We studied a group of patients with visual snow who reported that the onset of visual snow was triggered by intake of illicit drugs (HPPD). Most patients had used XTC, of whom almost 60% reported visual snow started within 2 days of intake. Migraine was absent in all patients with HPPD and present in more than half (54.1%) of patients with visual snow who had never used illicit drugs prior to visual snow onset. This suggests that migraine is not a shared factor between the groups.

The relationship between visual snow and HPPD has not been extensively investigated. In early descriptions of patients with HPPD [14], visual snow was listed as one of the possible symptoms, but until recently the direct comparison between patients without a history of illicit drug use (VSS) and patients with visual snow after illicit drug use (HPPD) has not been made. In a recent web‐based study, the groups were compared for the first time, and their clinical characteristics did not differ (except for a later age at onset and male preponderance in the HPPD group) [2]. This is in line with our observations. Patients from both groups gave similar descriptions of their visual snow, already at their different and independent recruitment sites. Furthermore, results on the additional visual symptoms and symptom severity (measured by the VHI) were similar. This supports the conclusions of the previous study that HPPD can manifest within the visual snow spectrum.

In contrast, our results on migraine prevalence are different. In the web‐based survey, 57% of HPPD patients were reported to have migraine [2], whereas we observed no migraine in our HPPD patients. We believe these contrasting findings may result from different data collection methods. The previous web‐based survey used a single nonspecific question (“Have you ever been diagnosed with migraine, or have you had a headache of moderate or severe intensity in the past?”) [2], whereas we used a structured interview by a physician, thereby reducing the chance of false positives. This is supported by the relatively high percentage of migraine in the VSS group (72% [2]) in the web‐based survey compared to earlier studies (59% [1] and 47% [9]). The strong preponderance of males in our HPPD group likely also has influenced the low prevalence of migraine in our study, as migraine is more prevalent in women. However, we would still have expected several migraine cases among 22 males if migraine were to play an important role. As another possible explanation, we hypothesize that migraine patients may avoid illicit drug use to avoid triggering a migraine attack, but there are no clear data on this topic.

The absence of migraine in HPPD suggests that, although the clinical phenotype may be like VSS, different initiation mechanisms may play a role. If there was an important interaction with migraine (i.e., the presence of migraine mechanisms is necessary to develop visual snow after drug use), we would have expected more migraine cases in our HPPD group. This observation, however, does not exclude that both disorders, HPPD and VSS, share a final common pathway in their pathophysiology. A final common pathway would certainly explain the identical symptomology.

To our knowledge, there are no studies investigating pathophysiological correlates in both VSS patients and HPPD patients. In the field of VSS, progress in unraveling its pathophysiology is being made using positron emission tomography [4], visual behavioral testing [5], visual evoked potentials (VEPs) [6, 19, and (functional) magnetic resonance imaging (MRI) [7, 20, but patients with illicit drug use prior to onset have been excluded in these studies. Similarly, in the field of HPPD, no patients with VSS have been included. In addition, the number of pathophysiological studies in HPPD patients is limited and primarily focused on users of LSD, the first group to report persistent visual complaints after illicit drug intake. It was hypothesized that LSD is neurotoxic for serotonergic inhibitory neurons and that this causes less inhibition, leading to increased excitation (disinhibition theory) [21, 22. In LSD users, increased electroencephalographic coherence in the occipital region with reduced VEP latency was found [21, 22. More recent research has focused on MDMA. There is increasing evidence that MDMA is toxic for serotonergic neurons [23, 24, 25, leading to increased visual cortex activation demonstrated with transcranial magnetic stimulation functional MRI and positron emission tomography [26, 27, 28, 29, but attempts at replication show heterogenous results [30]. Interestingly, these MDMA studies were performed with persons without visual complaints, raising the question of whether activation would be stronger in persons with HPPD complaints. Of additional interest is the reversibility of the observed changes caused by MDMA, which still needs further investigation [29]. Our observation of the two cases with temporary visual snow after previous occasions of XTC use (i.e., before the visual snow became chronic after the more recent occasion of illicit drug use) suggest there could be an important preventive message for cases still experiencing temporary symptoms: refrain from further usage of illicit drugs. Finally, it should be noted that HPPD constitutes a wide clinical spectrum itself. Strictly speaking, the DSM‐V diagnosis of HPPD is “the reexperiencing, following cessation of use of a hallucinogen, of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogen” [15]. However, the diagnosis is now also commonly used for other perceptual symptoms that are not flashbacks to the drug intoxication, but continuous symptoms that started after the intoxication. “Type 2 HPPD” has been the proposed term for the latter [12]. Our patients and those from the previous web‐based study [2] can be categorized in this category. Future research should elucidate whether visual snow is the main symptom within this category or whether there are other types of visual symptoms.

