Hallucinogenic Persisting Perception Disorder: A Case Series and Review of the Literature

Hallucinogen persisting perception disorder (HPPD) is defined by recurrence of perceptual disturbances that originally occurred during acute hallucinogen intoxication and persist after drug cessation. The condition may present intermittently or continuously and is distinguished from routine drug "flashbacks" by the DSM-5 on the basis of associated distress or functional impairment. Previous work has proposed subclassifying post-substance perceptual disturbances into transient/benign and chronic/distressing syndromes, and HPPD has historically been linked to classic serotonergic hallucinogens such as LSD and psilocybin. More recently, however, non-classical agents—entactogens (MDMA), dissociatives (ketamine, PCP), cannabinoids (including synthetic THC) and others—have been implicated, and estimates of prevalence vary widely because of limited large-scale data and diagnostic overlap with conditions such as migraine aura, focal epilepsy, narcolepsy-cataplexy and visual snow syndrome (VSS). This paper, presented by Martinotti and colleagues, set out to describe the clinical phenotype and investigation findings of a tertiary neuro-ophthalmology case series of HPPD and to synthesize published case reports. The investigators aimed to characterise the visual symptoms, implicated substances, examination and investigation results, treatments tried and recovery outcomes in their series, and to compare these features with those reported in the literature, highlighting parallels and differences with VSS. The work is a retrospective case series supplemented by a targeted literature review of case reports published between 2000 and 2020.

The primary dataset comprised de-identified cases contributed by four neuro-ophthalmologists across five Australian healthcare sites. To be included, cases had to meet DSM-5 diagnostic criteria for HPPD; given reports implicating non-classic drugs, the investigators did not restrict inclusion to classical hallucinogen exposure alone. Fourteen cases were submitted, and one was excluded for diagnostic uncertainty, leaving 13 cases for review. For each patient the team recorded demographic features, visual symptoms (using a pre-specified list of 24 items derived from DSM-5 criteria and a prior comprehensive review), the illicit drug(s) used closest to symptom onset, visual examination findings, neurologic and ophthalmic investigations, treatments and recovery status. For the literature review, MEDLINE and PubMed were searched for HPPD case reports published from 2000 to 2020 using the terms "hallucinogenic persisting perception disorder" OR "hallucinogen persisting perception disorder" and limiting to case reports. The initial search returned multiple publications that were screened; after exclusions for non-relevance, minimal clinical information, language or failure to meet diagnostic criteria, a set of published case reports was assembled for synthesis. The paper reports descriptive summaries (counts, means and proportions) of clinical features, investigations and treatment responses across both the new case series and the identified literature cases. No formal meta-analysis or hypothesis testing is described; the approach is a qualitative and quantitative synthesis of case-level data where available.

