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

1. Introduction

Demoralization is a form of existential suffering characterized by poor coping and a sense of helplessness, hopelessness, and a loss of meaning and purpose in life [1]. Demoralization is highly prevalent (13–53%) among patients with serious medical illness (e.g., advanced cancer and acquired immunodeficiency syndrome [AIDS], etc.) [2], [3], [4] and is associated with high physical symptom burden and poor quality of life [5,6]. Highly demoralized patients can screen negative for major depressive disorder (MDD); [3,4] and compared to MDD, demoralization is more strongly associated with suicidal ideation [6]. Demoralization-focused psychotherapies are available, but few have demonstrated efficacy when compared to an active control condition, and effect sizes have been modest [7–9].

While there are significant safety and ethical concerns with psychedelic medicines [10], recent trials of the serotonin 2A receptor (5HT2AR) agonist psilocybin, administered with adjunctive psychotherapy (henceforth “psilocybin therapy”), have found this intervention to be safe and to produce significant, enduring symptomatic improvement in a variety of psychiatric disorders, including demoralization and other forms of existential distress among patients with life-threatening cancer [11–14]. This may be a result of the increase in personal meaning attributed to one's lived experiences that has been demonstrated among both healthy volunteers [15] and patients [16,17] administered psilocybin. How psilocybin therapy may affect demoralization in other clinical populations remains unknown.

Early in the AIDS epidemic, demoralization was identified as a substantive clinical problem among the bereaved [18]; decades later, many older, long-term AIDS survivors (OLTAS) also suffer from demoralization. OLTAS are people diagnosed with human immunodeficiency virus (HIV) or AIDS prior to the clinical availability of protease inhibitors (∼1996), which were pivotal in transforming HIV from a terminal diagnosis to a chronic disease. Today over half of all people living with HIV (PLWH) in the United States of America are >50 years old [19]. And in San Francisco, California there are an estimated 2616 older long-term AIDS survivors (Personal communication, 2020: Ling Hsu, San Francisco Department of Public Health). The needs of OLTAS can be inferred from the data on samples of older PLWH, which indicate high rates of depression, anxiety, post-traumatic stress disorder (PTSD) and loneliness [[19], [20], [21]]. Key stakeholders in the OLTAS community have also identified renewed meaning in life and healthier coping with traumatic loss as two major mental health challenges (Personal communications, 2015: Jesus Guillen, Matt Sharp, and Vince Crisostomo). While meta-analysis has found a low certainty of evidence for group psychotherapies for PLWH [22], some data do support the efficacy of existential group psychotherapy for older PLWH [23], and yet no studies have examined how to treat distress specifically among OLTAS.

While psychedelic agents have long been used in traditional communal settings for rites of healing and prayer, and while psychedelics were administered with adjunctive group therapy to hundreds of participants prior to federal drug scheduling, [24] no modern clinical trials have investigated the safety or feasibility specifically of psilocybin-assisted group therapy. Yet mid-century [25] and modern [[26], [27], [28]] research on psychedelics emphasizes that an important therapeutic mechanism may be the enhanced capacity for interpersonal connection that patients can experience for days after drug administration. Indeed, the optimal method for delivering psilocybin therapy remains an open question.

We performed this pilot study to assess the safety, feasibility, and potential efficacy of psilocybin-assisted group therapy for demoralization in a population with serious, but not immediately life-threatening, medical illness—OLTAS men. Given the novel population, novel clinical approach, and the fact that the risks and benefits of psilocybin therapy remain poorly characterized, this study was designed to address clinical implementation issues, including participant recruitment, tolerability, and protocol adherence. Measures of clinical efficacy were exploratory.

2. Methods

3. Results

Eighteen eligible participants were enrolled from 17 July 2017 to 24 August 2018, and the last 3-month follow-up contact occurred in January 2019. (See Fig. 2) Participant demographics and baseline clinical characteristics are presented in Table 1. All 18 participants began the intervention, were administered study drug, completed the primary endpoint assessment and the 3-month follow-up safety evaluation, and were included in intent-to-treat analysis. Overall attendance of group therapy visits was 95%.

