Group Format Psilocybin-Assisted Therapy: Commentary on the HOPE trial (HOPE: a pilot study of psilocybin-enhanced group psychotherapy in patients with cancer)
Benjamin R. Lewis*, Kevin Byrne, Anna Beck
University of Utah, Salt Lake City, Utah, USA
Depression and depressive symptoms are an all too common bedfellow for many cancer patients, adding to an already daunting array of symptoms requiring palliation1-4. Without successful treatment, depression significantly increases mortality rates5,6, sabotages quality of life7, reduces cancer treatment compliance8, and multiplies the rates of completed suicide rates four-fold9,10. Not surprisingly, caregivers for depressed cancer patients experience a degree of depression and hopelessness strongly correlated with these same clinical features in patients11.
Standard antidepressants including selective serotonin reuptake inhibitors (SSRIs) have several key therapeutic disadvantages. A significant fraction of patients does not fully respond to these treatments. Achieving a full treatment effect may take up to 6-8 weeks. Finally, the multifaceted polypharmacy of cancer therapy often results in drug-drug interactions with these daily medications, increasing the risks for toxicity or dangerous side effects. There is an urgent need for new, rapid-acting antidepressant treatments that have fewer side effect risks.
Psilocybin may provide new hope. Considered a ‘classic psychedelic’: it resides in a class of compounds of 5HT-2A agonists like lysergic-acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline. These compounds reliably induce alterations in brain functional connectivity with associated profound changes in conscious experience thought to be related to downstream therapeutic effects12-14. Following decades of a politically generated moratorium on clinical trials, a recent resurgence of clinical and research has revived development of new practices for safe administration15.
Psilocybin-assisted therapy (PAT) has emerged in recent years as a safe, feasible, and highly effective treatment option for refractory depression16-20. Affected cancer patients have duly been the target of several randomized controlled trials on PAT to date21-24. These studies have demonstrated rapid and significant symptom relief following a single high-dose psilocybin administration in an individual format. Results are also durable, lasting 6 months21-23 and even >5 years for up to 80% of participants25. Furthermore, these studies demonstrated that the psilocybin experience was well-tolerated by patients without any serious adverse events. It is worth comparing this magnitude of effect to the remission rates expected with standard antidepressant treatment: 36.8% remission rate with first trialed antidepressant26.
The current accepted model of PAT employed in clinical trials employs an individual model across preparatory sessions (2 hours each), 1-3 individual psilocybin sessions (8 hours each), and subsequent integration sessions (2 hours each) generally with two therapists present for each encounter. This model is resource intensive and presents challenges for scalability and accessibility. A protocol involving a single psilocybin session with this format requires 40+ clinician hours per participant. Group formats dramatically expand the scale on which these treatments can be offered. Furthermore, there are reasons to hypothesize synergistic effects between the psilocybin experience and group process which might be uniquely helpful for symptoms of depression. Our research group has completed a 12-person pilot study on the safety and feasibility of group-format PAT (HOPE: a pilot study of psilocybin-enhanced group psychotherapy in patients with cancer)27,28. This study is the first modern study to employ a full group format for this intervention.
Nonetheless there is a long history of classic psychedelics used in group settings for spiritual purposes by indigenous groups. There have been a number of group format serotonergic psychedelic studies conducted prior to rescheduling of these compounds by the DEA29 however design of these early modern trials was heterogeneous, lacking in rigor, with resultant difficulties in interpretation. Prior to the HOPE trial there have been two recent trials employing variations on group format. This includes a study of PAT for 30 patients with major depressive disorder associated with a cancer diagnosis run at The Aquilino Cancer Center24 as well as a pilot study of PAT for male AIDS survivors with demoralization30. Both of these studies reduced the standard 2:1 therapist to participant ratio, however neither employed a group-format psilocybin dosing session.
We investigated the safety and feasibility of group format PAT with the HOPE trial, a single-arm, open-label pilot study of group psilocybin-assisted psychotherapy in 12 participants with symptoms of depression and anxiety associated with a cancer diagnosis. This study was designed to assess the safety and feasibility of a full group model intervention that employs a group psilocybin administration session (25mg) as well as group preparation and integration sessions, with cohorts of four participants at a time. This study demonstrated the safety and feasibility of this model of psilocybin-assisted therapy with all participants completing the intervention and no serious adverse events. There was a total of twelve AEs across six participants which were self-limited. While this study was not designed to test efficacy we demonstrated a clinically substantial reduction in HAM-D scores from baseline to the 2-week primary endpoint (21.5 to 10.09, F1,9.00=33.81, p<0.001, d=1.71) and 26-week endpoint (21.5 to 14.83, F1,6.49=15.58, p=0.006, d=1.28). We also demonstrated significant improvement in measures of quality of life and well-being (FACIT-Sp)27. We also observed significant correlation between scores on the Mystical Experience Questionnaire (MEQ-30)- a 30-item questionnaire designed to assess experiential aspects of the psilocybin experience- and HAM-D scores at the 2-week primary outcome timepoint.
