Study design

The HOPE trial (HOPE: A Pilot Study of Psilocybin Enhanced Group Psychotherapy in Patients with Cancer) is a pilot study at the Huntsman Cancer Institute of psilocybin-assisted group therapy for patients with cancer meeting criteria for a DSM-5 depressive disorder that involves three 120-min group preparatory sessions, one high-dose (25 mg) group psilocybin session, and three 120-min group integration sessions utilizing a 1:1 therapist to participant ratio (and effectively cutting the clinician hours in half from the current standard individual model). The study was approved by an institutional IRB and participants completed an informed consent process in person prior to screening procedures and study enrollment. In addition to primary outcome measures we collected qualitative survey-based data to inform questions as to the group-format design utilizing a survey as well as free-form written responses.

10/12 participants completed the qualitative survey (HOPE Patient-Reported Experience Questionnaire) administered at 2 weeks post completion of the full study intervention. This included the following questions (5 = strongly agree, 4 = agree, 3 = neutral, 2 = disagree, 1 = strongly disagree). See Supplementary materials for full survey administered with results.

1. I felt like the group format psilocybin session worked well and maximized my individual therapeutic response.

2. I felt an increased connection to other group members in virtue of having a group format psilocybin session and having contact with their individual processes.

3. I felt like the group psilocybin session was a natural extension of the group process initiated through the preparatory sessions.

4. I felt like having a communal music track worked well.

5. I would have preferred to have an individual music track with headphones.

The total duration of the intervention from the first preparatory session to the final integration session was 3 weeks. Referrals were made from within the Huntsman Cancer Institute. Screening involved an initial chart review and contact with referring provider and primary oncologist. Participants were then contacted over the telephone prior to enrollment to discuss the study eligibility and timeline requirements and answer questions (Please see Appendix 1 for inclusion and exclusion criteria.). Prospective participants then met individually with a study co-investigator for a full psychiatric and medical evaluation and screening questionnaires (PHQ-9, Columbia Suicide Severity Rating Scale) to ascertain eligibility. Participants were then paired prior to the first preparatory session with an individual therapist who works with them through the intervention. The group process did not follow a specific manual but utilized a supportive-expressive model commonly employed within cancer support groups.

Study therapists were drawn from a ten person multidisciplinary therapist team comprised of social workers, psychologists, a nurse, and MDs who had completed a two day training in psychedelic-assisted therapy in March 2020 led by Mary Cosimano MSW, Alan Davis PhD, and Rafael Lancelotta MS, LPC as well as a subsequent half-day training led by Mary Cosimano in January 2021. Two therapists had also completed the CIIS Certificate Program in Psychedelic Therapy and Research.

Integration sessions (3)

The first integration session took place on the Monday following the Saturday dosing day and the integration period extended a total of 2 weeks with sessions on Monday, Friday, and the following Friday. These sessions (120 min each, again with a 30 min ‘break-out’ session with assigned individual therapists) were held in the same auditorium in the Huntsman Cancer Institute, using the same format as the preparatory sessions with participants and therapists arranged in a circle. See Appendix 2 for photos of the space used. Again, the lead therapist led the group process with input from other study therapists.

These sessions included the following points of emphasis:

1. a.Individual sharing of experiences. Reflections on the experiences of other participants.
2. b.Revisiting of intentions and how these surfaced or didn't surface during the experience.
3. c.Revisiting existential themes.
4. d.Exploration of spiritual themes that arose.
5. e.Reflection and exploration of the group experience during the session.
6. f.Strategies for ongoing integration of insights and psychological material including mindfulness practices, returning to the music playlist, journaling/writing/artwork/other creative expressions.
7. g.Reflections on the temporary nature of this group and the experience itself, the impending end of the group process.
8. h.Reflections on how, when, and if to share this experience with others in participants' lives: partners, friends, etc.
9. i.Gathering feedback as to the group format and protocol.

Space

Regarding the premium on “set and setting” emphasized in psychedelic research, it is worth noting that our space availability presented certain challenges. To hold a psilocybin session in an infusion room in a cancer hospital for patients who have deep familiarity (and a range of associations, not altogether positive) with this space was a concern for our team. The choice of this space resulted from practical necessity rather than careful deliberation: it was the space we had available within the institution that would accommodate the size and nature of this intervention. This was discussed with participants from the first preparatory group, including careful description of the space, as well as an opportunity for participants to walk through the space beforehand to increase comfort. Even prior to enrolling in the study, participants were informed about the group nature of this intervention and the spaces we would be using. This offered time for questions and concerns to be raised and discussed both individually as well as in a group format. The study team took additional measures to de-medicalize the space with decorations and flowers. We also formalized a process of ‘settling into’ the space on the dosing day with participants having a set aside time in the morning (prior to dosing) to personalize their individual bay. This did not result in any negative reports. We suspect analogous constraints will present across other research sites and it is reassuring that approaching these constraints intentionally seemed to mitigate negative outcomes. Two participants described difficulty with the use of eyeshades: “would have preferred option of eye shades or no eye shades”, “the mask and eye shield combination was too much for me. I also could have used some gentle stretching on the medicine day.” Similarly, two participants felt the space constraints were too confining: “Instead of being in a reclining chair, maybe a couch or cot of some sort. Otherwise I thought the environment and set and setting was just what I needed”. One person suggested the dosing day “include some outside time”: a reasonable suggestion that nonetheless poses certain logistical challenges in the context of a monitored research study.