Absolute dosage of oral psilocybin ranged 22–32 mg with a mean of 27·1 mg (SD 3·1). No serious adverse events (SAEs) were attributed to psilocybin. During the medication visit, no participants required physical restraint or emergent medications for psychiatric or general medical concerns, and all psilocybin-related adverse events were self-limited and expected, although there were two unexpected post-medication visit psilocybin-reactions.

Adverse events occurring during the medication visit included both moderate and severe anxiety reactions (n = 8). Four participants experienced paranoia and one experienced transient thought disorder (i.e., dissociation with repeated self-talk). Four experienced self-limited, asymptomatic, severe hypertension that waxed and waned in conjunction with their anxiety symptoms; similarly, another eight participants experienced self-limited, moderate hypertension (See Fig. 3). The two participants with severe hypertension and severe anxiety also both met SCID-5-PD criteria for borderline personality disorder (BPD). Another participant, an HIV non-progressor who had never become ill from HIV, had severe nausea during the medication visit and experienced visual and tactile hallucinations of himself repeatedly vomiting and soiling his pants. He later reported that these hallucinations were related to his intention for the medication visit—to understand better the experiences of loved ones who had died during the AIDS epidemic.

Fourteen participants experienced expected adverse reactions to psilocybin that were at least moderate in severity; seven participants experienced severe, but self-limited, expected adverse reactions. Two unexpected psilocybin reactions occurred: one participant, two days after his medication visit, experienced a moderate post-traumatic stress flashback during which he vividly re-experienced content that was not related to the psilocybin experience, but instead related to a sexual assault that happened years prior. The flashback was accompanied by nausea, tinnitus, panic and insomnia and left him unable to work for two days. Notably, he reported having a similar flashback years before when he started taking efavirenz, an antiretroviral and 5HT2AR agonist. Another participant with SCID-5 diagnosed generalized anxiety disorder, panic disorder, and BPD, in addition to decades of heavy polysubstance use, initially experienced significant anxiolysis after his medication visit. However, ten days later he reported severe anxiety, which he described as a deeply felt sense of being rejected by the other group members. He then had a lapse in his methamphetamine use (after having been sober from all substances for one month prior to the study) and withdrew from the study intervention but completed most subsequent assessments.

For details on safety measures, see Table 3. No change in suicidal ideation over time was detected with the C-SSRS, and no suicidal behavior was detected during the intervention. SAHD showed no meaningful change from baseline to 3-month follow-up. At end-of-treatment, participant-reported benefit and harm from the intervention were, on a 7-point Likert scale (1= none at all; 7=extremely), mean 6·61 (SD 0·6) and 1·17 (SD 0·38), respectively. Mean total ChEQ score was 37·11 (SD 26·0) or 28% of the maximum possible score. Mean MoCA showed no meaningful change from enrollment to end-of-treatment. Mean scores on AUDIT and DUDIT did not worsen from baseline to 3-month follow-up, suggesting that on average participation in the study did not lead participants to engage in more substance use.

The pre-specified primary clinical outcome of change in demoralization showed a robust pre-post improvement from baseline to end-of-treatment (mean difference −6·67 [SD 6·51]) and from baseline to 3-month follow-up (mean difference −5·78 [SD 6·01]) with a standardized effect size of η_p² = 0·47, 90% CI 0·21–0·60 for change over these three timepoints (Fig. 4). At end-of-treatment and 3-month follow-up, respectively, 88·9% and 66·7% of participants demonstrated at least a 2-point reduction in demoralization compared to baseline, and 50% and 33·3% demonstrated a > 50% reduction in demoralization compared to baseline. Change over time was also detected with all secondary clinical outcomes except for state anxiety (η_p² = 0·16, 90% CI 0·0–0·32) and antiretroviral medication adherence (η_p² = 0·08, 90% CI 0·0–0·22), the latter of which demonstrated a ceiling effect with 99% (SD 1·8) mean adherence at baseline. Notably, participants seemed to improve over time with respect to their symptoms of both PTSD (PCL-5, η_p² = 0·27, 90% CI 0·05–0·43) and complicated grief (ICG-R, η_p² = 0·45, 90% CI 0·19–0·58) (Fig. 5). See Supplemental Table S1 for secondary clinical outcomes data.

