risk and optimize therapeutic effects from psychedelic treatments. The most frequently coded themes related to (1) biological and physical safety, (2) psychological safety and well-being, (3) aspects of setting, and (4) potential for expectancies. Prioritizing biological and psychological safety was evident in the materials from all sites. Furthermore, we identify potential contributors to expectancy unrelated to safety and suggest that these extrapharmacological elements be studied systematically in future research.

Conclusions:

Ideally, future research should strive to maximize safety while attempting to minimize extraneous expectancies.

Keywords: psychedelic-assisted psychotherapy, psilocybin, safety, expectancies, reflexive thematic analysis, Psychoeducation

A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Conclusions from Two Decades of Research

Classic (or serotonergic) psychedelics, such as psilocybin, are a broad class of psychoactive substances that can produce substantially altered states of consciousness and perception and are often defined pharmacologically by their partial agonist activity at the serotonin 2A receptor (5-HT_2AR).^1–3 Psilocybin, compared with other psychoactive substances used in recreational settings, has low risk of toxicity and low addiction potential, yet can result in challenging experiences and carry psychological risks in addition to benefits.^2,4 Common somatic side effects are mild and include transient nausea, transient increases in blood pressure and heart rate, and headache.^5,6 The acute subjective effects of psilocybin last for about 4–6 h and can include vivid imagery, perceiving patterns in one’s surroundings, audiovisual synesthesia, altered experience of time and space, strong activation of emotions, insight, meaning, anxiety, feeling overwhelmed, recall of autobiographical memories, and a sense of connectedness, awe, self-transcendence, as well as dissociation and delusional thinking.^7–10 Some psychedelics were synthesized within the past century (e.g., lysergic acid diethylamide, LSD) while others have been used in ritual practices for generations in certain cultural contexts (e.g., mescaline and psilocybin mushrooms).^2,11 In contemporary contexts, psychedelics such as psilocybin are used in both recreational and clinical research settings (mushroom and synthesized, respectively).

Recreational use of psilocybin outside of supervised clinical settings occurs in a variety of contexts for a wide number of motivations. Psilocybin is ingested by individuals alone, in small groups, as well as at large social events (e.g., concerts) for reasons including recreation, psychotherapeutic benefit, enjoyment, aesthetic enhancement, creativity, spirituality, and to feel closer to nature as well as others.¹² Psychedelic use in recreational settings has been associated with some positive outcomes, such as markers of physical health¹³ and lower levels of psychological distress and suicidality among psychoactive substance users.¹⁴ However, recreational use of psilocybin is also associated with some noteworthy risks. For example, convenience survey studies have indicated that up to 14% of individuals consuming psilocybin in naturalistic settings have reported high levels of distress and persisting adverse psychological effects,^15,16 although these should not be considered population base rates. While psychedelics are also administered in underground therapy settings,¹⁷ often little is published about such contexts, so they are not explicitly addressed here, although we note reports of problematic safety considerations and cases of abuse in these settings.¹⁸

Extrapharmacological factors are widely believed to significantly influence the therapeutic value and effects of an experience,¹⁹ commonly referred to as “set and setting.”²⁰ “Set” refers to the mindset, expectancies, and intentions of a person before an experience with a psychedelic.²¹ This can include personality, mood, beliefs, as well as their beliefs and expectations about psychedelic experiences. “Setting” refers to the immediate physical space in which the substance is consumed.²² This includes the research team, facilitators, or therapists, as well as music, artwork, and safety equipment. Most clinical research with psychedelics emphasizes the importance of set and setting to maximize safety, reduce the risk of harmful experiences, and enhance therapeutic response.²³

In clinical research settings, psilocybin is administered in a highly controlled manner, which may enhance safety and enhance beneficial outcomes. Psilocybin has been shown to improve mood disorders,^24–33 smoking and drinking behavior in substance use disorders,^34–36 and increase well-being,^28,37–41 all with very few serious adverse events attributable to the psychedelic (but they can and do occur). While large phase 3 studies are necessary before firm conclusions can be drawn regarding the efficacy of psychedelics as a treatment,^42–44 available data show therapeutic potential and a reasonable safety profile compared with other treatments for these disorders (although, again, adverse events attributable to the psychedelic can and do occur in psychedelic research).

Psilocybin mushroom use in recreational settings has not been directly compared with psilocybin administered in a laboratory setting, but the accumulated data suggest the possibility that the risks of adverse events may be lower in controlled settings, for example, as in contemporary clinical trials. Additionally, careful monitoring and therapeutic support associated with the controlled administration of psychedelics in contemporary research may enhance the impact of psychedelics on positive psychological outcomes.⁴⁵ However, psychedelic experiences may involve challenging or negative emotions and difficult content regardless of whether they are administered in recreational or research settings.¹⁵ While these can to some extent be managed with safety procedures in research settings, risks nonetheless remain.²³ In terms of persisting adverse effects from sessions, 3 of approximately 250 (0.9%) participants who were administered psilocybin at Johns Hopkins University through May of 2016 reported persisting adverse psychological effects, which were resolved after receiving therapeutic support.¹⁵ Similarly, in a pooled analysis of 110 participants administered psilocybin between 1996 and 2008 at the University of Zurich, “a few” (p. 1448) participants experienced transient mood lability, concentration issues, and memory impairment, and one participant sought professional help for severe emotional distress lasting for weeks following psilocybin administration.⁴⁶ However, these are likely underestimates and a meta-analysis of adverse events shows higher rates.⁴⁷

Several common procedures may have accounted for psilocybin’s tolerable safety profile in controlled settings (see Johnson et al.²³) Participants are screened for various medical and psychological conditions that may be contraindicated for high-dose psychedelic administration, such as serious heart conditions and personal or family history of psychotic or bipolar disorders.²³ Medical providers are immediately available in these settings to administer rescue medications and care if any medical concerns arise. Rescue medications can be administered, although this practice is quite rare, if a participant experiences severe anxiety or behavioral disturbances during their psychedelic experience (typically benzodiazepines, or second-generation antipsychotics; for two examples, see Goodwin et al.²⁷ and Holze et al.⁴⁸) as well as antihypertensive medications should a participant experience critically high blood pressure.²³ Most sites also provide participants with one or two therapists, monitors, guides, or facilitators to provide psychological support throughout the medication session.^49,50 Lastly, participants are provided with psychoeducation for safety purposes delivered verbally and/or in writing in visits leading up to the drug administration session.

