Case analysis of long-term negative psychological responses to psychedelics

Bremler and colleagues used a two-phase, self-selected recruitment design to identify people reporting long-term negative psychological responses after taking psychedelics. Recruitment was via social media and online fora between November 2021 and April 2022. Phase 1 comprised an online onboarding questionnaire collecting demographic information, drug-use parameters, and symptom reports; phase 2 consisted of semi-structured interviews with a purposive subsample selected for severity (for example, new or worsened psychiatric diagnoses, HPPD-like symptoms, or other prolonged distress lasting >72 hours after use). The investigators pre-specified a target of 15 interviews and prioritised invitees according to three criteria: (1) emergence of a formal psychiatric diagnosis with psychotic features after the experience, (2) emergence or worsening of other psychiatric symptoms after the experience (a broad list was provided in the survey), and (3) symptoms consistent with Hallucinogen Persisting Perception Disorder (HPPD) as defined by DSM criteria.

A total of 84 participants provided consent but only 32 completed the full online survey; 30 of these completed the Challenging Experience Questionnaire (CEQ). The CEQ mean score for completers was 62.1 ± 31.8 (n = 30). From the survey completers the study team invited 20 individuals for interview, four did not respond and one was excluded for recent psychedelic use; fifteen participants completed semi-structured interviews (average duration ~60 minutes). The interviewed group comprised 8 female, 1 non-binary and 6 male participants. Mean age at the time of the psychedelic experience was 25 (SD = 7.4), and time since the experience ranged from 2 months to 25 years (mean = 6.8 years). LSD was the most commonly implicated substance (7 of 15 interviewed), followed by MDMA (6 of 15) and psilocybin (4 of 15); eleven interviewed participants reported a single drug during the index event and four reported polydrug use.

Across the 32 survey completers and the 15 interviewed participants anxiety-related symptoms predominated. In the full survey sample, anxiety was reported by 26 of 32 participants (87%) and panic by 20 of 32 (63%). Within the interviewed sample anxiety and panic were also highly prevalent (reported in ~93% and ~87%, respectively). Other commonly reported prolonged phenomena included flashback-like intrusive re-experiencing (12 of 15, 80%), derealization (7 of 15, 47%), and feelings of disconnection or stigmatization (7 of 15, 47%). Formal psychiatric diagnoses reported as arising or being confirmed after psychedelic use included depressive and anxiety disorders (several cases across the samples) and a smaller number of psychotic-spectrum or trauma-related diagnoses: in the interviewed sample there were two new bipolar diagnoses and one case of PTSD with psychotic features (3 of 15, 20%). HPPD-like visual symptoms were described by some participants, but only one of the 32 survey completers reported a formal HPPD diagnosis. Thematic analysis of interview transcripts identified recurring potential causal factors grouped into four domains: (A) drug- and use-related factors (unknown or unusually high doses, heavy recent frequency of use, unclear drug purity, polysubstance combinations or abrupt medication changes); (B) individual vulnerability (prior diagnosed or undiagnosed mental health problems, and family history of psychiatric illness); (C) negative or unsafe expectations and environments (unsafe or stressful incidents during the experience, negative priming, and major life stressors surrounding the event); and (D) interpersonal and social supports (relationship tensions with others present during the experience and lack of social or clinical support afterwards). Eleven of the 15 interviewed participants described their acute psychedelic experience as negative or frightening; nearly all of these cases involved classic serotonergic psychedelics. By contrast, most participants reporting generally pleasant acute experiences had used MDMA. On causality the investigators propose a parsimonious interacting model: psychedelics increase psychological ‘‘plasticity’’ in a dose-dependent manner, and when heightened plasticity co-occurs with an adverse context or pre-existing vulnerability, longer-term negative psychological outcomes are more likely. The model emphasises the interaction between drug factors (especially high or uncertain dose and substance-specific effects), set/setting/matrix factors, and individual susceptibility including young age. The authors note exceptions to the two-factor model, for example several cases following MDMA that involved post-acute low mood where serotonin-related mechanisms might play a role, and one case of high-dose LSD-associated HPPD. Limitations highlighted by the investigators include the selective, self-selected recruitment strategy, retrospective self-reporting with variable time elapsed since the event (mean ~7 years), inability to verify drug purity or dose, substantial questionnaire attrition (62%), and a small interview sample size. They therefore emphasise that prevalence or incidence cannot be inferred from these data. Suggested implications and future directions mentioned by the authors include the need for larger, ideally prospective or population-based studies, targeted investigations of specific symptom clusters (for example psychotic outcomes), consideration of next-of-kin or carer interviews to capture more severe cases, better recording of recruitment sources, and broader inclusion of other compounds such as ketamine and cannabis in future research.

The study concludes that prolonged adverse psychological responses to psychedelics are real but challenging to study. Using a selective mixed-methods approach the researchers identified recurring risk factors and distilled a simple plasticity × context model to explain how acute experiences can evolve into longer-term difficulties. The authors hope their proof-of-principle work will encourage further research that improves understanding, reduces occurrence, and informs risk-mitigation strategies.