Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study

Demoralization is described as existential suffering marked by helplessness, loss of meaning, and poor coping, and it is common among people with serious medical illnesses. Previous psychotherapies targeting demoralization have shown limited efficacy against active controls, and recent trials of psilocybin administered with adjunctive individual psychotherapy have demonstrated safety and durable symptomatic improvements for depression, anxiety and existential distress in patients with life-threatening illness. However, it is unknown whether psilocybin therapy can ameliorate demoralization in other clinical populations, or whether a group-based delivery model is feasible and safe. This pilot study sought to assess safety, feasibility, and preliminary clinical effects of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with substantial traumatic loss, social isolation and multimorbidity. Given the novelty of both the target population and the group-based approach, the investigators prioritised implementation outcomes (recruitment, tolerability, retention and protocol adherence) while treating clinical efficacy as exploratory.

Anderson and colleagues conducted a single-site, single-arm, open-label pilot study in an outpatient unit of an academic medical centre. The intervention combined preparatory individual sessions, a course of group psychotherapy, a single high-dose oral psilocybin administration session, and follow-up group and individual integration. Treatment spanned roughly seven weeks and comprised three hours of preparatory individual psychotherapy, 12–15 hours of group psychotherapy (90-minute sessions twice weekly), one eight-hour medication visit, and a two-hour individual integration session the day after drug administration. Three sequential cohorts were run, each with six participants and two therapists (total n = 18). Inclusion criteria required participants to be gay-identified, English-speaking cisgender men aged 50 or older who reported an HIV/AIDS diagnosis prior to the widespread availability of protease inhibitors (≈1996), and who scored ≥8 on the 16-item Demoralization Scale-II (DS-II). Standard exclusion criteria for psilocybin were adapted and applied, and cohort composition aimed to enhance homogeneity and rapid trust-building. Group therapy was adapted from Brief Supportive-Expressive Group Therapy (SEGT) with modifications for integration of the psilocybin session; sessions began and ended with brief breathing and guided mindfulness exercises. Crystalline psilocybin was dosed orally at 0.30 mg/kg for Cohort 1 and escalated to 0.36 mg/kg for Cohorts 2 and 3 after tolerability was established. Each participant had at least one of their group co-therapists act as a medication-session guide. Primary feasibility outcomes were recruitment and retention; safety was assessed via adverse event interviews at every visit, the Columbia-Suicide Severity Rating Scale (C-SSRS), the Challenging Experiences Questionnaire (ChEQ) after medication visits, and cardiovascular monitoring during sessions. The primary clinical outcome was change in mean demoralization (DS-II) from baseline to end-of-treatment and to 3-month follow-up. Secondary measures included PTSD symptoms (PCL-5), complicated grief (ICG-R), state anxiety, cognitive screening (MoCA), and substance use screens (AUDIT/DUDIT for later cohorts). Analyses were intent-to-treat with missing data handled by single imputation (baseline observation carried forward). Given the nested group design, two-way repeated measures ANOVAs with participants nested within cohorts were used, reporting partial eta squared (hp2) with 90% confidence intervals; a bias-corrected within-subject effect size (drm) with 95% CIs was also calculated for comparison with other studies.