The type and extent of predrug administration psychoeducation participants receive may vary, along with other aspects of study settings. The information provided in these materials may enhance safety but may also introduce various psychological expectancies in participants that influence study findings.^51,52 Expectancy effects refer to expectations that a participant may develop about what might occur during (process expectancy) and after (outcome expectancy) a psychedelic treatment,⁵² although there is much variability in the way in which the term is used.⁵¹ For instance, materials that emphasize the potential for transformative mystical-type subjective experiences may increase the likelihood that participants will report such mystical-type outcomes during the course of their experience (process expectancy) and/or when integrating the experience (outcome expectancy). In this example, these expectancies acquired through the content of materials (rather than the psychedelic experience) may impact study outcomes (either by enhancing reported benefits or leading to disappointment if certain expectations are not realized). Another related, yet distinct term, is “functional unblinding” which refers to the phenomenon whereby a participant realizes which randomly assigned condition they are in. Both functional unblinding, expectancy effects, and their interaction pose a serious challenge for randomized controlled trials assessing the efficacy of psychedelics,⁵³ although efforts are underway to assess these and related aspects of clinical trials.⁵⁴

A recent clinical trial included an assessment of the influence of potential expectancy effects.⁵⁵ The authors used a sample (n = 55) from a clinical trial comparing psilocybin and escitalopram (a selective serotonin reuptake inhibitor often used in the treatment of generalized anxiety and depression) for use with participants diagnosed with moderate-to-severe major depressive disorder (MDD).²⁵ Expectancy was assessed in terms of efficacy-related expectancy (i.e., “how much improvement in your mental health do you think will occur?”).⁵⁵ Suggestibility, or the degree to which an individual is likely to comply with suggestions of others, was also measured. Among participants who received escitalopram, pretrial expectancy was associated with therapeutic response as measured by the Hamilton Depression Rating Scale. This relationship was not observed among participants who received psilocybin, instead, suggestibility was likely to predict therapeutic response on this same measure of depression severity. These findings provide initial evidence that for psilocybin use in clinical trials, outcome expectancy may not be as influential in biasing outcomes, although the influence of process expectancy on outcomes remains largely untested. Furthermore, the influence of the content of preparation on expectancy, especially among susceptible participants, remains an empirical question. As such, the content of psychoeducation materials requires comprehensive evaluation to contextualize results from human studies.

The present study

In this study, we conducted an analysis of written materials used in human participant studies with psilocybin. We first identified psilocybin studies conducted in therapeutic contexts or with healthy volunteers in the past two decades on clinicaltrials.gov (January 1, 2000, to May 30, 2021). We then contacted the principal investigators (PIs) for each of these studies, asking them to provide all study documents provided to participants and to guide study staff on what to verbally convey to participants. We also asked PIs and key study personnel to answer a structured series of questions about their study site procedures. After receiving these documents and answers, we conducted a reflexive thematic analysis^56,57 of study documents and questionnaire responses to better understand these materials. Our research questions were: (1) what kinds of safety information are conveyed in these documents and (2) what expectancies might be (perhaps inadvertently) introduced through these documents?

Method

Participants

We collected the preparatory materials from 18 sites at which at least one psilocybin study has been or is currently being conducted. These sites were located across five countries and included studies conducted with healthy and therapeutic participants. Clinical disorders represented include MDD, obsessive-compulsive disorder, headache disorders, substance use disorders (including alcohol use disorder and tobacco use disorder), chronic illness, anorexia nervosa, anxiety and depression with cancer, treatment-resistant depression, depression with mild cognitive impairment or early-onset Alzheimer’s disease, as well as healthy participants.

Materials

The data of interest in this study include the preparatory materials for psychedelic administration sessions provided by sites that have conducted psilocybin research (see Table 1). The types of materials are varied and include responses to a set of structured questions described in the Procedure section, handouts provided to participants, and instructions used by therapists and session guides. Depending on the site, some of these materials may have been translated into English from another language. We also requested information about music playlists and photos of the psychedelic sessions room.

Table 1.

Definitions and Frequencies for Themes Across Sites

Themes (ordered by frequency)
Biological and physical safety (106 codes; 12 sites)	Any mention of efforts to protect bodily integrity and functioning, which may involve considerations of risks in the physical environment and medical precautions of all kinds
Psychological safety and well-being(91 codes; 13 sites)	Any mention of efforts to reduce risks of adverse experiences, persisting psychological adverse events, and to generally promote psychological safety
Potential for expectancies(67 codes; 15 sites)	Any mention of any aspect of the acute subjective effects of psychedelics, side effects, or outcomes that may not be necessary for safety considerations and are not required to explain basic study procedures. These are parts of the materials that could inadvertently influence the psychedelic experience or its effects
Aspects of setting(67 codes; 18 sites)	Any mention of how the room is staged, furniture in the room, objects in the room, or any other physical or aesthetic features of the location
Social safety (54 codes; 9 sites)	Any mention of efforts to reduce risks of being taken advantage of in any form during vulnerable or suggestible states and to boost feelings of rapport with the study team, facilitators, and therapists
Preparation instructions for participant(53 codes; 10 sites)	Any mention of how participants can get ready for the psychedelic administration session
Engaging with music(50 codes; 18 sites)	Any mention of music played during the psychedelic administration sessions
Integration(39 codes; 18 sites)	Any mention of practices, meetings, or processes after the psychedelic administration session to discuss or otherwise psychologically “integrate” the psychedelic experience
Religious or spiritual content(37 codes; 12 sites)	Any mention of practices, rituals, beliefs, or mindsets related to major world religious and/or spiritual traditions
Facilitator training(35 codes; 9 sites)	Any mention of training for study facilitators (including guides, monitors, therapists), often but not always in the form of a study training manual or certification materials
Psychoeducation about psilocybin(30 codes; 12 sites)	Any mention of definitions of psilocybin and descriptions about its cultural history, chemical structure, toxicity, addictive potential, common effects, or treatment potential from research
Participant handouts(26 codes; 5 sites)	Any mention of interactive therapeutic exercises administered virtually or in paper-pencil format (e.g., homework in the cognitive behavioral therapy) paradigm
Aspects of set(24 codes; 11 sites)	Any mention of participant personality variables, expectations of the session, mood right before the sessions (information that people receive about the psilocybin session) (e.g., what they have heard from friends)
Drug administration practices(24 codes; 6 sites)	Any mention of how the medication is administered in session
Facilitator resources(23 codes; 3 sites)	Any mention of information or contacts available for session facilitators (including guides, monitors, therapists) to provide additional clarification around study procedures or for social–emotional support
Therapeutic framework mentioned(23 codes; 18 sites)	Any mention of the concepts of applications of established psychotherapeutic approaches (e.g., cognitive behavioral therapy, acceptance and commitment therapy, dialectical behavior therapy, psychodynamic, psychoanalytic)
Expectation management(22 codes; 11 sites)	Any mention of clarification about the psychedelic experience, reframing potential “bad” experiences, normalizing non-extreme experiences
Grounding techniques(21 codes; 10 sites)	Any mention of practices to create a sense of security or relaxation during stressful periods of the session (e.g., meditation and breathing techniques)
Journaling(21 codes; 11 sites)	Any mention of writing about the psychedelic experience as a means of integration
Addressing touch(14 codes; 6 sites)	Any mention of touch or addressing touch or consent to touch
Engaging with art(14 codes; 10 sites)	Any mention of interacting with art or art practices during or after the psychedelic session
Verbal instructions (no materials)(14 codes; 10 sites)	Any mention of instructions to the study team to convey information verbally rather than with written study materials
Nature contact(11 codes; 11 sites)	Any mention of deliberately seeking out and spending time in natural settings for the purposes of psychological integration
Indigenous content(8 codes; 4 sites)	Any mention of practices, artifacts, art/music, philosophy, or ideas from indigenous cultures
Exclusion criteria mentioned(7 codes; 2 sites)	Any mention of criteria that would exclude participants from further participation in the study
Intention setting(6 codes; 4 sites)	Any mention of setting an intention for the session
Group-based integration(5 codes; 1 site)	Any mention of interactions among participants for therapeutic processes or for the purposes of generalized social support
Placebo effects information provided(2 codes; 2 sites)	Any mention of what the placebo substance will be for the control group (in un-blinded studies)

