Migraine prevalence in visual snow with prior illicit drug use (Hallucinogen Persisting Perception Disorder) versus without

Visual snow describes a persistent pan-field visual disturbance experienced as countless tiny, continuously present dots, often likened to "TV static". Many patients also report additional visual symptoms such as palinopsia (afterimages or trailing of moving objects), enhanced entoptic phenomena, photophobia and nyctalopia. When these accompanying symptoms are present, the condition is described as visual snow syndrome (VSS). The pathophysiology of visual snow is unclear; some evidence implicates increased cortical excitability. Epidemiological data are limited, but a single population study estimated prevalence at 1.4%–3.3%. Clinical series have reported an elevated prevalence of migraine, particularly migraine with aura, among people with visual snow compared with the general population, suggesting a possible shared mechanism. Visual snow has also been reported as a persistent symptom following recreational use of hallucinogens. The DSM-5 diagnosis hallucinogen persisting perception disorder (HPPD) is commonly applied to persistent visual complaints after hallucinogen use, and visual snow can be one of the manifestations. A recent web-based study found few clinical differences between persons with VSS who never used illicit drugs and those with possible HPPD, and reported high migraine prevalence in both groups. To examine whether migraine is an important shared trait or risk factor for visual snow across these presentations, the researchers studied patients presenting with visual snow after illicit drug use (HPPD) and compared them with visual snow patients who had never used illicit drugs prior to symptom onset. The primary outcome was lifetime prevalence of migraine.

Cases were recruited from a national consulting clinic for illicit/recreational drug use (Brijder) in the Netherlands, where persons with somatic or psychiatric complaints after drug use may be seen. Identified patients with visual snow following drug use were contacted by email and, following written informed consent, underwent a structured telephone interview covering visual symptoms, details of illicit drug use, medical history and headache history. Headache disorders were diagnosed according to the International Classification of Headache Disorders, 3rd edition (ICHD-3). Controls were patients with visual snow who had never used illicit drugs prior to onset; these were largely recruited from the Leiden University Medical Center (LUMC) Neurology outpatient clinic and included patients described previously. A third group comprised patients who had used illicit drugs but could not reliably confirm that use occurred more than 12 months before visual snow onset; this group was labelled "HPPD not excluded". The researchers defined HPPD cases as those in whom visual snow began within 12 months of illicit drug intake, and required that descriptions of visual snow matched prior criteria (dynamic, continuous tiny dots across the entire visual field). Controls had to meet previously published visual snow criteria; meeting full VSS criteria (additional symptoms) was not required because prior work suggested those who do not meet the additional symptom criterion are otherwise similar. Impact of visual snow was measured using a Visual Snow Handicap Inventory (VHI), a 25‑item instrument adapted from the Tinnitus Handicap Inventory; total scores range 0–100 and are categorised from "slight or no handicap" to "catastrophic handicap." Participants completed a questionnaire on recreational drug use and a family history questionnaire including parental migraine. The primary outcome was lifetime prevalence of migraine (with or without aura); the authors also examined 1‑year prevalence (at least one migraine attack in the prior 12 months). Statistical analyses used Mann–Whitney U tests for numerical variables and chi‑squared tests for categorical variables, with p < 0.05 considered significant. SPSS v26.0 was used. The study received ethical approval from the LUMC ethics committee and all participants provided written informed consent.