Thirteen patients were included in the case series: 12 males and one female, median age 26 years. Drugs recorded as most proximate to symptom onset varied: six of 13 patients (46.2%) had used a classic hallucinogen (LSD, psilocybin, 25N-NBOMe) closest to onset, with LSD the single most common trigger (4/13). Three patients (23.1%) had recently consumed MDMA, two patients associated symptom onset with cannabinoids (natural or synthetic THC), one with methamphetamine, and one patient was unsure. Precise intervals between exposure and symptom onset were not consistently available. Visual disturbances were heterogeneous: all 13 patients reported visual snow. Other frequent phenomena included persistent floaters (61.5%), palinopsia (53.8%), photopsia (53.8%), and photophobia (53.8%). The investigators noted five features not typically included in DSM-5 HPPD descriptions—nyctalopia, photophobia, entoptic phenomena, metamorphopsia and monocular vertical diplopia. Certain phenomena were not reported in this series (macropsia, pareidolia, visualizations, fractals, recurrent synaesthesia, distorted perception of distance, monochromatic vision). Routine ophthalmic and neurologic investigations were usually normal. Visual acuity (assessed in 11 patients) and automated visual fields (10 patients) were normal in all tested individuals. Colour vision testing (Ishihara) was normal in 9 of 10 patients; one patient (case 10) showed reduced colour perception (5/17 OS, 4/17 OD). Nine patients had brain MRI: seven were normal, two showed minor, clinically insignificant findings (a developmental lingual gyrus change and non-specific scattered T2 hyperintensities). Optical coherence tomography (eight patients) produced measurements within normal ranges; electroretinography and visual evoked potentials performed in two patients were reported as normal. Treatment and outcome data were incomplete. Treatment information was available for 12 patients and recovery status for eight. Two patients fully recovered, two partially recovered and four did not recover. Six patients received no pharmacologic treatment; among the four untreated with recorded outcomes, three did not recover and one (case 13) fully recovered following an episode of acute MDMA intoxication. Pharmacologic therapies included antiepileptic drugs (three patients; agents not always specified), benzodiazepines (one full recovery reported), SSRIs and SNRIs (used in some partially recovering patients), and lamotrigine combined with benzodiazepines, an SSRI and psychological and sensory interventions in one partially recovered patient. Tinted glasses were tried in one patient without benefit. The literature synthesis comprised 24 published HPPD case reports. Across these reports the mean age of first drug use was 19.5 ± 3.7 years and mean age at symptom onset 24.3 ± 6.6 years, with a male:female ratio of 2.4:1. Classical hallucinogens were frequently implicated—LSD in 17/24 cases (70.8%)—but a wide range of agents were reported (psilocybin, ketamine, PCP, MDMA, methamphetamine, cocaine, ibogaine and natural or synthetic THC). THC was reported in association with many cases (reported as the most common drug overall), often alongside classic hallucinogens; four literature cases followed isolated THC intoxication. Symptoms in the literature differed from the new series: visual hallucinations were common among case reports (13/24, 54.2%), while visual snow was described in 5/24 cases (20.8%). EEGs were reported in about 41.7% of literature cases and were mostly normal, though one patient had transient occipitotemporal epileptiform discharges. Neuroimaging was generally normal or showed non-specific findings. Treatments in the literature most commonly included benzodiazepines (10/24, 41.7%), antiepileptic drugs (8/24, 33.3%), SSRIs (7/24, 29.2%) and antipsychotics (6/24, 25%). Recovery across published cases was variable: 25% fully recovered, 54.2% partially recovered and three patients experienced no recovery, with two of these patients having died by suicide.

Martinotti and colleagues interpret their findings as showing that HPPD typically presents with positive visual phenomena while standard ophthalmic and neurologic investigations (visual acuity, automated fields, OCT, MRI, electrophysiology) are commonly normal. They stress that a careful drug and symptom timeline is therefore crucial for diagnosis and can reduce unnecessary specialist testing when other neurologic features are absent. A notable observation in their series was the universality of visual snow, and the frequent occurrence of floaters, palinopsia, photophobia, photopsia and nyctalopia—features that are not all captured by the current DSM-5 HPPD description. The authors suggest that updating diagnostic criteria to include visual snow, nyctalopia, photophobia and floaters may better reflect the typical clinical phenotype and aid recognition. The study highlights overlap between HPPD and visual snow syndrome: both disorders commonly present with similar positive visual phenomena and tend to lack objective ophthalmic findings. Differences noted include a more abrupt onset and later age in HPPD, and the usual presence of recent recreational drug exposure in HPPD as the key differentiator from primary VSS. The investigators discuss that multiple classes of psychoactive substances (classic and non-classic hallucinogens, cannabinoids, MDMA, dissociatives) have been linked to HPPD, implying potentially diverse neuropharmacological mechanisms. Regarding treatment, the authors note that management is based on case reports rather than controlled trials. In the combined datasets benzodiazepines were the pharmacologic intervention most consistently associated with complete recovery, though overall full recovery was uncommon. Antiepileptic drugs showed mixed results: some literature cases improved while responses in VSS and other series have been variable and sometimes unfavourable. The team therefore calls for caution in generalising treatment efficacy and emphasises the need for controlled studies. Limitations acknowledged by the investigators include referral bias—neuro-ophthalmologists involved routinely research VSS so cases with visual snow may have been preferentially referred—small sample sizes, retrospective case ascertainment, incomplete or variable investigation and treatment data, and imprecise timelines between substance exposure and symptom onset in several patients. In conclusion, the authors recommend thorough history-taking focused on substance exposure in patients with unexplained positive visual phenomena, suggest consideration of HPPD beyond classic hallucinogen exposures, and advocate for comparative studies of HPPD and VSS and randomised controlled trials to clarify pathophysiology and optimise treatment strategies.