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The frequency with which each theme was applied is reported in parentheses. This number reflects the number of instances in which the code was applied. Additionally, the number of sites to which this code was applied is reflected in parentheses above.

Procedure

We searched clinicaltrials.gov to identify psilocybin studies that have been conducted between January 1, 2000, and May 30, 2021, because of the significant proliferation of such trials in this timeframe. We included sites that have completed studies and those that are conducting ongoing trials with psilocybin. Our search, conducted on May 30, 2021, resulted in 54 studies across 20 sites. We then reached out to a PI(s) at each site requesting materials provided to participants (verbally or in writing) about the subjective effects of psychedelics and posed a series of structured questions, which were:

What music (if any) did you use in your study/studies? A playlist would be ideal but providing a sense of the genres/artists would be just fine.
What does the session room look like? Are there any pieces of art or religious symbols? Is there a window? Are there pieces of furniture in the room?
Therapy—What would you say is the dominant theoretical orientation of any psychotherapy involved? For example, is it cognitive behavioral therapy (CBT), acceptance and commitment therapy (ACT), psychodynamic, or psychoanalytic?
Integration—What do you encourage participants to do in the week after their session? This might include journaling, meditation, and exercise.

After the responses to these questions as well as the other study documents were collected from each site, we conducted a qualitative analysis of these question responses and documents. Of the 20 sites contacted, 18 submitted materials that could be qualitatively analyzed for this study.

Analysis

Our aim was to provide a systematic qualitative description of the study materials. While qualitative analyses are typically performed on participants’ self-reported experience, in this case, the analyses were done on written study materials. Across the 18 sites, all 18 submitted an email response to the qualitative structured questions described above (with a total of 27 email responses from various PIs at each site), 9 sites provided room images, 6 provided preparation instructions for participants, 5 provided facilitator materials, 5 provided music playlists, 4 provided participant worksheets, and 2 provided a study synopsis worksheet.

For the qualitative analysis, we used a reflexive thematic analysis approach.⁵⁶ Specifically, we used the “merged” approach,⁵⁸(p. 25) a six-phase process of thematic analysis proposed by Terry and colleagues. We adopted an inductive, iterative, and interpretative approach, which rests on the assumption that having coders read the materials and discuss them repeatedly as a group can provide a coherent set of themes in the documents.⁵⁷ We examined how these materials might affect psychedelic experiences in ways that appeared intended (such as enhancing safety) and unintended (such as introducing positively biased or idiosyncratic expectancies about how the experience might feel).

In the first two stages, (1) data familiarization and (2) coding, the qualitative team repeatedly read the materials and discussed them in iterative group discussions. We used NVivo⁵⁹ qualitative coding software to generate codes that captured themes in the materials, as well as the idiosyncrasies associated with the various sites (following procedures established by Terry and colleagues⁵⁷) Any given excerpt could be coded for one or more codes, which would enable us to examine how themes related and co-occurred. In the third stage (3) theme development, the team refined the codes generated in earlier stages. In the fourth and fifth stages (4) reviewing themes and (5) defining themes, the candidate themes developed in stage 3 were further elaborated, clarified, and adjusted until the themes were well-organized around our two research questions (regarding safety information and inadvertent expectancies). The final thematic map is available in Figure 3, and the definitions for the themes are available in Table 1. In the final stage, (6) producing the report, the team unpacked the thematic map (in the next section), along with “exemplar” excerpts from the source materials that illustrate the themes (see Sumner et al.⁶⁰ and Thal et al.⁶¹ for examples of past uses of this approach in a psychedelic context).

Fig. 3. — Final thematic map of the four main themes across the stages of psilocybin trials.

Results

Our qualitative analysis of the psilocybin study materials resulted in several themes, with the following as the most frequently applied themes: biological and physical safety, psychological safety and well-being, potential for expectancies, and aspects of setting (see Table 1; Fig. 1).

Fig. 1. — Distribution of theme references. This figure illustrates the frequency (in parentheses) of excerpts coded for a given theme in proportion to the total number of excerpts coded in this study (n = 895).

Further, we elaborate on the most frequently coded themes using de-identified and summarized source materials.

Biological and physical safety

Biological and physical safety was the most referenced code in this study. The biological and physical safety theme accounted for 106 of all 895 themes applied by coders in this study. Overall, our team found that biological safety was most likely to be emphasized through preparation instructions for participants and participant handouts, as evidenced by theme overlap/co-occurrence.

Preparation instructions for participants

Biological and physical safety were often communicated in the preparation instructions for participants, which could be both written and verbal. In almost all of the preparation instruction materials that we gathered, participants were informed that they would need to complete comprehensive screening evaluations, including the collection of biological samples of urine and blood, to ensure biological safety. Additionally, even when enrolled in the study, participants were notified that additional screening may be required to ensure that potentially pregnant participants were not administered psilocybin. In other cases, these samples were used to ensure that no medications or drugs (including herbal supplements) that might potentially adversely interact with psilocybin were in participants’ blood work prior to administration. Furthermore, as part of the preparation phase, at some sites, participants were sometimes instructed to titrate doses of prescribed medications to an appropriate level (or discontinuing), supervised by study physicians or psychiatrists working on the research team (e.g., monoaminergic psychiatric medication). It is likely that participants across sites were communicated this information in their informed consenting process, which we did not include in our analyses.

