Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives

Hallucinogens are a diverse group of natural and synthetic compounds that profoundly alter consciousness, cognition, emotion and perception, with visual distortions being the most prominent sensory effect. Their use spans millennia in ritual and healing contexts and re-emerged in Western medicine and culture in the 20th century, with LSD as the archetypal synthetic hallucinogen. Contemporary patterns of use include ceremonial contexts as well as recreational poly‑substance settings and novel psychoactive substances, and there is growing clinical concern about adverse psychiatric sequelae even in people without prior psychopathology. This paper by Martinotti and colleagues reviews original studies on Hallucinogen Persisting Perception Disorder (HPPD), a relatively rare condition in which perceptual disturbances experienced during acute intoxication recur after the drug has been cleared. The authors set out to summarise suggested etiologies, the range of substances implicated, clinical features of the two proposed subtypes (HPPD I and HPPD II), psychiatric comorbidities, and reported therapeutic strategies, aiming to provide a comprehensive qualitative synthesis of the original literature.

The investigators performed a PubMed search on 15 September 2017 using the terms "Hallucinogen Persisting Perception Disorder" OR "Hallucinogen Persisting Perceptual Disorder". The search initially returned 46 records. Inclusion criteria were original articles in English, comprising open‑label or double‑blind trials, prospective or retrospective observational studies, and case reports that described perceptual distortions in people with prior substance use. Excluded materials were reviews, commentaries, letters and studies enrolling adolescents. All authors concurred on eligibility criteria. After title and abstract screening 17 records were removed; 29 full texts were reviewed and 25 papers met the inclusion criteria and were incorporated into the qualitative synthesis. The extracted text refers to a Figure documenting the selection flow, but that figure is not provided in the available extraction.