Considerations:

1. A.The nature and specific description of the site of the medicine session should be discussed upfront with participants, even prior to enrollment
2. B.Even sub-ideal settings can be personalized and made more welcoming. A ‘medicalized’ environment – if handled intentionally – is not necessarily something to be avoided: in fact, the psychological ‘content’ that can be facilitated here is potentially quite therapeutically useful, provided this is facilitated in a sensitive manner.
3. C.Features of an “ideal” space for group-based interventions remain incompletely characterized at this time. It is worth noting that participants in our trial reported that the ability to hear fellow group members during the psilocybin session enhanced a sense of group connection and was NOT experienced as a distraction.
4. D.We propose that softening the parameters of the space as well as the therapist-to-participant ratio place may necessitate a stronger emphasis on screening and group cohesion, However it is unclear from our experience whether closer proximity or lack of partitioning would have had a positive or negative impact.
5. E.Provision of a separate, more private ‘break-out’ room may be a useful feature for group work given heterogeneity of subjective experience. While the parameters for using this space remain unclear, simply having the availability can provide reassurance both to participants as well as study therapists, which likely has effects on the experience itself. In our study we did not end up using this space however had one scenario arise where the participant requested to leave the group space given perceived intolerability of the music. This was handled supportively by the individual therapist with additional support from the lead therapist and proved to be a transitory state that was worth moving through within the parameters of the group space. While we can imagine scenarios where this ‘break out’ room may prove necessary it seemed equally if not more important in the context of the individual therapeutic work in this situation to continue to hold the space in a group format. This participant confirmed this in subsequent integration sessions, describing a newfound ability to be present even with difficult emotional material in her life and in fact expressed deep appreciation for the music playlist and the therapist support to remain present in the group space through the experience.

Therapist team structure and numbers

Our model employed a 1:1 participant to therapist ratio with an additional lead therapist role not assigned to any particular participant. The lead therapist led the group process during the preparation and integration sessions and provided an overseeing role during the psilocybin session. This role was important for several reasons: a) this allowed individual therapists to focus primarily on the participant they were working with through what was a personally immersive process, b) it provided structure and a sense of leadership for the group of participants as a whole who had both the support from the group container but also from the dyad, c) it provided an additional layer of support for study therapists to process the experience, d) it ensured that the numerous practical necessities of the process were monitored from a perspective of more distanced objectivity and attention to the study demands.

The break-out sessions into participant/therapist dyads was felt by participants to be a critical component of the intervention. This served to establish rapport, comfort, security/safety, and allowed for deeper exploration of autobiographical themes and intentions for the psilocybin session. We did not employ a formalized approach to assigning therapists however the team discussion about this prior to starting the intervention was an important part of our process to ensure the best fit based on available knowledge of participants throughout the screening process. Our protocol allowed for additional contact with the assigned therapist between group sessions as well as after the intervention and a majority of participants engaged with this, feeling this to be a helpful form of support.

Considerations:

1. A.There is compelling rationale for one-on-one therapeutic contact, even if optimal frequency and duration of these one-on-one interactions remains unknown. If further reductions in therapist:participant ratio are pursued, we recommend strategizing ample one-on-one contact through the process.
2. B.While it brings the challenge of larger group size, including all therapists in the group process is an effective way of facilitating a sense of cohesion, safety, trust, and collective experience.
3. C.The lead therapist provides a critical role due to more objective distance
4. D.A limiting factor to number per cohort is the logistics of screening and enrolling of participants within a certain time window. Given the premium on effective screening for engaging in a group process like this it is reasonable to target lower group numbers, particularly initially.

Group process

Groups were run in a supportive-expressive group therapy style which incorporated specific education and information regarding the psilocybin experience and dosing day. This did not involve a specific manual. Groups focused on building connections, exploring feelings associated with death and dying, expressing emotions, examining life priorities, and utilizing the support of important relationships with family and friends (Kissane & Ngan, 2015). We also incorporated mindfulness meditation techniques as well as guided-imagery sessions.

Questions #1–3 assessed participant responses to the group format with all participants reporting significant positive impressions of the group-based protocol and no negative reports. Free-form qualitative reports also supported the success of this model.

While group-based interventions offer a number of advantages in terms of efficiency, and possible benefits as to therapeutic outcomes in certain populations, there is a concomitant increase in the number of variables throughout the process that introduce logistical challenges as well as unpredictability.