Eighteen participants were enrolled across three cohorts between July 2017 and August 2018; all 18 began the intervention, received psilocybin, completed the primary endpoint assessment and the 3-month safety follow-up, and were included in intent-to-treat analyses. Overall attendance at group therapy sessions was 95%. Absolute oral psilocybin doses ranged from 22 to 32 mg (mean 27.1 mg, SD 3.1). No psilocybin-related serious adverse events were reported. During medication sessions, 8 participants experienced moderate-to-severe anxiety reactions; four had paranoid reactions and one had a transient thought-disorder-like dissociation with repetitive self-talk. Hypertension was observed: four participants experienced self-limited severe, asymptomatic hypertension and eight had moderate hypertension; the two participants with severe hypertension met diagnostic criteria for borderline personality disorder (BPD). Fourteen participants had at least moderate expected adverse reactions to psilocybin, and seven experienced severe but self-limited expected reactions. Two unexpected post-medication reactions occurred: one participant had a moderate PTSD flashback two days later associated with nausea, tinnitus, panic and insomnia and was unable to work for two days; another participant reported severe anxiety ten days post-session, lapsed to methamphetamine use and subsequently withdrew from the intervention while completing most assessments. No change in suicidal ideation was detected on the C-SSRS and no suicidal behaviour occurred during the study. Participant-rated benefit at end-of-treatment averaged 6.61 (SD 0.6) on a 1–7 Likert scale, while perceived harm averaged 1.17 (SD 0.38). Mean ChEQ score was 37.11 (SD 26.0), approximately 28% of the maximum. Cognitive screening (MoCA) showed no meaningful change, and AUDIT/DUDIT scores (collected in Cohorts 2 and 3) did not worsen to 3-month follow-up. The pre-specified primary clinical outcome, demoralization (DS-II), showed robust pre–post improvement: mean difference baseline to end-of-treatment was −6.67 (SD 6.51), and baseline to 3-month follow-up was −5.78 (SD 6.01). Change across the three time points yielded a large effect (partial eta squared hp2 = 0.47, 90% CI 0.21–0.60). At end-of-treatment, 88.9% of participants had at least a 2-point reduction in DS-II; at 3 months this was 66.7%. Fifty percent and 33.3% of participants achieved >50% reduction in demoralization at end-of-treatment and 3 months, respectively. Most secondary clinical outcomes also improved over time except state anxiety (hp2 = 0.16, 90% CI 0.0–0.32) and antiretroviral adherence (hp2 = 0.08, 90% CI 0.0–0.22), the latter showing a ceiling effect with mean baseline adherence of 99%. Notable improvements were observed for PTSD symptoms (PCL-5, hp2 = 0.27, 90% CI 0.05–0.43) and complicated grief (ICG-R, hp2 = 0.45, 90% CI 0.19–0.58).

The investigators conclude that psilocybin-assisted group therapy was feasible to deliver, relatively safe under the study conditions, and associated with preliminary improvements in demoralization and other measures of trauma-related distress in a sample of demoralized OLTAS men with substantial psychiatric comorbidity. Recruitment and retention were high and group attendance was excellent, although the sample was self-selected and many participants were highly motivated, retired or on disability, which may have facilitated participation. Compared with prior modern psilocybin trials that used individual psychotherapy, this cohort displayed greater clinical complexity and higher rates of non-serious adverse reactions; the authors attribute the elevated frequency and severity of expected adverse events in part to this complexity. Cardiovascular reactivity (moderate-to-severe hypertension) was more common than in some prior studies but generally resolved with non-pharmacological measures and clinician support; one participant with trauma history and BPD had prolonged severe hypertension that responded to environmental and interpersonal interventions. Two participants with BPD had challenging medication visits and difficulties integrating experiences in the group setting, although both reported short-term improvements post-treatment. The authors therefore recommend that high-complexity populations undergoing this protocol receive comparable levels of medical screening, preparatory work and post-drug psychotherapy. Effect-size estimates for demoralization compared favourably with effect sizes reported in pooled analyses of psilocybin trials for depression and with a large trial of non-psychedelic meaning-centred group psychotherapy for cancer patients. Nonetheless, the investigators acknowledge important limitations: small sample size, open-label uncontrolled design, potential selection bias (seven participants had substantial prior psychedelic experience), cohort differences in dose and number of group visits, and limited generalisability of findings beyond OLTAS men. The study team noted that stringent exclusion criteria needed for rigorous blinding (for example excluding individuals with any prior psychedelic use) would have been impractical for this population, which informed their decision not to include a placebo arm. Finally, the authors argue that group-based delivery may offer efficiency and therapeutic advantages for addressing social isolation and stigma, while emphasising the need for larger, randomised, well-blinded trials to determine efficacy and safety more definitively. They also highlight the unmet mental health needs of long-term AIDS survivors and call for further research into treatments for demoralization, complicated grief and trauma-related disorders in medically complex populations.