Suggested etiologies: The literature presents several, non‑exclusive neurobiological hypotheses. One prominent idea is chronic disinhibition of visual processing due to dysfunction of cortical serotonergic inhibitory interneurones with GABAergic outputs, possibly caused by LSD or related drugs; this could impair sensory filtering. Reverse tolerance or sensitization after LSD exposure has also been proposed to explain persistent symptoms after drug cessation. Structural or functional impairment of visual pathways has been hypothesised, including transient or lasting dysfunction of the lateral geniculate nucleus (LGN) and altered activity in occipital regions such as the right lingual gyrus (noted in research on visual snow). Psychological and environmental triggers, and a subtle over‑activation of visual networks that interacts with anxiety in predisposed individuals, are described in some reports. Substances implicated: Across the included literature the majority of reported HPPD cases were linked to LSD or phencyclidine (PCP): 14 studies totalling 294 patients. Cannabis was associated with perceptual disturbances in seven cases; single reports linked symptoms to MDMA or to a combination with PCP; two cases involved synthetic cannabinoids. One unique case of HPPD‑like visual disturbances was attributed to risperidone in a patient without a history of substance use. Clinical features: The authors describe two clinical subtypes. HPPD I (benign flashbacks) is typically short‑lived, reversible, and causes minimal functional impairment; some patients view these as benign or even desirable re‑experiences. HPPD II is portrayed as long‑lasting or slowly reversible, more pervasive, and substantially impairing. Latent periods between intoxication and symptom recurrence are highly variable, ranging from minutes to years. Episodes may be spontaneous or triggered, continuous or intermittent. Onset phenotypes differ, with HPPD I often preceded by mild auras and slight dissociation, whereas HPPD II can begin abruptly with intense depersonalisation/derealisation and more frequent, longer and more intense events. Psychiatric comorbidity: Depressive and anxiety symptoms, and severe disorders such as major depressive disorder, bipolar disorder and schizophrenia spectrum disorders, are reported alongside HPPD. Nevertheless, HPPD may occur independently of other psychiatric diagnoses. Two observational cross‑sectional studies compared schizophrenic patients with prior LSD use who developed HPPD (SCZ+HPPD, n=49) versus those who did not (SCZ, n=57), yielding 106 patients in total. No demographic differences were found between groups, but SCZ+HPPD patients reported more distressing LSD experiences ("bad trips", p<0.05). PANSS positive scores did not differ, whereas SCZ+HPPD patients had lower PANSS negative, general psychopathology and total scores (p<0.05). In those studies 67% of comorbid patients could distinguish perceptual distortions from psychotic hallucinations; additional reports describe the identification of precursory cues in some patients. A single case report described risperidone‑associated visual distortions developing after dose increases in a psychotic patient without prior substance abuse. Therapeutic findings — first‑line medications: Several classes of medications have been reported in case reports, small open trials and individual cases. Presynaptic α2 adrenergic agonists (clonidine, lofexidine) have shown symptom alleviation in some patients; clonidine was evaluated at 0.75 mg/day in nine patients in one report, and a single patient achieved remission on 0.25 mg three times daily for two months. Benzodiazepines are commonly used: alprazolam (0.25–0.75 mg/day) and clonazepam (typical ranges 0.5–1.5 mg/day, with reports up to 4–6 mg/day) produced benefit in several cases. In an open clinical trial 16 HPPD patients treated with clonazepam 2 mg/day showed significant improvement that persisted through a 6‑month follow‑up after discontinuation; clonazepam also improved cannabis‑related cases in other reports, though some focal visual phenomena persisted. Antipsychotics: First‑generation antipsychotics at low doses (haloperidol, trifluoperazine, perphenazine, sulpiride, zuclopenthixol) were sometimes helpful but require monitoring for extrapyramidal effects; haloperidol reduced hallucinations in one study but transiently exacerbated flashbacks. The role of second‑generation antipsychotics is inconsistent: risperidone has been reported both to worsen and to improve symptoms in different cases, and some data suggest ineffectiveness in comorbid psychotic populations; aripiprazole is mentioned as a possible low‑dose option based on limited evidence. Antiepileptics and mood stabilisers: Visual phenomena interpreted as paroxysmal have prompted trials of anticonvulsants. Phenytoin is no longer favoured owing to side effects. Case reports and small series describe valproate, carbamazepine, oxcarbazepine, gabapentin, topiramate, lamotrigine and levetiracetam producing benefit in some patients; valproate (1500 mg/day) improved but did not abolish alcohol‑triggered visual hallucinations in one case, levetiracetam reduced some visual symptoms and depersonalisation, and lamotrigine was effective in a recent severe case with EEG abnormalities. Antidepressants and other medications: Antidepressants have been used for co‑occurring mood and anxiety disorders rather than for isolated HPPD II. Sertraline has conflicting reports of both worsening and improving visual disturbances; other SSRIs generally showed no benefit. Reboxetine (a norepinephrine reuptake inhibitor) demonstrated some success in LSD‑induced HPPD comorbid with major depression. Naltrexone, calcium channel blockers and beta blockers (propranolol 20–60 mg/day or up to 240 mg/day; atenolol 25–50 mg/day) have been tried in refractory or anxiety‑prominent cases. Investigators also note a theoretical rationale for dopaminergic enhancers to improve sensory gating via COMT inhibition, but evidence is preliminary. Brain stimulation: Repetitive transcranial magnetic stimulation (rTMS) is proposed as a potential neuromodulatory approach based on cortical hyperexcitability hypotheses and computational work on network dynamics, but no clinical rTMS studies in HPPD have been reported. Suggested targets include visual cortical areas and the occipitotemporal sulcus, ideally guided by functional neuroimaging.

The authors acknowledge a methodological limitation: their literature search was restricted to DSM terminology to avoid inclusion of non‑hallucinogen‑related "flashback" phenomena, which may have excluded studies using ICD nomenclature. They note that HPPD is rare and unpredictable; although precise prevalence is unknown, DSM‑5 reports an estimate of 4.2% in the extracted text. Diagnosis is more frequently made in people with prior psychological issues or substance misuse, but the disorder can follow a single exposure, most commonly to LSD though other agents have been implicated. Martinotti and colleagues emphasise that some presentations may reflect heightened vigilance to ordinary visual phenomena, given frequent co‑occurrence of anxiety, obsessive‑compulsive traits, health anxiety and paranoia in affected individuals. They propose adopting an operative nomenclature, Hallucinogen Persisting Perception Spectrum Disorders (HPPSD), to capture the clinical range from benign, transient HPPD I to severe, persistent HPPD II. The authors highlight that diverse substances, including natural and synthetic cannabinoids, are increasingly implicated, suggesting a multifactorial aetiology and the plausibility that different subtypes may respond to different treatments. Clinical management considerations raised include the relative resistance of tracer and trailing phenomena to treatment, the additional challenge posed by coexisting psychiatric disorders, and the heuristic value of concepts such as the "lysergic psychoma" to explain how induced psychopathology might trigger further pathological responses. Regarding therapy, the authors report that combinations of medications tailored to comorbid psychiatric and neurological conditions are often required, but they stress the paucity of high‑quality controlled data. They conclude that controlled clinical trials and further research are needed to clarify HPPD/HPPSD aetiology, mechanisms and optimal pharmacological and neuromodulatory treatment strategies.