Characterising the clinical associations of hallucinogen persisting perception disorder: a retrospective cohort study
Matt Butler, Ellen Moore, James Rucker, Katharine Lynch-Kelly, Danish Hafeez, Ed Prideaux, Timothy R. Nicholson, Mark J. Edwards, Thomas Pollak
Translational Psychiatry April 24, 2026 DOI: 10.1038/s41398-026-04042-1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Retrospective cohort study Peer reviewed |
|---|---|
| Sample size | 25,778 |
| Population | Individuals diagnosed with HPPD in the TriNetX global federated health research network |
| Topics | Anxiety Depression |
| Keywords | Fibromyalgia Retrospective cohort study Distress Population Comorbidity Schizophrenia object-oriented programming Psychopathology Depression economics Clinical psychology Odds ratio Chronic pain |
| Citations | 1 |
| Key findings | Anxiety and functional somatic syndromes are significantly more common in individuals with HPPD than in psychedelic-using controls, and anxiety and post-viral fatigue predict HPPD development in psychedelic users. |
Abstract
Hallucinogen persisting perception disorder (HPPD) is characterised by episodes of altered perception linked to past psychoactive drug use, accompanied by distress and functional impairment. To date, clinical characterisation has been limited in scale. Using TriNetX, a global federated health research network of electronic health records, we conducted a retrospective cohort study comparing clinical associations in individuals with HPPD versus population and psychedelic-using controls. Cumulative incidences of psychiatric and medical disorders were compared. Cox proportional hazards models assessed risk factors for developing HPPD, and odds ratios (ORs) were used to evaluate associated conditions following diagnosis. We identified 25,778 individuals diagnosed with HPPD. Prior to diagnosis, high rates of comorbidities were observed, including depressive episodes (29.2%), anxiety disorders (26.2%), chronic pain (15.9%), headache syndromes (14.7%), post-viral fatigue (12.3%), ADHD (6.6%), and fibromyalgia (6.7%). Anxiety and functional somatic syndromes were significantly more common in the HPPD group than in psychedelic-using controls (p < 0.001). Anxiety (OR 1.5) and post-viral fatigue (OR 1.9) predicted HPPD development in psychedelic users. HPPD diagnosis was associated with increased risk of subsequent functional somatic syndromes (OR 2.0) and psychiatric disorders (OR 1.4) versus psychedelic-using controls. This largest-to-date study of HPPD highlights its psychiatric and somatic complexity, with strong associations with anxiety and functional somatic syndromes. Several methodological limitations are acknowledged. Further research should explore overlapping pathophysiological mechanisms linking HPPD, visual disorders (e.g. visual snow syndrome), anxiety, and functional somatic syndromes.
Comparable studies
Other observational and cohort studies on anxiety, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders Patients with generalized anxiety disorder or panic disorder with or without agoraphobia | 1992 | Observational cohort | n = 22 |
| Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report Patients with a depressive disorder | 2015 | Observational study | |
| Patterning of Cognitive and Somatic Processes in the Self-Regulation of Anxiety: Effects of Meditation versus Exercise Regular practitioners of physical exercise or meditation | 1978 | Retrospective study | n = 77 |
| Dynamic coupling of whole-brain neuronal and neurotransmitter systems Healthy humans | 2020 | Observational study | |
| Psychedelics not linked to mental health problems or suicidal behavior: A population study Randomly selected United States adults | 2015 | Observational cohort | n = 135,095 |