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This article describes Hallucinogen Persistent Perception Disorder (HPPD), as well as its etiology, pathophysiology, presentation, management, and prognosis.

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= Disease Entity = Hallucinogen Persisting Perception Disorder (HPPD) is a rare clinical condition in which patients who have had previous exposure to a hallucinogenic substance continue to experience perceptual distortions months to years after complete cessation of the initial substance use. The phenomenon was initially described in 1954, but it was recognized as a clinical syndrome in 2000 with the release of the revised Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR)<ref name=":0">Orsolini L, Papanti GD, De berardis D, Guirguis A, Corkery JM, Schifano F. The "Endless Trip" among the NPS Users: Psychopathology and Psychopharmacology in the Hallucinogen-Persisting Perception Disorder. A Systematic Review. Front Psychiatry. 2017;8:240.</ref>. There are two recognized forms of this disorder: Type 1 and Type 2. Type 1 HPPD is associated with brief “flashbacks” which are random in timing and short lived. Type 2 HPPD patients experience chronic and recurrent hallucinations which “wax and wane” in intensity over a period of months to years<ref name=":1">Halpern JH, Lerner AG, Passie T. A Review of Hallucinogen Persisting Perception Disorder (HPPD) and an Exploratory Study of Subjects Claiming Symptoms of HPPD. Curr Top Behav Neurosci. 2018;36:333-360.</ref>. While this HPPD is most commonly diagnosed in patients with a history of preexisting psychological disturbance or chronic substance abuse, it can arise in any patient after even a single use of a triggering hallucinogenic drug<ref name=":2">Martinotti G, Santacroce R, Pettorruso M, et al. Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives. Brain Sci. 2018;8(3)</ref>. == Etiology == HPPD is most commonly seen after the use of lysergic acid diethylamide (LSD). HPPD however has also been reported after cannabis, 3,4- methylenedioxymethamphetamine (MDMA/“ecstasy”), and other novel psychoactive substances (NPS)<ref>Espiard ML, Lecardeur L, Abadie P, Halbecq I, Dollfus S. Hallucinogen persisting perception disorder after psilocybin consumption: a case study. Eur Psychiatry (2005) 20(5–6):458–60.10.1016/j.eurpsy.2005.04.008</ref><ref>Annis HM, Smart RG. Adverse reactions and recurrences from marihuana use. Br J Addict Alcohol Other Drugs (1973) 68:315–9. doi:10.1111/ j.1360-0443.1973.tb01263.x </ref><ref>Gaillard MC, Borruat FX. Persisting visual hallucinations and illusions in previously drug-addicted patients. Klin Monbl Augenheilkd (2003) 220:176–8. doi:10.1055/s-2003-38173</ref><ref>Creighton FJ, Black DL, Hyde CE. ‘Ecstasy’ psychosis and flashbacks. Br J Psychiatry (1991) 159:713–5. doi:10.1192/bjp.159.5.713 </ref><ref>McGuire P, Fahy T. Flashbacks following MDMA. Br J Psychiatry (1992) 160:276. doi:10.1192/bjp.160.2.276a</ref><ref>McGuire PK, Cope H, Fahy TA. Diversity of psychopathology associated with use of 3,4- methylenedioxymethamphetamine (‘Ecstasy’). Br J Psychiatry (1994) 165:391–5. doi:10.1192/bjp.165.3.391</ref>. Though the precise pathogenesis of HPPD is still unknown, it may result from the consumption of any substance with hallucinogenic properties, especially those which possess pharmacological and clinical effects similar to those of LSD<ref name=":0" />. == Pathophysiology == The exact pathophysiologic mechanism underlying HPPD is poorly understood. The primary neurobiological hypothesis is that persistent hallucinations are the result of chronic disinhibition of visual processors and subsequent dysfunction in the central nervous system following consumption of hallucinogens (e.g., LSD)<ref>Abraham, H.D.; Aldridge, A.M. Adverse consequences of lysergic acid diethylamide. Addiction 1993, 88, 1327–1334.