In addition to primary outcome measures this study gathered qualitative data from study participants regarding response to the group-based protocol. 10/12 participants completed this qualitative survey, administered at 2 weeks post completion of the full study intervention28. We found that participants felt that the group format was well-tolerated and perceived to be a critical component of their therapeutic process.
This study has several limitations in addition to its small size. The lack of a control group problematizes assessment of efficacy of psilocybin and suggests amplification of likely expectancy effects. Five out of twelve participants had prior experience with classic psychedelics: a higher rate than predicted by estimated population prevalence and suggestive of possible selection bias. Our participant sample was predominantly Caucasian with limited diversity. This continues rather than improves upon a concerning trend in the field to date. Use of a non-manualized supportive-expressive group psychotherapeutic intervention also presents challenges for replicability.
Despite these limitations, the HOPE trial represents a requisite first step on the path of redesigning PAT into a scalable treatment capable of relieving depressive symptoms in cancer patients. With less intensive resource utilization and a group format, HOPE does promote ‘hope’ for relief from a debilitating and far-reaching bedfellow of depression in the cancer world.
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- Grassi L. Psychiatric and psychosocial implications in cancer care: the agenda of psycho-oncology. Epidemiol Psychiatr Sci. 2020; 29: e89.
- An E, Lo C, Hales S, et al. Demoralization and death anxiety in advanced cancer. Psychooncology. 2018; 27(11): 2566-2572.
- Walker J, Sawhney A, Hansen CH, et al. Treatment of depression in adults with cancer: a systematic review of randomized controlled trials. Psychol Med. 2014; 44(5): 897-907.
- Pinquart M, Duberstein PR. Depression and cancer mortality: a meta-analysis. Psychol Med. 2010; 40(11): 1797-810.
- Satin JR, Linden W, Phillips MJ. Depression as a predictor of disease progression and mortality in cancer patients: a meta-analysis. Cancer. 2009; 115(22): 5349-61.
- Arrieta O, Angulo LP, Núñez-Valencia C, et al. Association of depression and anxiety on quality of life, treatment adherence, and prognosis in patients with advanced non-small cell lung cancer. Ann Surg Oncol. 2013; 20(6): 1941-8.
- Colleoni M, Mandala M, Peruzzotti G, et al. Depression and degree of acceptance of adjuvant cytotoxic drugs. Lancet. 2000; 356(9238): 1326-7.
- Shim EJ, Park JH. Suicidality and its associated factors in cancer patients: results of a multi-center study in Korea. Int J Psychiatry Med. 2012; 43(4): 381-403.
- Zaorsky NG, Zhang Y, Tuanquin L, et al. Suicide among cancer patients. Nat Commun. 2019; 10(1): 207.
- Mystakidou K, Tsilika E, Parpa E, et al. Caregivers of Advanced Cancer Patients: Feelings of Hopelessness and Depression. Cancer nursing. 2007; 30(5): 412-8.
- Carhart-Harris RL, Leech R, Hellyer PJ, et al. The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci. 2014; 8: 20.
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- Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine. 2022; 387(18): 1637-1648.
- Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. 2011; 384(15): 1402-1411.
- Carhart-Harris RL, Bolstridge M, Rucker J, et al. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry. 2016; 3(7): 619-27.
- Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 2018; 235(2): 399-408.
- Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA psychiatry. 2021; 78(5): 481-489.
- Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016; 30(12): 1181-1197.
- Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 2016; 30(12): 1165-1180.
- Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of general psychiatry. 2011; 68(1): 71-8.
- Agrawal M, Emanuel E, Richards B, et al. Assessment of Psilocybin Therapy for Patients with Cancer and Major Depression Disorder. JAMA Oncology. 2023; 9(6): 864-866.
- Agin-Liebes GI, Malone T, Yalch MM, et al. Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. J Psychopharmacol. 2020; 34(2): 155-166.
- Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163(11): 1905-17.
- Lewis BR, Garland EL, Byrne K, et al. HOPE: A Pilot Study of Psilocybin Enhanced Group Psychotherapy in Patients with Cancer. Journal of Pain and Symptom Management. 2023; 66(3): 258-269.
- Lewis BR, et al. Group format psychedelic-assisted therapy interventions: Observations and impressions from the HOPE trial. Journal of Psychedelic Studies. 2023.
- Trope A, Anderson BT, Hooker AR, et al. Psychedelic-Assisted Group Therapy: A Systematic Review. J Psychoactive Drugs. 2019; 51(2): 174-188.
- Anderson BT, Danforth A, Daroff PR, et al. Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine. 2020; 27: 100538.