Considerations:

1. A.Supportive Expressive Group Therapy principles, in combination with education regarding the effects of psilocybin, provide a potentially effective ‘hybrid’ group model that can serve to prepare group members for their psilocybin experience, while building group bonds that can potentially enhance the psilocybin experience.
2. B.Provide balance between education about the effects of psilocybin and allowing time for the open exploration of emotions and development of group relationships.
3. C.Emphasize safety and confidentiality from the outset of the group process.
4. D.While adhering to supportive expressive group therapy themes seems to be of benefit, it can be helpful to maintain an open attitude towards whatever arises in the group experience, and it is not necessary to follow a rigid structured group format.
5. E.Recognize that individuals in the group have varied prognoses and experiences, and to emphasize that individual experiences can edify rather than detract from the group dynamic.

Music

Our intervention employed a playlist designed by a member of the study team member (https://open.spotify.com/playlist/4wgi37zvjxdBHiwX9S04ot?si=6934241d8f6548dc). There are many questions as to optimal use of music as a therapeutic agent during psychedelic-assisted therapy which at present remain unanswered. The playlist was presented as a therapeutic tool for the session itself: that even negative reactions to the music can be invited in (similar to difficult psychological content) and that there may be significant personal benefit or insight as a result. We made the decision to use a speaker system in the room rather than individual head-sets: this was aligned with implicit and explicit emphasis on the group nature of the intervention. If there were other noises in the room from participants or therapists this too was to be welcomed in as a feature rather than a bug. As a study team we felt that this emphasized the communal nature of the experience and the connection between participants. This strategy is also parsimonious in terms of study cost, ensuring sound consistency and quality for participants, and minimizing wires in the group space presenting a trip hazard.

Participant reports were mixed as to the success of a communal playlist based on questions #4 and #5. While a significant majority of participants felt that a communal track worked well some participants did express a preference for a more individual music experience with headphones. One participant expressed a desire for “choosing my own music. I had to cry and release my emotion, but I felt like the music was too sad, and I couldn't stop crying. It would have been nice to listen to something happier.”

Considerations:

1. A.There may be good rationale for not using personal headphone sets for participants provided that the use of a communal speaker-driven music playlist is framed explicitly and deliberately during the preparation sessions.
2. B.While participants are still directed internally, there are possible therapeutic benefits to opening up the sense of what is therapeutically directed for them: i.e. just as the particular music tracks can be emphasized as a specific tool the noises in the room itself and the relationship to other participants can itself be framed and employed as a therapeutic tool. The mantra “all is welcome” is helpful in characterizing this for participants and therapists alike, i.e. on inspection this is a radical invitation that doesn't draw lines. This emphasis is equally as important for the therapist group. The limits and optimization of this strategy remain unknown however it does suggest interesting directions for further research.
3. C.If a “break-out” room is used this necessitates a strategy for the playlist within that space.
4. D.There remain important questions as to the therapeutic value of more personally designed playlists vs. protocol driven playlists.

Potential issues and future directions

Group-based psychedelic-assisted therapy models have significant promise both in terms of efficiency and scalability of the intervention as well as augmentation of therapeutic effect there are some caveats worth mentioning. Even with explicit emphasis on themes of acceptance and ‘letting go’, group format preparation and integration can nonetheless implicitly suggest that there are more or less ‘right’ or ‘wrong’ ways the session can go. This can present with comparison between group members and potentially even subtle marginalization of a group member who may have had a divergent experience from the norm. Classic psychedelics have demonstrated effects at increasing suggestibility (Carhart-Harris et al., 2015). This psychological effect can likely be leveraged in therapeutic directions. However, it also suggests that certain risks may be amplified in a group setting given known dynamic of enhanced social suggestibility within groups even sober. Hypothesized enhanced suggestibility in this format also implies a large degree of care, deliberation, and consistency in terms of therapist contributions during the group process. Effects of enhanced suggestibility have no doubt contributed to the frequency of coercive or abusive behaviors on the part of psychedelic therapists which has been receiving increased visibility as of late (Ross LK, n.d.). This tension between more open-ended and non-directive styles of therapy and more directed therapeutic approaches presents an ongoing series of empirical questions for the field.

It remains an open question as to whether non-directive, supportive psychotherapy models present the optimal behavioral adjunct to psychedelic therapy, or whether more directive and structured therapy approaches (e.g., CBT, ACT, mindfulness-based interventions) might be the most efficacious adjunct. More directive approaches may require clearer conceptual frameworks regarding the pathogenic mechanisms that undergird the patient's specific malady, as well as a clear conceptualization of how the specific psychological processes activated by a given psychedelic (and accompanying behavioral techniques) might be leveraged to target these mechanisms. To optimize the efficacy of psychedelic-assisted group therapy, the field should strive to develop nomothetic and idiographic psychedelic treatment models, while being attentive to the pitfalls of enhanced suggestibility and possibilities of coercion.