Edited by: Liana Fattore, Consiglio Nazionale Delle Ricerche (CNR), Italy
Reviewed by: Oussama KEBIR, Institut national de la santé et de la recherche médicale, France; Maurizio Coppola, Azienda Sanitaria Locale CN2, Italy
Specialty section: This article was submitted to Addictive Disorders, a section of the journal Frontiers in Psychiatry
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Hallucinogen-persisting perception disorder (HPPD) is a syndrome characterized by prolonged or reoccurring perceptual symptoms, reminiscent of acute hallucinogen effects. HPPD was associated with a broader range of LSD (lysergic acid diethylamide)-like substances, cannabis, methylenedioxymethamphetamine (MDMA), psilocybin, mescaline, and psychostimulants. The recent emergence of novel psychoactive substances (NPS) posed a critical concern regarding the new onset of psychiatric symptoms/syndromes, including cases of HPPD. Symptomatology mainly comprises visual disorders (i.e., geometric pseudo-hallucinations, haloes, flashes of colors/lights, motion-perception deficits, afterimages, micropsia, more acute awareness of floaters, etc.), even though depressive symptoms and thought disorders may be comorbidly present. Although HPPD was first described in 1954, it was just established as a fully syndrome in 2000, with the revised fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). HPPD neural substrates, risk factors, and aetiopathogenesys still largely remain unknown and under investigation, and many questions about its pharmacological targets remain unanswered too. A critical mini review on psychopathological bases, etiological hypothesis, and psychopharmacological approaches toward HPPD, including the association with some novel substances, are provided here, by means of a literature search on PubMed/Medline, Google Scholar, and Scopus databases without time restrictions, by using a specific set of keywords. Pharmacological and clinical issues are considered, and practical psychopharmacological recommendations and clinical guidelines are suggested.
Hallucinogen-persisting perception disorder (HPPD) is a long-lasting and potentially permanent syndrome characterized by a spontaneous recurrence of perceptual/visual disturbances which are reminiscent of those generated while a subject was intoxicated with hallucinogens. According to the Fifth Version of Diagnostic and Statistical Manual of Mental Disorders (DSM-5), HPPD is defined as the following criteria ( following cessation of use of a hallucinogen, the reexperiencing of one or more of the perceptual symptoms that were experienced while intoxicated with the hallucinogens (e.g., geometric hallucinations, false perceptions of movement in the peripheral visual fields, flashes of color, intensified colors, trial images of moving objects, positive after images, haloes around objects, macropsia, and micropsia); the symptoms in criterion (A) cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; the symptoms are not due to a general medical condition (e.g., anatomical lesions and infections of the brain, visual epilepsies) and are not better accounted for by another mental disorder (e.g., delirium, dementia, schizophrenia) or hypnopompic hallucinations.
Before diagnosing an HPPD, post-traumatic stress disorder, depersonalization, derealization, and hallucinogen-induced psychotic mood or anxiety disorders should be excluded (
Overall, prevalence of HPPD has been generally considered low (
Hallucinogen-persisting perception disorder was first described in 1954 (
Hallucinogen-persisting perception disorder is characterized by a plethora of visual disturbances (e.g., geometric imagery, afterimages, false perceptions of movement in the peripheral fields, flashes of light, etc.) (
Main clinical and psychopathological characteristics in HPPD.
Psychopathological and clinical features | Description |
---|---|
Teleopsia | Objects are perceived much further away than they actually are |
Pelopsia | Objects are perceived nearer than their actual size |
Macropsia | Objects are perceived larger than their actual size |
Micropsia | Objects are perceived smaller than their actual size |
Criticism/egodystonic psychosis | Patient manifests criticism toward own thoughts and perceptual disturbances, as well as experiencing perceptual disorders perceived as inconsistent with one’s self concept or ego state |
Depersonalization | A state in which some individual feels that either he/she him/herself or the outside world is unreal |
Derealization | A state in which an individual feels a detachment within the self-regarding one’s mind or body or being a detached observer of oneself (e.g., Feeling like being inside a transparent bubble) |
Feeling of body being light or heavy | |
Visual trailing | Transient disturbance of visual motion perception of unknown origin (i.e., subject perceives a series of discrete stationary images trailing in the wake of otherwise normally moving objects) |
Haloes around objects | A geometric shape, usually in the form of a disk, circle, ring, or rayed structure around an object really present |
Afterimages/palinopsia | An image that continues to appear in one’s visual field after the exposure to the original image has ceased |
Other visual disturbances | Flashes of color |
Intensified colors | |
Colored images | |
Geometric imagery | |
False perception of movement of images in the peripheral-field |
The pathogenesis of HPPD is currently unknown, even though it has been frequently reported to be associated with the intake of LSD (
Two types of HPPD have been proposed here, accordingly to Lev-Ran (
The present systematic mini review aims at providing an overview of HPPD, by specifically focusing on both clinical manifestations and psychopharmacological approaches, in general, and among NPS users.
A critical mini review was conducted, following the methods recommended by the Cochrane Collaboration (
We considered studies about HPPD, and whenever available, evaluating the relationship between HPPD and NPS. The authors examined all titles/abstracts and obtained full texts of potentially relevant papers. Two reviewers (LO and DP), independently and in duplicate, read the papers and selected papers according to the inclusion criteria. Duplicate publications were excluded. All the articles identified by the data sources, reporting original data related to HPPD in general and, more specifically, among NPS users, were considered in the present review. All experimental and observational study designs, including case reports and case series, were included as limited data have been published so far. Narrative and systematic reviews, letters to the editor, and book chapters were excluded, even though they were used for retrieving further secondary searches. To be included in the present review, studies were required to meet the following criteria: (a) empirical and peer-reviewed study; (b) at least an abstract with estimates and/or full results available/complete; (c) investigate HPPD in general and more specifically among NPS users; (d) human studies; and (e) provide data on psychopathological features and/or psychopharmacological treatments in these cases.