Our study has several limitations. The study may be prone to recall bias. HPPD cases could have incorrectly identified the illicit drugs as the trigger of their visual snow instead of another, yet unknown risk factor (e.g., stroboscope light in discothèques), or perhaps there are no exogenous risk factors. However, we believe the large number of individuals describing a clear temporal relationship between illicit drug use and onset of visual snow, in our study and other studies [2, 13, warrants attention to illicit drugs as a potential important risk factor for developing visual snow. Nonetheless, the risk of a noncausal relationship increases with a longer time window between drug use and onset of symptoms. It may be argued that in future studies only persons with visual complaints less than 48 h after drug use should be included. Another important limitation is the small sample size, especially of female cases, thereby limiting our conclusion on migraine prevalence to males. Also, HPPD cases were slightly younger and may still develop migraine later in life, but we consider this unlikely, because age at onset for migraine in the VS(S) controls was well below age at onset for visual snow in the HPPD group. Selection bias might have played a role as well. VS(S) patients were recruited via a neurology outpatient clinic that is a tertiary headache center as well, increasing the a priori chance of comorbid migraine. However, that other studies also observed a high prevalence of migraine in other recruitment settings [2, 9 suggests that our observation is not biased. In addition, the patients were referred for continuous visual complaints and not because of headaches. Interestingly, there is some evidence that VSS is more severe when comorbid migraine is present [31]. Theoretically, it could be that our clinic only attracted the more severe cases and consequently observed more migraine. However, this bias would still not explain the absence of migraine in the HPPD group, which had similar severity (VHI) scores. Finally, we could not compare responders and nonresponders of the consulting clinic of recreational drug use. Despite these limitations, we still would have expected more migraine diagnoses in the HPPD group if migraine plays a key role in the pathophysiology. The major strength of this study is that we were able to study confirmed HPPD patients; patients' symptoms had a clear temporal relationship with illicit drug use, and therefore they presented at a drug consulting clinic experienced in HPPD diagnosis. Additionally, we used the gold standard for migraine diagnose, a structured interview. Lastly, in our experience the VHI was an easy tool to assess symptom severity, and we believe this questionnaire could serve as an outcome measure in future studies.

Given the popularity of recreational drug use, we believe future research should target visual snow as a potential aftereffect of illicit drug use. Especially XTC use has increased in the past years. It is the second most used drug in the Netherlands after cannabis (2.8% of Dutch adults used XTC at least once in the past year) [32]. This could explain why XTC and cannabis were reported as the most common causes of HPPD. In contrast, LSD use is rare (0.2% of adults used LSD at least once in the past year). Perhaps even more worrisome, MDMA concentrations in XTC pills are rapidly increasing; in 2008 mean MDMA concentration per pill was 87 mg, in 2013 this was 148 mg, and in 2018 this rose to 171 mg [32]. These trends could have unfavorable aftereffects. In one exploratory survey in nightlife participants (of whom almost 50% indicated they had used XTC in the past year), visual snow was reported by 17% of the participants, suggesting visual snow is more common than earlier reports suggest [33]. Unfortunately, this survey contained no detailed information on whether symptoms were temporary or chronic. Additional population‐based cohort studies are therefore necessary to better estimate the incidence of visual snow, and both illicit drug use and migraine should be studied as risk factors. Future studies investigating potential pathophysiological mechanisms for visual snow should not only aim to replicate the earlier promising findings [4, 5, 6, 7, 20 but also include HPPD patients as a separate group.

In conclusion, in contrast to our hypothesis, none of the HPPD participants had migraine, whereas migraine was quite prevalent in visual snow controls without prior use of illicit drugs. Although data on migraine could be skewed by differences in sex between the two groups, we believe our observations suggest that migraine is not the common variable and that at least partly different pathophysiological factors may play a role. Furthermore, we believe users of XTC and other hallucinogens should be aware of visual snow as a possible persistent aftereffect, and that this potential risk warrants further research.