Hallucinogen Persisting Perception Disorder

From EyeWiki

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)[1]. 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[2]. 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[3].


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)[4][5][6][7][8][9]. 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[1].


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)[10][11]. Chronic disinhibition may occur from destruction and/or dysfunction of cortical serotonergic inhibitory interneurons involving the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA)[12][13][14][15]. 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[16]. 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[17].



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[1][3]. Other, non-visual symptoms can include recurrent synesthesias, dissociation, auras, depersonalization, and derealization[3]. Accompanying these hallucinations and sensory disturbances, the patient may report severe anxiety, which can escalate to full blown panic attacks[1]. 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[11][18].

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[11][18]. 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[2]. 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[11][18]. HPPD II is often not associated with “auras”, and rather begins suddenly, without warning[11][18]. The patient may even perceive a partial or total loss of control during the intense manifestations of HPPD II[3].


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:

  1. Reexperiencing one or more of the perceptual symptoms that were experienced while intoxicated with hallucinogens.
  2. The symptoms in criteria A cause clinically significant distress or impairment in important areas of functioning such as social and occupational environments
  3. 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[19][20].

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


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[2]. Benzodiazapines may also be used to eliminate HPPD I and significantly reduce the severeity of HPPD II[11][18][21][22]. 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[11]. These are particularly helpful in treatment of HPPD II with co-morbid anxiety disorders[11]. Non-pharmacological management could include brain stimulation treatment, but this has not been fully substantiated or investigated.


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[11][18]. There is a consistent subgroup within those patients with HPPD II that require constant pharmacologic intervention[11][18].


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