Psilocybin-Assisted Early Palliative Care for Demoralization and Chronic Pain: An Open-Label Pilot Study

Demoralisation syndrome is described as a common and under-recognised form of existential distress in cancer and palliative care, marked by hopelessness, helplessness, and loss of meaning. The authors note that it is associated with serious outcomes including suicidal thinking, and that there are currently no evidence-based pharmacological treatments for demoralisation as a primary target. Chronic pain is also common in cancer populations and frequently co-occurs with psychological and existential distress, creating a substantial burden for patients and a challenge for routine palliative care. The paper argues that a transdiagnostic intervention, such as psilocybin-assisted therapy (PAT), may be attractive because it could address multiple dimensions of suffering at once. The study was designed to address several gaps: PAT had not yet been tested in people with both demoralisation and chronic pain, nor within a real-world multidisciplinary outpatient palliative care model that includes medical, psychosocial, and spiritual support. Zarrabi and colleagues therefore set out to assess the safety, feasibility, and acceptability of PAT delivered alongside multidisciplinary palliative care support in cancer patients across the illness trajectory, while also exploring early changes in demoralisation, pain, and related symptoms. A further aim was to examine a facilitation model that included a spiritual health clinician as a core member of the psychedelic care team.

This was an open-label pilot study approved by the Emory Institutional Review Board and registered on Clinicaltrials.gov. Participants were recruited between 1 November 2022 and 9 January 2024, mainly from Emory’s Winship Cancer Institute and outpatient palliative care programme, with some additional recruitment through online advertising and word of mouth. The study was overseen by the Winship Cancer Institute Data Safety and Monitoring Board. Eligibility required a diagnosis of solid or liquid cancer made at least 1 year before screening, cancer survivorship at any stage, an oncologist-estimated prognosis of more than 6 months, moderate-to-severe demoralisation, chronic pain for more than 3 months with an average pain score of at least 5 on the Brief Pain Inventory, age 26 to 85 years, and availability of a trusted person to receive the participant after dosing. The extracted text also indicates exclusion of several psychiatric, cardiovascular, neurological, and medication-related conditions, including use of drugs considered incompatible with psilocybin. Participants taking opioids, benzodiazepines, or cannabinoids could remain on those regimens, but other prohibited medications were tapered off if needed, generally within 4 weeks. The study had three phases. Phase 1 covered screening and medication tapering. Phase 2 included baseline assessment, three preparatory sessions, the psilocybin dosing day, and three integration sessions, with the primary endpoint at Day 42, six weeks after baseline. Participants also had multidisciplinary palliative care visits before and after dosing, including support from a social worker and from a physician or advanced practice provider. Phase 3 consisted of remote follow-up assessments at Day 56 and Day 98 to assess durability and capture later adverse events. Preparation and integration sessions were about 2 hours each, and palliative care visits were about 1 hour. Participants received a single 25 mg oral dose of pharmaceutical-grade synthetic psilocybin. The therapeutic model used a dyad of a mental health clinician and a spiritual health clinician, rather than two mental health clinicians, and these facilitators were present for preparation, the full dosing day, and integration. The dose was delivered in a living-room-like treatment space with eyeshades, music, and a supportive, non-directive approach. The multidisciplinary palliative care team provided an added layer of medical, psychosocial, and spiritual support. The primary outcomes were safety, feasibility, and acceptability. Safety was assessed through adverse event reporting, hourly vital signs during the dosing session, and suicidality assessment with the Columbia Suicide Severity Rating Scale. Feasibility was judged mainly by retention and missed visits, with an 80% threshold for success. Acceptability was measured with a satisfaction item and a retrospective questionnaire about memorable, meaningful, educational, and spiritually significant aspects of the session, with 60% set as the threshold for success. Exploratory outcomes included demoralisation, pain intensity and interference, pain catastrophising, anxiety, depression, and flourishing, alongside acute psychedelic experience measures such as the Mystical Experience Questionnaire and Challenging Experience Questionnaire. The study was not powered for inferential testing; analyses were descriptive, using medians and interquartile ranges at baseline, Day 42, and Day 98, with Cohen’s d reported as an effect size. SAS version 9.4 was used for analysis.

