Older adults in psychedelic-assisted therapy trials: A systematic review

Research into psychedelic compounds has resurged after decades of legal restrictions, with recent trials of psilocybin and MDMA receiving regulatory attention such as Breakthrough Therapy designations for major depressive disorder and PTSD. Earlier waves of research treated tens of thousands of people, but older adults have been underrepresented in contemporary psychedelic-assisted therapy (PAT) trials despite high burdens of conditions like depression, anxiety, existential distress and PTSD in older populations, and despite the predominance of new cancer diagnoses occurring in people aged 65 and older. Bouchet and colleagues set out to quantify how frequently older adults (defined here as age 65 or older) have been enrolled in clinical trials of psychedelic-assisted therapies and to examine safety data for this subgroup. The study is a systematic review following PRISMA-P 2020 guidance and aims to describe prevalence, participant characteristics, therapies used, indications studied, and adverse events reported in older adults within eligible PAT trials.

The investigators conducted a systematic review using searches of PubMed, Embase and EBSCO, with data extraction finalised on 14 September 2023. The review followed the 2020 PRISMA-P protocol; the specific search algorithm is reported in supplemental materials (not reproduced here). Initial screening used titles and abstracts, with full-text review when eligibility could not be determined from abstracts alone. Study selection was carried out independently by two-person teams (YB and ZS, or YB and LB) using Rayyan software, with disagreements escalated to a three-person adjudication (YB, ZS, LB). LB also screened bibliographies of included articles. Data extraction was performed manually by LB and checked by YB, ZS and AY, collecting information on study design, participant demographics (including age and gender), psychedelic compound, dose and route, therapeutic indication, concomitant non-drug therapy, and outcome measures. For studies that enrolled older adults the study team contacted original trial teams to request more detailed adverse event (AE) information; only two teams provided additional AE data. Eligibility criteria included clinical trials published in English using psychedelic substances to treat psychiatric conditions, addiction, or existential distress related to serious illness. The investigators included randomized controlled trials and open-label studies; where available, details of psychotherapy used alongside drug administration were recorded. The review identified and recorded study characteristics including publication year, trial design and the specific psychedelic agents used.

From 4,376 articles identified by the initial search (plus 20 additional records identified from references), 36 studies met inclusion criteria. Included articles spanned 1967–2023 and comprised 22 randomized controlled trials and 14 open-label studies. Across the 36 studies a total of 1,400 participants were enrolled. Psychedelics examined across studies included psilocybin (14 studies), MDMA (9), LSD (8), ayahuasca (3) and DPT (3); no included trials involved DMT, mescaline or ibogaine. Indications covered a range of conditions: psycho-existential distress related to serious illness (10 studies), PTSD (7 MDMA studies), treatment-resistant or recurrent major depressive disorder (8 studies, including psilocybin and ayahuasca trials), anxiety disorders, social anxiety in autism, obsessive–compulsive disorder, body dysmorphic disorder, personality disorders, and substance use disorders (alcohol, tobacco, narcotics). Regarding concomitant psychotherapeutic approaches, about 70% of studies paired psychedelics with supportive, non-directive psychotherapy. Manualised interventions reported included cognitive behavioural therapy (CBT) for addiction, cognitive behavioural conjoint therapy for PTSD, motivational enhancement therapy, mindfulness-based therapy, guided affective imagery and acceptance and commitment therapy. Older adults were rare in the dataset: only 19 participants were identified as aged 65 or older, representing less than 1.4% of the pooled 1,400 participants. The mean age of these 19 individuals was 69.6 years (SD 4.9), with the oldest participant aged 81. According to the extracted text, 10 of the 19 older adults received psilocybin; the allocation of the remaining older participants across LSD, DPT or other agents is not reported clearly in the extraction. Adverse event data were obtained for 10 of the 19 older adults from two study teams; all 10 had received psilocybin-assisted therapy in the context of serious illness. Psychiatric AEs were transient and mild-to-moderate in four individuals: anxiety (n = 2), paranoid ideation (n = 1), and a thought disorder (n = 1). These events were managed by study therapists without pharmacological intervention or psychiatric hospitalisation. No cases of persistent psychosis or hallucinogen-persisting perceptual disorder (HPPD) were reported among these older participants. Medical AEs among the same 10 participants were dominated by transient hypertensive episodes (blood pressure >140/90 mmHg), with the highest recorded systolic pressure being 186 mmHg; these resolved without additional intervention or long-term sequelae. Two participants experienced headaches after discharge (both time-limited, one resolving spontaneously within 30 minutes, the other with OTC NSAIDs). Two participants reported gastrointestinal symptoms (one during dosing that self-resolved, the other post-discharge). No serious adverse events (SAEs) were reported in the older-adult subgroup. By contrast, across all adult participants (ages 18–81) the authors note 16 psychedelic-related SAEs in the included literature, 13 of which occurred in more recent studies, but none of these SAEs were reported in older adults within the provided AE data.

