Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases

Litjens and colleagues introduce Hallucinogen Persisting Perception Disorder (HPPD) as a drug‑induced, long‑lasting disturbance of perception that resembles a ‘‘persistent drug trip’’. The Introduction summarises that classical hallucinogens (for example LSD and psilocybin) produce acute visual distortions such as altered colours, geometric patterns and trailing, and that a minority of users report persistent recurrent perceptual symptoms severe enough to meet DSM IV‑TR criteria for HPPD. Prevalence estimates vary widely across populations and study methods; the authors note limited, heterogeneous epidemiological data and uncertainty about which drugs and neurobiological mechanisms are implicated in HPPD. The paper sets out to review the available evidence on HPPD and drug‑related alterations in visual processing, with particular attention to serotonergic mechanisms. In addition to the literature review, the authors report a series of 31 previously unpublished clinical cases from an addiction psychiatry service, many of which implicate ecstasy (MDMA) as a suspected precipitant. The stated aim is to integrate clinical, pharmacological and neurophysiological evidence to clarify possible etiological pathways for HPPD and to highlight gaps for future research.

The paper is presented as a comprehensive review of the HPPD literature combined with a descriptive case series. The extracted text does not detail a formal systematic search strategy (databases, keywords, dates) or explicit inclusion/exclusion criteria for the literature review; therefore it should be understood as a narrative synthesis of available evidence rather than a registered systematic review. Clinical cases were obtained from a psychiatric consultancy service at an addiction care centre in the Netherlands. Between the start of the intake period and October 2012 there were 104 intakes; from these the investigators selected 31 cases that they judged to meet DSM IV‑TR criteria for HPPD. Selection criteria for inclusion in the case series included a psychiatric diagnosis of HPPD by a physician in addiction medicine, report of at least two different visual phenomena, and a minimum frequency of one disturbed perception episode per week. One individual was excluded because of a headache history suggestive of migraine; no extensive neurological testing was routinely performed as part of the intake. Cases were assessed using a standardised symptom checklist developed during four years of intakes; the checklist covered social, somatic and a broad range of perceptual and psychiatric symptoms. A subset of patients (five) underwent ophthalmological assessment and eight had neurological assessment on their own initiative; these investigations reportedly did not reveal abnormalities. The presentation and history of drug exposures were recorded, and lifetime exposure levels were categorised by the authors as low, moderate or extensive according to predefined thresholds described in the extracted text. Analysis of the case series was descriptive; no inferential statistics are reported.

From the literature synthesis, the authors report that most documented HPPD cases have been associated with drugs that act as agonists at serotonergic 5‑HT2A receptors. Classical hallucinogens (ergotamines such as LSD, tryptamines such as psilocybin and DMT, and phenethylamines such as mescaline and 2C compounds) show psychoactive potency that correlates strongly with 5‑HT2 receptor affinity, and 5‑HT2A partial agonism is emphasised as the primary mediator of hallucinogenic effects. The case series comprised 31 previously unpublished patients identified as possible HPPD. These individuals primarily self‑referred or found the service online; about 80% had learned of the consultancy via the internet. Most cases reported multiple recurring visual phenomena, with high prevalence of visual snow, positive afterimages, flashes, illusory motion (trailing), and an increased awareness of floaters. In addition to visual symptoms, many patients reported other perceptual disturbances (auditory or sensory), and psychiatric comorbidities were common: approximately 71% reported anxiety or panic around the period of drug use, 39% reported derealisation and 32% depersonalisation, and 45% reported unusual head sensations (pressure, clicks, dryness). The majority of cases attributed symptom onset to ecstasy (MDMA), though in many instances poly‑drug exposure or uncertainty about the specific causative occasion was noted. A minority of patients underwent ophthalmological or neurological assessment; these investigations were reportedly normal in the assessed individuals. Neurophysiological and pharmacological evidence summarised by the authors includes: post‑mortem and imaging data indicating a high density of 5‑HT2 receptors in primary visual cortex (V1); animal and primate studies showing that 5‑HT2A agonism can suppress strong neuronal responses while facilitating weak ones in V1; imaging reports of reduced serotonin transporter (SERT) levels in heavy MDMA users; and PET observations of decreased 5‑HT2A receptor density in recent MDMA users but increased expression in long‑abstinent users or in rats after 30 days. Experimental studies in animals indicate MDMA can be axon‑toxic to raphe projections, while single doses of LSD in rats altered expression of genes related to synaptic plasticity and glutamate signalling. The authors also note that benzodiazepines (GABA‑A receptor agonists) often relieve HPPD symptoms, whereas some 5‑HT2 antagonists have been reported to worsen symptoms, and that cannabis and ketamine have been implicated by some users though their primary mechanisms do not rely on serotonergic 5‑HT2A agonism. Epidemiological figures from prior studies are heterogeneous: pre‑DSM reviews and web surveys report widely varying rates of HPPD‑like symptoms among drug users, ranging from under 5% in some therapeutic LSD samples to up to 50% in multi‑substance abusers in older literature; web‑based questionnaires reported 61% of respondents with extensive drug histories experienced at least one recurring visual experience and 24% reported it as constant or near‑constant, but only a small fraction (about 4.2% in one survey) sought treatment.