Biological and physical safety were also often promoted through instructions across sites to refrain from drinking alcohol 24 h before administration, to get a good sleep and minimize stress in the week before administration, and to eat a light low-fat breakfast (and not to abstain from breakfast). At some sites, mention was made in materials of vital signs that were monitored before, during, and after administration of psilocybin. Additionally, across many sites, on-call study personnel and access to study physicians or psychiatrists were offered to participants for the duration of their enrollment in the study. Overall, five sites mentioned avoiding or limiting medication, substances (e.g., alcohol or coffee), or supplements specifically in their preparatory materials, and seven sites provided information to participants about vital sign monitoring in preparing instructions.

Participant handouts

Handouts administered to participants included information about the study and associated risks, as well as concise information about what to expect on session day for participants. In these documents, much of the information from preparation instructions (described above) was summarized, as well as contact information was provided. For example, the following is an excerpt from a participant handout from an anonymous site:

Sleep: Try to get a few nights of quality sleep before your dosing day, including the night before your dosing session. We want you to be as well rested as possible.

Stress: We encourage you to try and minimize stress for at least a few days prior to your dosing day and if possible, do not travel.

Alcohol: We recommend that you limit or abstain from alcohol use for at least a few days before dosing. You are instructed to NOT DRINK ALCOHOL in the 24 hours before your dosing session. Note: If you drink alcohol the day before your dosing session, we may have to cancel it.

Drug Use: As a reminder, as part of your participation in this study, illicit or nonprescription drug use, including legal marijuana, is NOT ALLOWED. We will test your urine for drugs before you dose. Note: If your test is positive, you will NOT be dosed.

Psychological safety and well-being

The psychological safety and well-being theme accounted for 91 of all 895 themes applied by coders in this study. Psychological safety and well-being was the second most referenced code in this study. Our team found that psychological safety and well-being were also emphasized across sites and study elements designed to facilitate psychological safety included expectation management and facilitator resources as evidenced by theme overlap/co-occurrence.

Expectation management

In many cases, participants’ expectations and intentions for drug administration sessions were explicitly discussed with facilitators in preparatory sessions. At some sites, this was framed as participants’ understanding of their “set” and at other sites, the word “expectations” was used; however, the function of these discussions was the same. Below is language from a facilitator resource, meant as a guide for a semi-structured interview during preparatory sessions:

It would be helpful for me to know whether you have any expectations for our time together, the psilocybin session, and the time after the psilocybin session. Do you have any expectations? In psilocybin therapy, particularly in a research trial, you might find that your experience and how you feel about it is completely different to what you had expected. Some people might not notice any changes in the way that they feel, others might feel very different. How would you feel if your expectations weren’t to be met? What would you do? It can be really useful to keep an open mind ahead of the psilocybin session, and try not to place too many expectations on the psilocybin session itself.

Additionally, participants were provided with information about the number and content of study sessions (i.e., how many preparatory, drug administration, and integration sessions), to encourage a full understanding of the extent of their participation, for example,

There will also be at least two psychotherapy meetings before the study sessions, so that you are fully aware of what to expect and to have all your questions answered.

Another aspect of expectation management across sites involved normalizing aspects of the drug administration day, for example: normalizing nerves or “jitters,” communicating that the participant does not need to “host” facilitators (i.e., make conversation to fill silence), that they should plan to be at the site for the whole day, that snacks and beverages will be available, and that music could be turned off or songs skipped (at most but not all sites) to reduce sensory stimulation. This basic information would appear relevant to managing arising distress and confusion.

Across virtually all sites, whether in written materials or verbal instructions, participants were encouraged in some form or another to “trust, let go, and be open” to the subjective effects of psilocybin—especially regarding potentially challenging experiences. This phrase likely originates from Pahnke,⁶² but has been popularized by Bill Richards, an influential researcher and figure in the psychedelic field. Such an approach is also highly similar to principles of mindfulness, defusion, radical acceptance, and experiential approach commonly discussed in the ACT literature.^50,63 Below is language from an anonymous site that conveys this meaning without invoking that particular phrase and sentiment:

Common themes that arise in those experiencing particularly challenging experiences are the fear of “never coming down,” “going crazy, “feeling as if one is dying, or feeling overwhelmed by the rapidity, profundity, or novelty of the experience. These are typically mitigated rapidly by “letting go,” “giving in,” or “going deeper.” Conversely, resistance, attempting to flee psychologically or physically, or “fighting” the experience almost inevitably leads to a more challenging state and/or prolonged difficulties.

Facilitator resources

Studies attempted to promote psychological safety and well-being not only in materials given to participants but also in the resources provided to study facilitators. These resources included checklists, direct instructions, guided interview forms, and handouts to record observations. Perhaps most importantly, in virtually all resources across all sites, guidelines around physical touch and addressing physical touch were provided to facilitators. Additionally, in these resources were instructions and guidelines for facilitators to manage challenging experiences. For instance, below is an excerpt from the preparation checklist:

Discuss role of facilitators
Discuss breathing/grounding techniques
Discuss and agree upon therapeutic touch boundaries during dosing session
Review potential for challenging experiences and heightened emotion
Explain the intent of dosing day is to focus inward and to have experiences without analyzing them
Encourage participant to allow experiences to emerge naturally without resistance or avoidance
Encourage an attitude of openness/curiosity

Potential for introducing expectancies

Finally, our team found that while virtually every site went through great lengths to address expectations for the purpose of safety, potential for expectancies was the fourth most referenced code in the study. The potential for introducing expectancies theme accounted for 68 of all 895 themes applied by coders in this study. These expectancies were most likely to be influenced by religious or spiritual content and drug administration practices. This content was often not relevant to safety and could potentially introduce extraneous or otherwise unanticipated content that could influence the psychedelic experience, described further in the subcategories below.

Religious or spiritual content

Five sites emphasized efforts to avoid any religious iconography or spiritual content in the materials we received, but we found that this was not a rule across sites. Seven sites (excluding 1 site who conducted their study explicitly in a religious context) referenced mantra-based chants in the music playlists or described the psilocybin administered in a “vessel.”

Some mentions of religious content also appeared in drug administration practices and aspects of setting (see below).

Drug administration practices

Several sites included guided meditations with possible religious/spiritual undertones as part of their drug administration day practices. In some cases, the psilocybin was administered to participants alongside a cup that could be interpreted as a goblet or chalice. In some cases, a chime or a meditation bell was used to mark the beginning or end of sessions. In the materials provided to us, seven sites used the drug administration practices described above as demonstrated in the content we had at our disposal. Additionally, this did not seem to be a result of geographic location or private versus academic setting, as these 7 sites were quite varied in location, affiliation, and treatment population. These practices may therefore reflect practices “handed down” as norms in the field—and are likely worth reconsidering and determining their relevance to the therapeutic administration of psychedelics. Take the example of a site that referenced using a goblet, calling it a “grail,” as well as indigenous content, see below:

Usually begin around 9:00 am; Baseline BP, after reclining for 5 minutes; Then capsule with water (Show our “grail”, copal-burner from Indians in Mexico). Drink all water in goblet. Time to look at photos, art books, trip to bathroom if needed, etc.