Bouchet and colleagues interpret their findings as demonstrating a striking underrepresentation of older adults in contemporary PAT trials: only 19 of 1,400 participants (less than 1.4%) were aged 65 or older. Most older participants received therapy for psycho-existential distress related to cancer or other life-threatening illness; only a single older adult was reported among MDMA trials for PTSD, despite the substantial lifetime burden of trauma in older populations. The review authors place the observed clinical outcomes in context, noting that among the 36 included studies 29 reported statistically significant clinical improvements while five did not reach statistical significance and two older trials from the 1970s did not report significance. They emphasise that the mechanisms of PAT remain incompletely understood and summarise three broad mechanistic domains described in the literature: neurocognitive changes (including effects on the default mode network and brain connectivity), neurochemical actions (classic psychedelics acting primarily as 5-HT2A receptor agonists/partial agonists and MDMA acting as a releaser/reuptake inhibitor of monoamines), and psychotherapeutic processes (therapeutic alliance, safety, and facilitation of deep emotional processing). The authors highlight the need to study these mechanisms specifically in older adults. Safety considerations are discussed with attention to age-related physiological changes. The general adverse event profile across studies was dominated by gastrointestinal, cardiovascular and psychiatric events that were mostly time-limited. For older adults the authors flag transient hypertension and GI upset as the principal medical AEs observed and note their potential to precipitate complications such as stroke, myocardial infarction or syncope in patients with cardiovascular or autonomic instability. They caution that MDMA’s amphetamine-like pharmacology may carry higher cardiovascular risk in older or medically complex patients and suggest that dose adjustments and additional precautions may be needed for individuals with cardiac comorbidity. Practical mitigations proposed by the authors include monitoring orthostatic blood pressures before discharge, ensuring adequate hydration, and consideration of antiemetics to reduce GI upset. The paper also discusses why older adults are commonly excluded from early-phase trials: age-related changes in pharmacokinetics and pharmacodynamics, increased medical comorbidity, and polypharmacy increase the complexity of safety assessment, motivating initial trials in healthier, younger populations. The investigators note an average upper age limit reported across PAT studies of 64.3 years (SD 8.52), effectively excluding many older adults. Ongoing trials that include older or medically complex participants are cited as likely to expand the evidence base. Limitations acknowledged by the authors include the very small number of older adults available for analysis, which limits the ability to draw firm safety conclusions; the fact that only two study teams responded with requested safety data; and incomplete reporting of medical comorbidities for the older participants in the available datasets. The authors recommend more rigorous investigation of PAT in older adults given the preliminary evidence of tolerability but emphasise the need for targeted trials to characterise risks and benefits in this population.

The authors conclude that patients aged 65 and older comprise less than 1.4% of participants in clinical trials of psychedelic-assisted therapies to date. In the limited safety data available for older adults (n = 10 with detailed AE information), medical adverse events were cardiovascular or gastrointestinal, resolved within 48 hours and produced no long-term sequelae; no psychedelic-related SAEs, psychiatric hospitalisations, persistent psychosis or HPPD were reported. While data are sparse, the review provides preliminary evidence that PAT can be tolerated by older adults and supports the need for well-designed clinical trials specifically enrolling older patients to more definitively evaluate safety and efficacy in this population.