4. Discussion

This pilot study demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy in a sample of demoralized, gay-identified, OLTAS men—a population with heterogeneous and complex past medical and psychiatric histories. Our sample demonstrated greater psychiatric comorbidity than has so far been seen in the modern literature on psilocybin therapy. We detected zero psilocybin-related serious adverse events and two unexpected adverse reactions. There were moderate-to-severe, self-limited, expected adverse reactions in 14 of 18 participants—a relatively high rate of adverse events that we, in part, suspect is related to the clinical complexity of our study population. The primary clinical outcome, self-reported demoralization, demonstrated robust change from baseline to end-of-treatment and to 3-month follow-up. Our findings resemble those of recent psilocybin therapy trials that found the treatment to be well-tolerated in different psychiatric populations and to produce significant improvements in mood, anxiety, and existential distress lasting weeks-to-months after a single drug treatment [14]. The data are consistent with two systematic reviews [38,39] of individual psychedelic therapy for distress in patients with life-threatening illness, both of which found promising signals of safety and potential efficacy. Also, a recent meta-analysis of modern psilocybin therapy trials found that across four small studies (N = 69), pre-post measures of depression resulted in a pooled standardized effect size of Hedge's g = 1·38, 95% CI 0·78 to 1·99 [40]. For comparison, our pre-post standardized effect size estimate for demoralization was d_rm=0·97, 95% CI 0·43 to 1·57. Finally, our results compare favorably to those of a large (N = 253) trial of a brief (8-week), non-psychedelic, meaning-centered group psychotherapy for advanced cancer patients, which found a within-group Cohen's d = 0·54 for spiritual well-being, d = 0·53 for hopelessness, and d = 0·67 for depression [8].

Modern trials of psilocybin have only administered the drug to carefully-screened clinical populations with adjunctive psychotherapy, and always in an individual format. The logistics of providing group therapy for patients with serious illness can be taxing [34] and are only compounded by the addition of psychedelic drug administration. Nevertheless, our rates of recruitment and retention were high, demonstrating the feasibility of our intervention, with the caveat that our population was highly motivated (many self-referred to the study), and most were on disability or retired and had flexible schedules. Finally, our sample of 18 participants received a total of 472 face-to-face therapist-hours. Had we provided the same number of contact hours to all 18 participants with individual, instead of group psychotherapy, this would have equaled about 954 therapist-hours. Administering psilocybin with adjuvant group psychotherapy may yet prove to be an important means of delivering this treatment not only because of its potential for cost-savings but also because of group therapy's unique capacity to address social isolation, shame and stigma [24]. While it was evident to our clinical team that processing experiences of shame in the group setting was difficult for some participants, anecdotally, it also seemed helpful for some to receive validation from other group members that they were not alone with their struggles (e.g., being victims of sexual abuse). Furthermore, whereas some participants were slow to build rapport and trust with the study clinicians in the group setting, several participants reported that they were able to connect quickly with the other group members and that this peer support was helpful in tolerating and making use of the intervention. Nevertheless, two participants with BPD (see below) spontaneously reported persistent challenges with integrating their psilocybin experiences in the group setting.

In many countries, psilocybin is regulated as a Schedule I drug (or the equivalent). In the United States, a Schedule I drug has “high potential for abuse, no currently accepted medical use in treatment… and a lack of accepted safety for use under medical supervision [41].” The final clause of this definition, however, is at odds with our data and those in the published literature, [14] which suggest that psilocybin can be safely administered under appropriate medical supervision. Whereas we detected no serious adverse reactions to psilocybin, the number and severity of the non-serious adverse reactions observed in our sample do suggest that conducting psilocybin therapy with a population as complex as ours, and at this dose, should likely only be done with at least the level of medical screening, preparation and post-drug psychotherapy provided here.

Regarding cardiovascular risk, our participants displayed higher rates of moderate-to-severe hypertension during the psilocybin session than have been reported in other studies with clinical populations and a comparable dose [14]. While this is concerning given the high cardiovascular disease burden among OLTAS, [42] it is notable that severe hypertension in our trial seemed to co-occur with intense anxiety and self-resolved when the clinicians could calm the participant with verbal reassurance. However, one participant with a significant trauma history and who met criteria for BPD was intermittently severely hypertensive for four hours. Whereas he likely would have benefitted from a low dose benzodiazepine, during this period his paranoia precluded the clinicians from offering oral medications. His-blood pressure and anxiety eventually responded to our darkening the room and increasing the music volume. Although our two participants with significant trauma exposure and clinically active BPD symptoms reported very challenging medication visits, both also reported brief but notable clinical improvement from their baseline for 1–2 weeks post psilocybin (i.e., one no longer had regular anxiety-related vomiting before leaving his home, and one came out as gay to his long-time support group). Prior reports suggest that persons with borderline personality traits may have more difficulty tolerating psilocybin and other altered states of consciousness, [43,44] but also that challenging psilocybin experiences may nevertheless be beneficial [45]. Together, these data provide support for further investigations of psilocybin therapy not only for mood and anxiety disorders, but also, with the proper conditions in place, trauma-related disorders such as PTSD, BPD, and complicated grief.