The study included 24 HPPD patients, 37 controls with visual snow (VS(S)), and 13 patients in whom HPPD could not be excluded. Descriptions of visual snow were highly similar across groups. HPPD participants were younger and predominantly male (22 of 24). Most patients in all groups met additional VSS criteria (two or more additional visual symptoms). Median VHI scores were 38 for both the HPPD and VS(S) groups and 26 for the "HPPD not excluded" group, with no significant differences between groups. Regarding illicit drugs and timing, 17 of 24 (70.9%) HPPD participants reported visual snow began after intake of XTC (MDMA). Of those XTC cases, three reported an estimated MDMA pill content (80, 220 and 225 mg) though without official test confirmation. Time from drug intake to onset ranged from the same day to up to 3 months; among XTC users, 10 of 17 (58.8%) reported onset within 2 days. Cannabis was reported as a trigger by seven of 24 (29.2%) cases. Other reported agents included psilocybin, cocaine, amphetamines, novel stimulants, ketamine and nitrous oxide. Eleven cases reported use of multiple drugs during the episode believed to have triggered visual snow. Five of 24 HPPD participants reported experiencing visual hallucinations during the drug episode; two of these identified visual snow among those hallucinations. Primary outcome — lifetime migraine prevalence — differed markedly between groups. None of the HPPD cases had migraine, compared with 20 of 37 (54.1%) in the VS(S) group (p < 0.001). When stratified by sex, 0 of 22 male HPPD patients had migraine versus 4 of 18 male VS(S) patients (22.2%; p = 0.020). The VS(S) female subgroup showed high migraine prevalence (16 of 19, 85.1%), but statistical testing was limited because only two females were in the HPPD group. In the "HPPD not excluded" group, migraine was reported in three of seven males (42.9%) and three of six females (50.0%). Applying criteria for probable migraine added only two additional cases, both in the VS(S) group. Analyses using 1‑year prevalence produced similar results. Overall, most migraine cases reported migraine with aura. The proportion of participants with a parent with migraine did not differ meaningfully between HPPD and VS(S) groups (26.1% vs 30.6%). Tension‑type headache occurred in six HPPD cases (one fulfilled criteria for chronic tension‑type headache); no other primary or secondary headache disorders were identified among HPPD patients.

The authors report that in their sample of confirmed HPPD patients whose visual snow had a clear temporal relationship with illicit drug use, migraine was absent, whereas more than half of visual snow patients without prior illicit drug use had lifetime migraine. Most HPPD cases had used XTC (MDMA), often with symptom onset within 2 days of intake. The absence of migraine in HPPD participants suggests that migraine is not a shared predisposing trait between drug‑triggered visual snow and visual snow in people without prior illicit drug use, although the authors acknowledge that both conditions could converge on a common final pathway explaining identical symptomatology. The authors contrast their findings with a prior web‑based study that reported substantial migraine prevalence in possible HPPD; they propose that methodological differences may explain the discrepancy. The present study used structured physician interviews and ICHD‑3 criteria, reducing risk of false‑positive migraine classification, whereas the web survey relied on a single, nonspecific question. The strong male predominance in the HPPD group may also contribute to lower observed migraine prevalence, but the authors note that they would still have expected some migraine cases among 22 males if migraine were a central factor. They also raise the possibility that people with migraine might avoid illicit drugs to prevent triggering attacks, but note there are no clear data on this behaviour. The authors discuss pathophysiological research: studies of VSS and HPPD have largely been conducted separately and often excluded patients with prior illicit drug use; hypothesis for drug‑related persistent visual symptoms include serotonergic neurotoxicity and cortical disinhibition, with mixed evidence across studies. They highlight the need for comparative pathophysiological investigations including both VSS and HPPD patients. Clinically, two cases in their series with temporary visual snow after earlier XTC use — that became chronic after a later episode — suggest a preventive message to avoid further drug use when transient visual symptoms occur. The authors note limitations including potential referral bias because recruitment occurred via a tertiary clinic that also manages headaches, a small number of female HPPD participants limiting sex‑stratified analyses, and inability to compare responders versus nonresponders to the drug‑consulting clinic. They consider the major strength to be the study of confirmed HPPD patients with a clear temporal link to illicit drug use. The authors conclude that, despite limitations, the absence of migraine in confirmed HPPD cases argues against migraine being a necessary predisposing factor for drug‑triggered visual snow, though shared downstream mechanisms remain possible.