Aspects of setting

Finally, the aspects of setting theme accounted for 67 of all 895 themes applied by coders in this study. This theme was unique in that coders were provided photos of the session room from 10 sites, allowing for the tagging of images with relevant themes. Aspects of setting were most likely to co-occur with religious or spiritual content and engaging with music.

Religious or spiritual content

In addition to the goblet, chalice, or altar described at a few sites, many sites described religious artwork such as mandalas. In images provided to us from various sites, candles, art from with indigenous connotations, and statues of the Buddha were featured in some of the rooms. These items were not prominent and whether or to what extent they had an any impact is unknown, but their presence is noted here for potential future reconsideration of their appropriateness. On the other hand, in some images, we received, a medical milieu predominated, with hospital beds on wheels, vital sign monitoring machines, cabinets with medical supplies, and wheelchairs present. While it is an empirical question, such sterile environments may not effectively produce a feeling of safety and comfort in some participants. On the other hand, some participants may feel safer at a medical level by seeing such reminders of the medical context. This is a set of variables for future study. Figure 2 contains two images meant to exemplify the variability in settings which exists across all sites.

Fig. 2. — Room images from anonymous sites.

Engagement with music

We received music playlists from four sites, however, music was mentioned in materials from 100% of sites either in directions to facilitators, and participants or in the responses to the email questionnaire described in the Method section. Therefore, music was considered a basic element of “setting” across all sites. In many cases, descriptions of music included descriptions of participants’ degree of autonomy over engagement with music. For instance, one site describes the process as follows:

The therapists actively encourage patients to listen to the provided music but are supportive of patients who prefer not to engage with the music. The request to take off the headphones or to mute the music is granted, but the commencement of music-listening should be suggested after a period of silence. Under no circumstances should the patient be pressed or urged to put on the headphones. If the patient does not tolerate the headphones, listening through the speakers is accepted.

On the other hand in instructions given to participants at another site, they were asked to engage with music in the following way:

The music is standardized, though we may pause for silence now and then. Let what you hear wash over you. Even if something doesn’t appeal to you, accept it. What is irritating one moment may become beautiful and inspiring the next.

Similarly, in the preparation instructions at another site:

About Music: Just let it wash over you; don’t have to like it, but accept it

Several sites do mention that participants can either listen to their favorite music or bring one to a few songs that can be played, as exemplified by the following site’s approach to music:

We do instruct the volunteers at the screening visits to bring their own playlist to listen to during the study session. We recommend to bring their favorite music, but also to try something new such as more spherical or electronic or meditative sounds. We recommend to put all music into playlists where they just have to press “forward” if the song does not match with their mood, so that they don’t have to search on their Ipods or MP3 players for something new.

Another aspect of engagement with music involved great variability between (and even within) sites in the type of music used. Below is a list of every genre/style of music mentioned in the materials provided (listed alphabetically):

Acoustic
Ambient
Avant-garde
Bells, Gongs
Chants (Indian)
Choral selections
Classical (Western)
Downtempo electronic
English language songs
Experimental/post-rock
Instrumental music
Jazz
Minimalist
Nature sounds
Neoclassical
New age
Psychedelics
Trance
Western/European-Centric vocalizations
World music/Indigenous

Furthermore, in some cases, this variability among a site seemed to be intentional and reflect music that was curated for a specific group. For instance, one site in an email response describes the site’s approach to music as follows:

We use several preselected playlists depending on the study.

Music included may also have been selected to mimic the acute subjective experience of psilocybin, as this one site indicates in their email response:

The cadence is intended to reflect the curve of the psilocybin experience.

Creating a thematic map

We further stratified these themes and subthemes into temporal phases of a psilocybin study––recruitment/screening, preparatory sessions, drug administration sessions, and integration. Across all sites, following a thorough screening and informed consent procedure, participants received preparatory sessions with psychoeducation about the upcoming psilocybin sessions as well as explanation of common reactions and challenges. During the psilocybin drug administration sessions, participants were typically provided eye shades and headphones and encouraged to listen to a prerecorded music playlist while facilitators were present. In the subsequent days following their sessions, participants usually met with their session facilitators to discuss and “integrate” insights and emotions that emerged during their psilocybin sessions. This temporal stratification alongside the four most common themes served to create our final thematic map (see Fig. 3).

Discussion

In this qualitative analysis of materials used in psilocybin studies in the past two decades, we found that the study materials emphasize various risks and attempt to promote safety and efficacy by providing information about biological, psychological, and social forms of safety. These practices and safeguards emphasize risks related to the effects of psilocybin and describe practices and mindsets that attempt to enhance the likelihood that participants will have positive, therapeutic experiences. Preparatory materials vary in content across studies and sites and here we have provided a systematic means of describing major themes in this content. Future research can address the type of content used in preparatory materials based on our analysis, and more research is needed to understand if and how these extrapharmacological factors may predict both benefits and harms.

The treatment model for the safe therapeutic use of psilocybin differs in several ways from conventional therapies typically used in mental health.⁴⁹ Psilocybin appears to induce a heightened sensitivity to context⁶⁴ and suggestibility.⁶⁵ Rather than the pharmacological action of the drug alone (e.g., activation of various 5-HT receptors) directly leading to a desired change, several contextual variables may also contribute toward effecting change in psilocybin therapy for mental health conditions, including individuals’ subjective experiences and expectation, and the quality of preparation and psychological support prior to, during, and following a psilocybin session.

Influence of Setting

The immediate environmental context (or “setting”) in which the substance is administered is considered an important therapeutic factor in clinical trials with psilocybin and other psychedelics.²² A primary theme was that study sites have consistently prioritized making the physical environment comfortable, warm, and inviting to participants, typically in a living room-like setting. Environmental cues may substantially impact participants’ mindsets, signaling to volunteers that not only are the therapeutic procedures safe but that they are also meaningful and powerful.⁶⁶ Comforting space and personal support may contribute to the occurrence of positive, emotionally salient, and highly meaningful “mystical” or “peak” experience, often described in spiritual terms.¹⁰ In the first wave of clinical research with LSD, investigators reported clinical impressions that the use of religious images, artifacts, and music amplified the occurrence of spiritual-type experiences reported by clinical research volunteers.⁶⁷ Previous research with naturalistic samples has also documented significant positive associations between being in a comfortable setting, including being comfortable with others present during a psychedelic experience, and well-being after the session.⁶⁸ Other studies have reported inverse associations between comfort of the environment and the intensity and duration of challenging experiences.^15,69 Future studies could explore how immersion in nature-based settings can potentiate the occurrence of therapeutic experiences, risks, and acute subjective effects.⁷⁰ More controlled studies testing the impact of setting in general are needed.

