Flashbacks and HPPD: A Clinical-oriented Concise Review

Hallucinogens include a range of natural and synthetic substances that produce transient intoxications marked chiefly by visual perceptual disturbances, often called "trips". A striking feature described with LSD and LSD-like agents is the recurrence, after intoxication has ended, of some or all perceptual symptoms experienced during the original episode. Prior work has implicated a wide variety of substances beyond LSD—psilocybin, mescaline, cannabis and synthetic cannabinoids, MDMA, PCP, dextromethorphan, ketamine and others—but the pathophysiology and clinical boundaries of these recurrent phenomena remain poorly specified. This review seeks to clarify terminology and clinical characterisation of recurrent substance-associated perceptual disturbances. Lerner and colleagues propose a two-part clinical taxonomy—HPPD I (benign, short-lived, non-distressing "flashbacks") and HPPD II (chronic, distressing, functionally impairing persisting perceptual disorder)—and aim to summarise hypothesised mechanisms, typical phenomenology, precipitants, differential diagnosis and pharmacological management for clinicians treating these presentations. The authors position the manuscript as a concise, clinically oriented synthesis to guide psychiatrists encountering such cases.

The extracted text does not provide a formal methods section describing a systematic search strategy, inclusion/exclusion criteria, databases searched or dates covered. The paper therefore appears to be a narrative, clinically oriented literature review rather than a systematic review or meta-analysis. Within that narrative frame, the authors synthesise previously reported clinical descriptions, neurophysiological findings (for example qEEG mapping), case reports and open-label treatment studies to build their typology and therapeutic recommendations. They draw on reports linking various substances to recurrent visual disturbances, discuss proposed biological mechanisms, catalogue clinical features and precipitants, and summarise pharmacological agents that have been used in clinical practice, noting the level of evidence for each when available. Because explicit methodological details (such as search terms, study selection process, or formal risk-of-bias assessment) are not clearly reported in the extracted text, the review should be interpreted as a clinical synthesis of the available literature rather than a systematic evidence summary.