The authors interpret the assembled evidence as supporting a role for serotonergic neurotransmission, in particular 5‑HT2A receptor‑mediated mechanisms, in the genesis of HPPD. They propose that a misbalance between excitatory and inhibitory signalling in low‑level visual processing (notably in V1 and possibly the lateral geniculate nucleus) could underlie persistent visual phenomena. In this model, GABA‑releasing inhibitory cortical interneurons that express 5‑HT2A receptors are singled out as plausible mediators: impaired inhibition could allow internally generated noise or prolonged neuronal activity to be perceived as visual phenomena such as visual snow, halos and afterimages. Computational and physiological work cited by the authors is used to illustrate how alterations in excitation/inhibition ratios could produce specific symptom types (for example increased excitation producing halos, or combined changes producing afterimages). MDMA is highlighted as an important finding of the review because, although not classically considered a hallucinogen, it combines potent serotonin release/reuptake reversal with moderate 5‑HT2A agonism. The 31 new cases strengthen the authors’ contention that MDMA can be implicated in HPPD‑like presentations, while acknowledging that poly‑drug use, variable drug purity and uncontrolled settings complicate causal attribution. The authors also observe that benzodiazepines’ therapeutic effects and the occasional worsening of symptoms with 5‑HT2 antagonists are consistent with an inhibition deficit hypothesis. Several limitations and uncertainties are acknowledged. Evidence remains sparse and heterogeneous, and much of the case and survey data are subject to recall bias, poly‑drug confounding and the uncontrolled nature of recreational drug use. The review did not present a transparent systematic search method in the extracted text, so literature coverage and selection are not fully reproducible. Differential diagnoses such as migraine with aura, persistent migraine aura, and occipital epilepsy share some overlapping visual phenomena and cannot always be excluded without detailed neurological and ophthalmological testing; routine EEG, MRI or ophthalmological tests can be normal in these disorders. The authors note knowledge gaps including the absence of studies of genetic risk factors in relation to HPPD, limited direct human neurophysiological data from confirmed HPPD patients, and incomplete characterisation of long‑term serotonergic receptor and transporter changes after various drugs. They recommend targeted future studies such as PET imaging of 5‑HT2A receptor density in visual areas, neurophysiological assessments of visual system excitability in HPPD patients, and investigations of potential sensitising interactions between different drug classes.

The authors conclude that HPPD is an uncommon but potentially disabling perceptual disorder that likely involves a disturbance in inhibitory/excitatory signalling within low‑level visual processing, with serotonergic neurotransmission and 5‑HT2A‑expressing cortical inhibitory interneurons as plausible contributors. Importantly, HPPD is not restricted to classical hallucinogens: the review and the 31 new clinical cases implicate ecstasy (MDMA) as a possible causative agent for HPPD‑like symptoms. Despite the condition’s relative rarity at the population level, the authors argue that HPPD merits further scientific attention to improve understanding of visual processing and to clarify mechanisms, risk factors and potential treatments.