Research suggests that music can help facilitate positive and therapeutic psilocybin experiences that enhance experiential richness and meaning of the experience.^71,72 While more controlled studies are needed, music can likely support emotional processing, augment visual imagery especially associated with autobiographical memories, and may even be associated with mystical experiences during psychedelic therapy (see Barrett et al.⁷³; Kaelen et al.⁷²; Strickland et al.⁷⁴) and to help evoke and support the intensity of emotions that can enhance therapeutic response and insight and provide an overarching nonverbal structure for the experience.^72,73,75,76 LSD, for example, has been shown to enhance feelings of wonder and transcendence compared with placebo.^72,75 However, it should be noted that in previous research some participants have reported that the music has been “incongruent” with the unfolding subjective experience and felt “intrusive.”⁷²(p. 8) Moreover, most study sites in our analysis indicated that the music they included in their playlists consisted of “world,” “classical,” and “ambient” music with instrumentals and vocalizations, and mostly absent of lyrics, which may not be congruent with all cultures. One small study found no significant difference between the two musical genres by either preference or therapeutic outcomes.⁷⁴ Further research is needed to determine which adaptations are needed to better suit the individual needs based on one’s cultural background and heritage.⁷⁷

Influence of Set

Several factors may shape the internal experience and mindsets of participants in psilocybin studies. The impact of preparation on participant experience appears to be largely due to its effect on shaping one’s mindset (i.e., “set”) and expectations. There has been a strong emphasis on providing detailed psychoeducational information to participants in psilocybin studies. Psychoeducation is intended to increase participants’ knowledge and understanding of the psychological and physiological effects of psilocybin so that they are prepared for challenging experiences should they arise and for informed consent purposes. Additionally, several study sites included in our analysis reported providing participants with instructions to direct their attention inward and to surrender (e.g., “trust, let go, and be open”)⁷⁸ during the psilocybin experience.⁶² Previous studies have found that individuals who are more prepared for and accepting of an intense experience may have less challenging and more therapeutic experiences.⁷⁹ Facilitators in the studies we analyzed were generally instructed to communicate to participants that they are in a safe place, that the experience is time-limited, and to provide emotional support for engaging with any challenging content that might arise. It appears that if set and setting variables are therapeutically optimized, the occurrence of acute distress could be accordingly reduced,²³ although this particular assumption has not yet been directly empirically tested.

Related to participant mindset or “set,” other expectancies are often introduced, some of which are likely intentional (to enhance psychological safety), while others seem less intentional and are likely less relevant to safety. These include characterizations of the acute subjective effects, outcomes, and psychological methods to cope with difficult aspects of the experience. These may influence the experience of, and/or report of, the acute subjective effects of psychedelics as well as their outcomes. We found that some studies described the acute subjective effects of psychedelics in specific ways that seem likely to impact the experience of participants by introducing expectancies.

Other potentially unintended expectancies include religious and spiritual content such as encouraging participants to trust in “god” or “a higher power” at challenging points of the drug administration day experience or explicitly sharing with participants that the mystical experience may be how the therapy process works. Additionally, utilizing a “goblet,” “chalice,” or “grail” in administering the medication (often referred to as a “vessel”) could introduce some implicit connotations and expectancies. The inclusion of religious or indigenous symbolism, art, and tools in the session room, even if intended to convey comfort, could likewise impact expectancies. These expectancies could perhapslead some participants to make supernatural attributions to their experiences that they otherwise might not have, although this has not been tested. One commentary recommended against the use of explicit religious content or symbols in psychedelic studies or treatment due to ethical concerns including the applicability of treatment across different faiths or lack thereof, and the potential for clinicians or scientists to overstep their role and provide metaphysical or religious direction.⁸⁰ This is particularly relevant given that some studies have found evidence that psychedelic experiences can lead to shifts in non-naturalistic beliefs,^81,82 and published commentary raising this as an ethical concern,⁸³ although the evidence that psychedelics alter religious beliefs is limited.⁸⁴

Despite findings related to the introduction of unintended expectancies, most of our thematic findings suggest that the shaping of expectancies may be an important part of the preparatory process and likely to enhance the likelihood of favorable outcomes. Recent research lends preliminary support to this view and has documented positive associations between expectancies of favorable changes and changes in clinical outcomes with psychedelics,^45,85,86 although see Szigeti et al.⁵⁵ for some contradictory results. The role of expectancies in psychedelic therapy raises important questions. Instead of eliminating expectancy effects, some researchers have called for their direct leveraging and synergizing with treatment interventions when treating psychiatric disorders to enhance clinical outcomes.^87,88 The presence of positive expectations has been shown to enhance the effectiveness of a variety of treatments and is responsible for a significant proportion of medication-induced change in many disorders.^89,90

While all medications are susceptible to expectancy effects, psychoactive medications may be particularly malleable in this regard, and perhaps psychedelics most of all, although this has not been tested.⁹¹ The contribution of expectancy effects may work synergistically with genuine psychedelic-induced subjective effects and therapeutic mechanisms to potentiate greater change. For instance, individuals who expect psilocybin will serve as a genuine source of healing may be more willing and able to engage in adaptive psychological processes during and after their psilocybin treatment. However, it is also important to note that overly positive expectancies could contribute to feelings of disappointment or demoralization when placebos are administered, or psilocybin experiences or therapeutic responses are less positive than anticipated. Furthermore, consistent with the notion of nocebo effects, discussion of challenging subjective experiences (e.g., anxiety, panic, and paranoia) may increase the probability that they will occur, although this is an empirical question, and such possibilities should be discussed in order to provide fully informed consent. Finally, another open empirical question is to examine study staff expectancies, which we were unable to address through our content analysis of preparatory materials. Future work might examine whether study staff’s prior experiences with psychedelics, which is common among study therapists in some settings,⁹² might influence the “set” with which they approach and interact with participants. Another factor worth investigating in terms of study staff expectancy is to examine whether training impacts expectancy as there is documented variability with which different mental health professionals view the therapeutic potential of psychedelics^93,94—especially as these views appear to be shifting.^93,95

Furthermore, psychedelic-assisted therapy is often based on the premise that psychedelic substances can act as catalysts or adjuncts to psychotherapeutic processes.^96,97 Some studies included in our analysis employed nonspecific supportive models while other study sites utilized explicit evidence-based therapeutic modalities (e.g., CBT, ACT). Eighteen sites made reference to a psychotherapeutic modality or modalities, with many sites integrating aspects of various modalities which include supportive nondirective psychotherapy, humanistic/person-centered, existential psychotherapy, transpersonal psychotherapy, cognitive behavior therapy, behavioral activation, guided imagery, ACT, psychodynamic psychotherapy, motivational interviewing, and brief expressive supportive group therapy. Although many sites also emphasized a non-directive psychological support model. The therapeutic frame of a study impacts the messaging provided during preparation and integration and thus, likely affects participants’ expectancies not only about whether the treatment will work but how the treatment will work, and what kinds of drug administration experiences are seen as valuable or desirable. A careful and systematic study will be necessary to determine in which contexts and for which clinical populations a nonspecific, supportive psychosocial container versus a specific therapeutic protocol is needed, as well as the optimal dosage of preparatory, medication, and integrative sessions.