Etiology and neurobiology: The authors report that LSD’s acute effects are largely mediated by postsynaptic 5-HT2 receptor partial agonism and suggest that recurrent imagery may reflect a persistent disinhibition of visual processing. Proposed mechanisms include LSD-induced dysfunction or loss of cortical serotonergic inhibitory interneurons with GABAergic outputs, defective sensory gating, cortical disinhibition evidenced by qEEG findings, sensitisation or reverse tolerance, and possible genetic vulnerability. The review emphasises that multiple mechanisms may be operative given the heterogeneity of substances and clinical presentations. Substances implicated and phenomenology: A wide array of agents have been associated with recurrent visual disturbances, most prominently LSD and psilocybin, but also mescaline, cannabis (including synthetic cannabinoids), MDMA, PCP, dextromethorphan, ketamine, ayahuasca, ibogaine, salvia divinorum and various inhalants. Reported visual phenomena include geometric hallucinations, perceived motion in peripheral fields, flashes or intensified colours, image trailing, positive afterimages, halos, distortions of size/distance (macropsia/micropsia), pareidolia, synesthesia, phosphenes, visual snow and acquired dyslexia. Clinical typology: Lerner and colleagues advance a two-subtype scheme. HPPD I (Flashback Type) is described as transient, often trigger-precipitated or spontaneous, benign and reversible; it typically causes little distress or functional impairment and is commonly regarded by experienced users as a "free trip." HPPD II (Hallucinogen Persisting Perception Disorder Type) is characterised as chronic, distressing, pervasive, slowly reversible or irreversible, and frequently associated with significant impairment across personal, social and occupational domains. The authors note an intermediate presentation in which newly generated visual imagery not present during the original intoxication may emerge. Clinical features, course and precipitants: Onset patterns differ: HPPD I often has a gradual onset, whereas HPPD II may begin abruptly. Both types can be spontaneous or triggered; reported precipitants include darkness, bright or flashing lights (for example police lights), exercise, noise, sexual activity, pregnancy and puerperium, photophobia, tobacco smoking, cannabis use, listening to acid/trance music, certain medications (phenothiazines, risperidone) and even electroconvulsive therapy in those with prior LSD exposure. Frequency, duration and intensity tend to decrease after HPPD I onset but often increase and become more intrusive in HPPD II. A latent period between intoxication and recurrence can range from hours to years. Insight is usually preserved in both types, although continuous unremitting imagery can transiently impair reality testing in some cases. The authors stress the importance of excluding organic or ophthalmological causes via physical, ophthalmic and neurological assessment, and occasionally EEG/CT/MRI. Comorbidity and affective features: HPPD I often occurs without prominent co-occurring psychiatric disorders and may be associated with relatively pleasant affect. HPPD II is frequently accompanied by anxiety, depressive symptoms, depersonalisation/derealisation and anticipatory anxiety that can resemble panic disorder and lead to avoidant behaviour. The review notes bidirectional relationships between HPPD and other psychiatric disorders—pre-existing conditions can precede HPPD onset, and HPPD may precipitate or worsen psychiatric morbidity. Pharmacological management: Evidence for treatments is primarily from case reports and open-label series; randomised controlled trials are lacking. Key treatment observations summarised include: - Benzodiazepines: Agents such as clonazepam (0.5–1.5 mg/day) are reported as among the most effective; other agents with some benefit include clorazepate, alprazolam (0.25–0.75 mg/day) and oxazepam. The authors note abuse potential as a concern in patients with substance-use histories. - Sympatholytic α2 agonists: Clonidine (recommended initial doses ~0.050–0.075 mg/day) and lofexidine have shown improvement in some patients, possibly via GABAergic effects or reduction of locus ceruleus adrenergic activity. - Serotonin–dopamine receptor antagonists: Contrary to expectation, risperidone aggravated symptoms in some cases and is associated with re-emergence of visual phenomena in patients with prior LSD exposure; low doses of some atypical antipsychotics (olanzapine 5–7.5 mg/day, quetiapine 25–75 mg/day, amisulpride 300–600 mg/day) and agents such as aripiprazole or asenapine have been reported as beneficial in select cases. - Typical dopamine antagonists: Older agents such as haloperidol were previously used but are largely not recommended; some clinicians still use low-dose perphenazine or zuclopenthixol with monitoring for extrapyramidal effects. - Antiepileptics: For paroxysmal visual phenomena interpreted as seizure-like, medications including valproic acid, carbamazepine, oxcarbazepine, gabapentin, topiramate, levetiracetam and lamotrigine (25–200 mg/day) have been tried with varying success. - SSRIs and SNRIs: Reports are mixed—sertraline has been reported to both worsen and improve symptoms. Citalopram, paroxetine, escitalopram and SNRIs such as duloxetine and milnacipram have been used, potentially helpful when anxiety or depression co-occurs. - Naltrexone: Used in chronic, unremitting cases that failed other therapies, on the hypothesis that distressing imagery might involve endogenous opioid mechanisms. - Calcium channel blockers: Verapamil and nifedipine have been tried, chiefly in patients with concomitant anxiety or mood disorders. - Beta blockers: Propranolol has been used to alleviate anxiety associated with visual imagery. - COMT inhibition and dopaminergic augmentation: A combination including tolcapone with levodopa/carbidopa is reported as helpful in some cases, on the rationale of improving sensory gating via dopaminergic mechanisms. Overall, no single pharmacological agent is universally effective. HPPD I patients seldom seek medication; HPPD II commonly requires more intensive, sometimes multi-drug approaches tailored to comorbid psychopathology.

The authors conclude that establishing consistent terminology and clear treatment targets is a necessary first step for clinical progress. They reiterate their practical distinction: HPPD I tends to be an independent, typically benign condition that may respond to a single agent (examples noted include clonidine, clonazepam or low doses of antipsychotics), while HPPD II is commonly associated with co-occurring psychiatric disorders and may require combinations of medications chosen according to the accompanying psychopathology. Lerner and colleagues emphasise that clinical experience and comprehensive knowledge of the phenomenon are important to achieving good outcomes, given the heterogeneous presentations and variable treatment responses. They note that some symptoms remit rapidly whereas others—such as trailing phenomena—can be resistant to therapy. The discussion closes with an appeal for controlled studies to better define pathophysiology, standardise terminology and rigorously evaluate the efficacy of different treatments across HPPD subtypes.