Characterising the clinical associations of hallucinogen persisting perception disorder: a retrospective cohort study

Hallucinogen persisting perception disorder (HPPD) involves episodes of altered perception after past psychoactive drug use, causing distress and impairment. In a large retrospective cohort study using electronic health records from 25,778 individuals diagnosed with HPPD, high rates of prior comorbidities were found, 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 more common in HPPD patients than in psychedelic-using controls. Anxiety (odds ratio 1.5) and post-viral fatigue (odds ratio 1.9) predicted HPPD development among psychedelic users. After diagnosis, HPPD was associated with increased risk of subsequent functional somatic syndromes (odds ratio 2.0) and psychiatric disorders (odds ratio 1.4) compared to psychedelic-using controls.

Study at a glance

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.