Limitations

Due to the large number and heterogeneity of documents that we collected, we cannot provide a comprehensive summary of the content of the study materials. Many of the study materials that we collected came in different formats from one another due to the nonstandardized format of these materials used across the field. Some documents were dozens of pages long, whereas some were only a few pages. At least one PI from every site answered our email query; however, some sites provided comprehensive materials including room images, participant handouts, facilitator handouts, and details on facilitator training––while other sites provided a combination of these materials to varying degrees, with roughly one-third of sites only providing the email response to our query. Additionally, some sites utilized manualized treatments for either all, or some parts, of their preparation sessions. However, much of what is communicated to participants likely falls beyond the bounds of the materials we received, especially in studies that did not utilize a manualized approach. Finally, as we have mentioned above, our analysis does not capture the information communicated to participants during the consenting process, or the verbal discussions following consent. Substantial discussion of risks, potential benefits, and other aspects of study participation that are typically covered during the initial informed consent process were not evaluated. That we did not analyze informed consent documents limits the degree to which our materials fully captured the preparation process.

The qualitative process that we used, reflexive thematic analysis, allowed us to identify themes through a process of iterative engagement with the materials by the qualitative team. However, there were limitations to this process, inherent to this qualitative method. The themes identified were roughly defined according to the expertise and inherently subjective judgments of the qualitative team, and where possible, in alignment with the literature on psychedelic-related concepts (e.g., set and setting). We also were able to quantify the themes that we identified in the documents; however, this should only be considered an approximation given that a more rigorous content analysis that established interrater reliability was not conducted.

It is important to note that best practices for psilocybin-assisted therapy and psilocybin administration have not been well-validated by prospective studies, representing an important area for future research. Additionally, it will be important to engage in critical discussion regarding how to design set and setting variables while considering the psychological safety of populations historically underrepresented in psychology and psychedelic research—for example, people of color—in future protocol development, to determine whether culturally informed care results in better outcomes, and if so, how it is prioritized.^77,98,99 Psilocybin (and psychedelic) research to date suffers from ongoing problems of low sample diversity,⁹⁸ and the preparatory materials are reflective of that. Ongoing and future research should attend to possible cultural differences in the way diverse participant groups engage with preparation materials. In general, more empirical work is needed to understand the impact, or lack thereof, on many of these contextual factors. In the meantime, publishing detailed descriptions of set and setting components will aid in understanding and facilitate efforts for field-wide standardization. The vast majority of aspects of preparation that are reflected in our qualitative analysis are not reported adequately in, or to the degree that they could be reasonably replicated based upon, the primary reports that have resulted from the respective studies that relied upon those methods. Thus, some standardization of reporting these details themselves may be useful. We encourage more thorough reporting of these preparation materials in future studies.

Conclusion

As the field of psychedelic research develops, standardization and systematic manipulation and measurement of study parameters will hopefully continue to progress. There is substantial room for improvment in reporting and standardization. In the meantime, it is imperative to understand current practices across the field. In this study, we gathered study materials from many psilocybin trials conducted in the last two decades and qualitatively analyzed these documents. While these documents varied substantially between studies, we identified themes intended to lower levels of risk and optimize therapeutic effects from psychedelic treatments. We also identified potential contributors to expectancy unrelated to safety that are possibly unintentional and may be extraneous to the aims of a given study. These safety and extrapharmacological elements should be systematically studied in future research.

Acknowledgment

The authors would like to acknowledge Dr. Brian Anderson at the University of California—San Francisco for sharing multiple materials with us for analysis.

Authors’ Contributions

D.B.Y.: Conceptualization, methodology, investigation, writing—original draft preparation, writing—review and editing, and supervision. M.G.: Methodology, investigation, formal analysis, writing—original draft preparation, writing—review and editing, and visualization. A.M.O.: Data curation, investigation, formal analysis, writing—original draft preparation, and writing—review and editing. G.A.L.: Formal analysis, investigation, and writing—original draft preparation. S.T.A.: Resources. K.E.A.: Resources and writing—review and editing. F.S.B.: Writing—review and editing. M.P.B.: Resources. R.C.H.: Resources. T.H.W.C.: Resources and writing—review and editing. M.P.C.: Resources. A.D.: Resources. A.K.D.: Resources. A.G.R.: Resources and writing—review and editing. R.G.: Conceptualization and resources. C.S.G.: Resources. G.G.: Resources. N.G.: Resources. K.G.H.: Resources. P.S.H.: Resources and writing—review and editing. F.H.: Resources and writing—review and editing. D.M.H.: Resources and writing—review and editing. M.W.J.: Resources and writing—review and editing. B.K.: Resources and writing—review and editing. S.K.P.: Resources and writing—review and editing. M.K.: Resources. M.E.L.: Resources and writing—review and editing. L.J.M.: Resources and writing—review and editing. F.A.M.: Resources. S.M.N.: Resources. C.R.N.: Resources and writing—review and editing. K.H.P.: Resources and writing—review and editing. N.M.R.: Resources. S.R.: Resources. K.S.: Resources. J.S.: Resources and writing—review and editing. L.S.: Resources and writing—review and editing. D.S.S.: Resources and writing—review and editing. F.X.V.: Writing—review and editing. B.W.: Resources. M.W.: Resources and writing—review and editing. M.E.Y.: Resources.