</ref><ref name=":3">Lerner, A.G.; Rudinski, D.; Bor, O.; Goodman, C. Flashbacks and HPPD: A clinical-oriented concise review. Isr. J. Psychiatry Relat. Sci. 2014, 51, 296–302</ref>. Chronic disinhibition may occur from destruction and/or dysfunction of cortical serotonergic inhibitory interneurons involving the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA)<ref>Abraham, H.D.; Duffy, F.H. Stable qEEG differences in post-LSD visual disorder by split half analyses: Evidence for disinhibition. Psychiatry Res. Neuroimaging 1996, 67, 173–187. </ref><ref>Abraham, H.D.; Duffy, F.H. EEG coherence in post-LSD visual hallucinations. Psychiatry Res. Neuroimaging 2001, 107, 151–163.</ref><ref>Garrat, J.; Alreja, M.; Aghajanian, G.K. LSD has high efficacy relative to serotonin in enhancing the cationic current ih: Intracellular studies in rat facial motorneurons. Synapse 1993, 13, 123–134. </ref><ref>Sander-Bush, E.; Burris, K.D.; Knoth, K. Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis. J. Pharmacol. Exp. Ther. 1988, 246, 924–928</ref>. This ultimately can cause disruption of the normal neurological mechanisms that are responsible for filtration of unnecessary stimuli in the brain. Furthermore, the long term recurrence of hallucinations that can be seen after withdrawal of stimulus could be the result of reverse tolerance or sensitization that emerges following exposure to LSD<ref>Stahl, S.M. Stahl’s Essential Psychopharmacology, 1st ed.; Cambridge University Press: New York, NY, USA, 1996.</ref>. On a macroscopic level, the lateral geniculate nucleus (LGN) of the thalamus, which is important in visual processing, has also been implicated in the pathophysiology of HPPD<ref>Schankin, C.J.; Maniyar, F.H.; Sprenger, T.; Chou, D.E.; Eller, M.; Goadsby, P.J. The Relation between Migraine, Typical Migraine Aura and “Visual Snow”. Headache J. Head Face Pain 2014, 54, 957–966.</ref>. == Presentation == The unifying symptomatology of all cases of HPPD (Types I/II) are a wide range visual disturbances. These include, but are certainly not limited to micropsia, macropsia, floaters, fractals, monochromatic vision, acquired dyslexia, visual snow, and other strange visual perceptions<ref name=":0" /><ref name=":2" />. Other, non-visual symptoms can include recurrent synesthesias, dissociation, auras, depersonalization, and derealization<ref name=":2" />. Accompanying these hallucinations and sensory disturbances, the patient may report severe anxiety, which can escalate to full blown panic attacks<ref name=":0" />. There is usually a latent, asymptomatic period following the initial intoxication, before the onset of returning visual disturbances and other hallucinations. This latent period could range anywhere from minutes to years<ref name=":3" /><ref name=":4">Lerner, A.G.; Gelkopf, M.; Skladman, I.; Oyffe, I. Flashback and hallucinogen persisting perception disorder: Clinical aspects and pharmacological treatment approach. Isr. J. Psychiatry Relat. Sci. 2002, 39, 92–99. </ref>. Type 1 (HPPD I) – This type is more commonly associated with prodromal “warning auras” wherein the patient reports feelings or self-detachment or bewilderment that precede the actual hallucinations<ref name=":3" /><ref name=":4" />. The episodes themselves are brief, and often described as “flashbacks”. The episodes tend to be more benign and may not result in the same level of distress or impairment as in HPPD II<ref name=":1" />. The frequency of recurrence of HPPD I is also lower than the frequency of HPPD II. Type 2 (HPPD II) – The type 2 HPPD has more long-term, sometimes irreversible, and distressing course. The persistent hallucinations tend to be extremely long lasting, with waxing and waning intensity over a course of months to years<ref name=":3" /><ref name=":4" />. HPPD II is often not associated with “auras”, and rather begins suddenly, without warning<ref name=":3" /><ref name=":4" />. The patient may even perceive a partial or total loss of control during the intense manifestations of HPPD II<ref name=":2" />. == Signs == Patients may be distressed or anxious. The various aspects of HPPD are largely self-reported by the patient that is presenting. == Symptoms Reported by DSM V == • Visual Hallucinations • Altered Motion Perception • Flashes of Color • Color Enhancement • Trails or tracers • Palinopsia • Halos • Micropsia • Macropsia == Other Symptoms Not Reported by DSM V == • Floaters • Visualizations • Fractals (curved geometric figures) • Repetitions • Keenness (eager awareness) • Pareidolia (ability to see shapes or make pictures out of randomness) • Superimpositions • Distorted Perception of Distance • Monochromatic Vision • Intense Fragmentation • Recurrent Synesthesia • Geometric Phosphenes • Imagistic Phosphenes (formed flash of light) • Acquired Dyslexia • Aeropsia/Visual Snow (seeing air) = Clinical Diagnosis = The DSM-V has 3 major criteria by which HPPD is defined. These are: A. Reexperiencing one or more of the perceptual symptoms that were experienced while intoxicated with hallucinogens. B. The symptoms in criteria A cause clinically significant distress or impairment in important areas of functioning such as social and occupational environments C. The symptoms cannot be attributed to an underlying medical condition and are not accounted for by another mental disorder or hypnopompic hallucinations. Importantly, other etiologies of this distress such as post-traumatic stress disorder, depersonalization, derealization, etc. must be excluded. Other causes of visual disturbances such as anatomical lesions, epilepsy, and schizophrenia must also be ruled out. Finally, an association between the first intake of the hallucinogenic drug and the onset of the HPPD symptoms must be established<ref>American Psychiatric Association. DSM 5. Diagnostic and Statistical Manual of Mental Disorders––Fifth Version. Arlington: American Psychiatric Association Publishing (2013). </ref><ref>Halpern JH, Pope HG Jr. Hallucinogen persisting perception disorder: what do we know after 50 years? Drug Alcohol Depend (2003) 69(2):109–19. doi:10.1016/S0376-8716(02)00306-X</ref>. = Differential Diagnosis = • HPPD • Post-traumatic stress disorder • Depersonalization • Derealization • Hallucinogen-induced psychotic mood/anxiety disorders • Anatomical brain lesions • Brain Infections (encephalitis) • Epilepsy • Schizophrenia • Delirium • Hypnopompic Hallucinations = Management = The mainstay treatment of HPPD is pharmacologic management. Alleviation of symptoms for patients with HPPD has been reported with pre-synaptic α2 adrenergic agonists, such as clonidine<ref name=":1" />. Benzodiazapines may also be used to eliminate HPPD I and significantly reduce the severeity of HPPD II<ref name=":3" /><ref name=":4" /><ref>Lerner, A.G.; Gelkopf, M.; Oyffe, I.; Finkel, B.; Katz, S.; Sigal, M.; Weizman, A. LSD-induced hallucinogen persisting perception disorder (HPPD) treatment with clonidine: An open pilot study. Int. Clin. Psychopharmacol. 2000, 18, 35–37.</ref><ref>Kemph, J.P.; DeVane, L.; Levin, G.M.; Jarecke, R.; Miller, R. Treatment of aggressive children with clonidine: Results of an open pilot study. J. Am. Acad. Child Adolesc. Psychiary 1993, 32, 577–581</ref>. These are generally considered to be the first line medications for treatment of HPPD. Second line medications include naltrexone, calcium channel blockers, and beta blockers<ref name=":3" />. These are particularly helpful in treatment of HPPD II with co-morbid anxiety disorders<ref name=":3" />. Non-pharmacological management could include brain stimulation treatment, but this has not been fully substantiated or investigated. == Prognosis == HPPD I – The prognosis is usually positive. The disease course is usually benign, non-distressing, and limited both in time course and severity. It may require treatment with medication, but the outcomes are generally very good. HPPD II – The prognosis is usually worse than in HPPD I. Some patients fail to adapt to the presence of these long-lasting, recurrent visual and sensory disturbances<ref name=":3" /><ref name=":4" />. There is a consistent subgroup within those patients with HPPD II that require constant pharmacologic intervention<ref name=":3" /><ref name=":4" />. = References =
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