Of 30 people who expressed interest, 26 were prescreened and 16 were eligible for screening. Fifteen were eligible, but one declined after learning more, three later became ineligible after consenting, and 11 proceeded to baseline visits. One participant withdrew before dosing because their goals shifted away from the study aims. In total, 10 participants received psilocybin and completed follow-up through Day 98. Among the 10 dosed participants, seven were female and nine were white. Most had a history of major depressive disorder, with six currently meeting criteria and three in remission; smaller numbers had panic disorder, generalised anxiety disorder, and PTSD. Six participants had advanced cancer, four were receiving active cancer-directed treatment, and two had graft-versus-host disease after bone marrow transplant. Seven participants chose to taper off prohibited medications before baseline, most commonly duloxetine. Pain phenotypes were mixed, with the most common being combined nociceptive and neuropathic pain, sometimes with nociplastic features as well. Safety findings were reassuring within the limits of a small pilot. There were no serious adverse events related to psilocybin or the intervention, and no changes in suicidal ideation on the Columbia Suicide Severity Rating Scale. All participants reported at least one adverse event during dosing, most commonly nausea and headache. Blood pressure and heart rate were monitored hourly over the 8-hour dosing session; the authors report no clinically meaningful rise in systolic or diastolic blood pressure, with a peak systolic pressure of 177 mmHg and peak diastolic pressure of 105 mmHg. Feasibility and acceptability targets were met. All dosed participants completed study visits, and 10 of 11 who began baseline/preparatory visits finished the trial. Primary assessments were fully completed for all dosed participants, and only four exploratory assessments were missing. Acceptability was high: all dosed participants rated the intervention as highly acceptable. Seven of 10 said it was among the five most meaningful and educational experiences of their lives, and six of 10 said it was among the five most spiritually significant experiences of their lives. Exploratory symptom outcomes suggested marked improvement, though these were not tested with inferential statistics. Demoralisation fell substantially from baseline to Day 42, with a median change of -14 points and Cohen’s d of -0.94, and improvement persisted to Day 98, with a median change of -11.5 points and Cohen’s d of -1.49. By Day 42, nine of 10 participants no longer met criteria for clinically significant demoralisation, and six still did not meet criteria at Day 98. The authors also report pronounced decreases in depression scores and that pain scores fell below the trial enrolment threshold by the study endpoint. The acute psychedelic experience was often intense and meaningful. The median total Mystical Experience Questionnaire score was 123, indicating a high level of mystical-type experience. The most prominent challenging experience themes were grief, physical distress, and fear. Regarding medication tapering, five of the seven participants who tapered off prohibited medications had restarted them by Day 98, while two remained off duloxetine and one participant remained off buprenorphine.

The authors interpret the study as showing that PAT can be delivered safely, feasibly, and acceptably alongside multidisciplinary palliative care for cancer patients living with both demoralisation and chronic pain. They emphasise that this is, to their knowledge, the first PAT study to include spiritual health clinicians as facilitators, and they present this triad model as a novel and potentially important adaptation for psychedelic care in palliative settings. They argue that the findings are notable because pain and demoralisation are common, overlapping sources of suffering in serious illness, and because most participants in this small cohort appeared to experience durable reductions in demoralisation and pain severity. The authors suggest that PAT may have potential as a multicomponent intervention that could address both psychological and pain-related distress, and they frame this as possibly representing a broader shift away from symptom-by-symptom treatment towards more integrated care. The discussion places the results in the context of earlier pilot studies in hospice patients and AIDS survivors with demoralisation, which also found PAT to be feasible. Zarrabi and colleagues state that the present study adds to that literature by extending PAT into outpatient palliative care and by formally incorporating a spiritual health clinician, which they believe may be valuable for supporting spiritually salient material and for scaling care in real-world settings. The authors also highlight several uncertainties. They note the very small sample size, the wide interquartile ranges and confidence intervals around exploratory outcomes, and the lack of a control group, blinding, randomisation, and statistical power for efficacy testing. They emphasise that the study is not generalisable and cannot establish efficacy. They also point out that participants had varied pain phenotypes, so future research should examine whether different pain subtypes respond differently to PAT, and whether demoralisation and pain improvements mediate one another. The fact that most participants had tapered and later resumed prohibited medications is presented as another area needing further study, including whether such tapers are always necessary. In terms of implications, the authors suggest that larger randomised trials are needed to test efficacy, identify predictors of response, and evaluate whether pain-specific elements should be added to the protocol. They also argue that the broader regulatory environment may soon make PAT more accessible in palliative care, increasing the importance of developing standardised, multidisciplinary models and training pathways for clinicians.

The authors conclude that PAT delivered by a multidisciplinary palliative care team was feasible and acceptable in demoralised cancer patients with chronic pain, and that no serious adverse events attributable to psilocybin occurred in this pilot study. They state that the findings support further research, including blinded randomised trials in more diverse populations, to clarify predictors of response and the potential role of PAT within routine outpatient early palliative care for pain and psychospiritual distress.