Author Disclosure Statement

S.T.A. is a consultant to Compass Pathways, Genomind, LivaNova, Neuronetics, and Sage Therapeutics, and has received research support from Compass Pathways. F.S.B. is a scientific advisor for WavePaths, Ltd., and MindState Design Labs, LLC. T.H.W.C. is a co-investigator/co-principal investigator on three psilocybin clinical trials at the Yale School of Medicine, which are variously funded by the National Institute of Mental Health, Heffter Research Institute, Usona Institute, the Steven and Alexandra Cohen Foundation, and the State of Connecticut. The author also serves as a continuing faculty member in the Psychedelic-Assisted Therapy Training Program offered by Integrative Psychiatry Institute and consults for Transcend Therapeutics. A.D. is a co-investigator on a psilocybin clinical trial at the Lundquist Institute at the Harbor-UCLA Medical Center that receives philanthropic funding from anonymous donors, the Samberg Foundation, Steven and Alexandra Cohen Foundation, and the Norris Foundation. A.K.D. is a board member of the Source Research Foundation. G.G. and L.J.M. are supported by the German Federal Ministry of Education and Research (grant 01EN2006A). G.G. is a co-founder and/or shareholder of OVID Health Systems, Berlin, and the MIND Foundation, Berlin. P.S.H. was previously in paid advisory relationships with Reset Pharmaceuticals Inc. and Silo Pharma and is currently in paid advisory relationships with the following organizations regarding the development of psychedelics and related compounds: Bright Minds Biosciences Ltd., Eleusis Benefit Corporation, Diamond Therapeutics, and Journey Colab Corporation. P.S.H. is also a co-founder of Equulus Therapeutics and Mycelial Health. M.W.J. serves as an advisor to AJNA Labs, Beckley PsyTech, Clarion Clinics, MindMed, Negev Labs, Reunion Neurosciences, and Otsuka Pharmaceutical Development & Commercialization. S.K.P. is a senior clinical consultant for Compass Pathways and has received funding as a co-investigator on psilocybin studies. A.G.R. is a paid scientific advisor to Innerwell and has received research funding from MicroDoz Therapy Inc., Mydecine Innovations Group Inc., Unlimited Sciences, the Council on Spiritual Practices, the Heffter Research Institute, NIH, and DOD. K.S. owns stock in MindMed and Compass Pathways. F.X.V. is the director on the board of the Heffter Research Institute and scientific advisor for the Usona Institute and the MIND Foundation. B.W. owns Axial Therapeutic Research, Inc., a company investigating the safety and effectiveness of alternative treatments for military veteran health.

Funding Information

D.B.Y received funding from The National Institute of Health, Heffter Research Institute, Ho Chiang Foundation, and the CPCR which was funded by a gift from the Steven and Alexandra Cohen Foundation as well as Tim Ferris, Matt Mullenweg, Blake Mycoskie, and Craig Nerenberg. F.S.B. received funding from the Steven and Alexandra Cohen Foundation, the Wana Brand Foundation, the Johns Hopkins Institute for Clinical and Translational Research, and the CPCR which was funded by a gift from the Steven and Alexandra Cohen Foundation as well as Tim Ferris, Matt Mullenweg, Blake Mycoskie, and Craig Nerenberg. G.A.L. received funding for this work from the National Institutes of Health T32DA007250 and Robert Tod Chubrich. A.K.D. is supported by funding from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, Blake Mycoskie, and the Steven and Alexandra Cohen Foundation. A.K.D. is also supported by the Center for Psychedelic Drug Research and Education in the College of Social Work at Ohio State University, funded by anonymous private donors. N.G. is supported by the New York State Psychiatric Institute. She has been a co-investigator on a study of psilocybin for major depressive disorder, funded by Usona Institute. She has received pay salary support from philanthropic contributions from the Steven and Alexandra Cohen Foundation, Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie. D.H. is working on an investigator-initiated trial (IIT) funded by Heffter Research Institute, another IIT funded by Revive Therapeutics, and a sponsored multi-site trial funded/managed by Beckley PsyTech. M.W.J. has received funding from the National Institute on Drug Abuse and the Heffter Research Institute. M.K.’s work is funded by the German Federal Ministry of Education and Research (BMBF). F.A.M. has recently received funding from the Arizona Biomedical Research Center to study whole mushroom psilocybin in OCD. The content shared for this article reflects work completed at our site prior to this award. S.M.N. has received research funding support through the Johns Hopkins Center for Psychedelic and Consciousness Research provided by Tim Ferriss, Matt Mullenweg, Blake Mycoskie, Craig Nerenberg, and the Steven and Alexandra Cohen Foundation, and was a co-investigator on a study of psilocybin for major depressive disorder, funded by Usona Institute. A.G.R. has received research funding support through the Johns Hopkins Center for Psychedelic and Consciousness Research provided by Tim Ferriss, Matt Mullenweg, Blake Mycoskie, Craig Nerenberg, and the Steven and Alexandra Cohen Foundation. J.S.’s investigator-initiated trial of psilocybin-assisted therapy for depression was funded by the Heffter Research Institute. He has served as a paid consultant to Usona Institute. F.X.V. has received funding from the Swiss Neuromatrix Foundation. M.Y. has received research funding support through the Johns Hopkins Center for Psychedelic and Consciousness Research provided by Tim Ferris, Matt Mullenweg, Blake Mycoskie, Craig Nerenberg, and the Steven and Alexandra Cohen Foundation as well as the Heffter Research Institute.

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PERMALINK

A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Assessment of Two Decades of Research

David B Yaden

Marianna Graziosi

Alexa M Owen

Gabrielle Agin-Liebes

Scott T Aaronson

Katja Ehrmann Allen

Frederick S Barrett

Michael P Bogenschutz

Robin Carhart-Harris

Terence HW Ching

Mary P Cosimano

Alicia Danforth

Alan K Davis

Albert Garcia-Romeu

Roland Griffiths

Charles S Grob

Gerhard Gründer

Natalie Gukasyan

Keith G Heinzerling

Peter S Hendricks

Friederike Holze

David M Horton

Matthew W Johnson

Benjamin Kelmendi

Stephanie Knatz Peck

Michael Koslowski

Matthias E Liechti

Lea J Mertens

Francisco A Moreno

Sandeep M Nayak

Christopher R Nicholas

Katrin H Preller

Nathalie M Rieser

Stephen Ross

Karina Sergi

Jordan Sloshower

Lukasz Smigielski

Dea Siggaard Stenbæk

Franz X Vollenweider

Brandon Weiss

Max Wolff

Mary Elizabeth Yaden

Abstract

Introduction:

Methods:

Results:

Conclusions:

A Field-Wide Review and Analysis of Study Materials Used in Psilocybin Trials: Conclusions from Two Decades of Research

The present study

Method

Participants

Materials

Table 1.

Procedure

Analysis

Fig. 3.

Results

Fig. 1.

Biological and physical safety

Preparation instructions for participants

Participant handouts

Psychological safety and well-being

Expectation management

Facilitator resources

Potential for introducing expectancies

Religious or spiritual content

Drug administration practices

Aspects of setting

Religious or spiritual content

Fig. 2.

Engagement with music

Creating a thematic map

Discussion

Influence of Setting

Influence of Set

Limitations

Conclusion

Acknowledgment