Limitations inherent to open-label pilot studies, such as small sample size and absence of a control condition, were expected. The primary clinical outcome, demoralization, is little known beyond the fields of psycho-oncology and palliative care, however, severe demoralization does often co-occur with MDD [3]. A selection bias is notable from the fact that seven of our 18 participants had a lifetime history of classic psychedelic use ≥10 times, three even ≥100 times, and one had used entactogens (e.g., MDA) ‘hundreds’ of times; this could have biased our sample toward rating the experience as more tolerable or helpful than a psychedelic-naïve sample might. However, we did not find an association between higher lifetime psychedelic use and either total score on the Challenging Experience Questionnaire or the DS-II change scores (data not shown). Also, Cohort 1 had fewer group therapy visits and a lower drug dose than did Cohorts 2 and 3, but our sample is too small to meaningfully assess for a dose-response relationship of psychotherapy or drug to the clinical outcomes. Finally, stringent exclusion criteria are necessary to adequately blind participants to moderate-to-high dose psychedelics (e.g., excluding for any lifetime psychedelic use), [46] but we anticipated that such exclusion criteria would have rendered recruiting for a group therapy study with our population unfeasible. We therefore elected not to employ such stringent exclusion criteria, and hence we did not include a placebo-control arm given the high likelihood of functional unblinding.

The mental health needs and life experiences of OLTAS may be difficult to generalize to other populations given the degree of adverse life experiences many of these individuals have faced, including childhood abuse, severe stigma, multiple life-threatening medical conditions, and repeated exposure to traumatic loss and subsequent social isolation. The mean degree of demoralization experienced by our sample at baseline was moderate-to-severe and yet half of our participants did not meet SCID-5 criteria for any of the diagnoses assessed at enrollment. One third of our sample were survivors of life-threatening cancer, and indeed the psychological struggles of OLTAS can resemble those of cancer survivors [47]. To summarize, OLTAS may serve as a unique, enriched model of a distressed population that has confronted serious adversity, traumatic loss, and both acute and chronic life-limiting illness.

The open-label, uncontrolled, safety, feasibility and clinical outcomes measured here make a compelling case for controlled and well-blinded trials of psilocybin therapy (either with adjunctive group or individual psychotherapy) for demoralization, complicated grief, and other forms of distress experienced by patients with serious medical illness and traumatic stress. This study also highlights the need for further attention to the mental health needs of long-term AIDS survivors. As we advance towards the ‘end of AIDS,’ it is important to remember that for many the epidemic is far from over.

Contributors

BA and JW designed the study and BA coordinated the study, collected the data, and wrote the report. BA, JW, JM, MB and JD analyzed the data. AD was the lead study clinician and supervised with BA the psilocybin administration sessions. AD, RD and CS contributed to the creation of the group psychotherapy approach and served as group therapists. EE, GAL and AT contributed to data analysis and served as study clinicians. All authors critically revised the report and contributed intellectual content.

Declaration of interests

The authors declare no financial conflicts of interest related to for-profit entities. The following grants supported work on this trial: NIMH R25 MH060482, NIH UL1 TR001872, US Department of Veterans Affairs (Advanced Neurosciences Fellowship and IK2CX001495). BA and JW received philanthropic gifts from the following individuals and non-profit organizations to support this trial: Carey Turnbull, Heffter Research Institute, River Styx Foundation, Saisei Foundation, Sarlo Foundation, Stupski Foundation, Usona Institute. JW is conducting a trial sponsored by the non-profit Usona Institute. MB receives consulting fees from Beneath the Surface Foundation.

Appendix. Supplementary materials