LO and DP independently extracted the data on participant characteristics, intervention details, and outcomes measures. Disagreements were resolved by discussion and consensus with a third member of the team (DDB). Data were collected using an
The set of keywords initially generated 260 results (Figure
Selection of retrieved studies.
Summary of all included studies.
Study | Study design | Sample characteristics | Substance implicated | Psychopharmacological treatment (dosage) | Summary of findings |
---|---|---|---|---|---|
( |
Observational study | 21 HPPD | LSD | BZDs (N/A) | An improvement was observed among HPPD subjects following the use of BDZs; while phenothiazine worsened HPPD |
Phenothiazines (N/A) | |||||
( |
Case report | 1 M, 18 years, student with a history of anxiety disorder | Cannabis and psilocybin | Amisulpride (100 mg daily) | Combination of risperidone and sertraline ameliorated HPPD symptomatology after 6 months of treatment |
Olanzapine (5 mg daily) | |||||
Risperidone (2 mg daily) | |||||
Sertraline (150 mg daily) | |||||
( |
Case reports | 2 HPPD (DSM-IV-TR criteria): M, 26 years, college student who developed HPPD with recurrent panic attacks after discontinuation of SC intake M, 24 yr, who developed HPPD experienced with anxiety features after discontinuation of SC intake |
SC | Clonazepam (1 mg/daily) | Clonazepam improved HPPD symptomatology |
( |
Case report | M, 18 years, with a history of heavy daily use of cannabis and SC who experienced HPPD | SC | Clonazepam (6 mg/daily) | For 3 years after SC consumption, the patient occasionally reexperienced the same symptoms developed during acute intoxication. These symptoms appeared during heavy cannabis consumption or in periods of boredom and inactivity |
( |
Case series | 3 HPPD (DSM-IV criteria): Case 1: F (first LSD usage: 14 years; at 21 years, first acute onset of an LSD-like euphoria and persistent visual distortions, e.g., trails of objects, particles in air, round objects) Case 2: M, 22 years, college student (first LSD usage: 15–18 years; at 20 years, first acute onset of persistent visual symptoms of afterimages, trailing of stimuli, orange/blue haloes around objects) Case 3: M, 40 years, married, builder (first LSD usage: 18 years; at 18 years, first acute onset of dots on a blank wall, intensification of lights, trails of his hand, anxiety, depression) |
LSD | RIS: 2–3 mg/daily 1–6 mg/daily 1–2 mg/daily |
RIS worsened LSD-like panic and visual symptoms |
( |
Case series | 2 HPPD (DSM-IV criteria) | LSD | Naltrexone (50 mg/daily) | Naltrexone caused a dramatic improvement in HPPD symptomatology. The remission was sustained also after discontinuation of naltrexone |
( |
Case report | M, 22 years who developed HPPD after an 8-month history of LSD abuse | LSD | Sertraline (100 mg/daily) | Sertraline determined initially an exacerbation of HPPD symptomatology, then it attenuated symptoms after 1 month’s administration |
( |
Observational study | 8 HPPD | LSD | Clonidine (0.025 mg for 3 times/daily) for 2 months | Clonidine may alleviate LSD-related flashbacks |
( |
Case series | 2 HPPD outpatients | LSD | Clonazepam | Clonazepam was efficacious in reducing HPPD symptomatology |
( |
Case report | 1 HPPD with comorbid MDE | MDMA, LSD, and cannabis | Reboxetine (6 mg/daily) | Reboxetine did not exacerbates visual disturbances either recurrence of depressive features |
( |
Observational study | 16 HPPD with anxiety features | LSD | Clonazepam (2 mg/daily) | Clonazepam was efficacious in attenuating both anxiety and HPPD symptomatology |
( |
Case report | F, 33 years with HPPD | LSD | Sertraline (200 mg daily) | Lamotrigine reduced almost completely visual disturbances of HPPD |
Citalopram (20–30 mg daily) | |||||
Fluoxetine (20 mg daily) | |||||
Risperidone (0.5–1 mg daily) | |||||
Lamotrigine (100–200 mg daily) | |||||
( |
Case report | M, 36 years with HPPD | LSD, cannabis, alcohol, cocaine | Clonidine | Clonidine did not improve symptomatology; while lamotrigine was associated with a significant symptomatology improvement |
Lamotrigine (200 mg/daily) | |||||
( |
Case report | F, 38 years with HPPD (DSM-5 criteria) | LSD | Risperidone (0.5 mg/daily) | Significant reduction in the frequency and intensity of panic attacks and perceptual disturbances within 3–4 weeks with low dosages of risperidone |
( |
Case report | M, 30 years, presented to the emergency department after surviving two subsequent suicide attempts by hanging, with a previous history of bipolar disorder and who developed HPPD | Cannabis | Citalopram (40 mg/daily) | Patient poorly responded to treatment and was found to have committed suicide |
LSD | Lamotrigine (50 mg/daily) | ||||
PCP | Mirtazapine (15 mg/daily) | ||||
Cocaine | |||||
( |
Web-based survey | 626 hallucinogens’ users | Cannabis | N/A | Long-term perceptual disturbances were mainly reported among LSD users |
MDMA | |||||
Psilocybin | |||||
LSD | |||||
Ketamine | |||||
( |
Web-based survey | 3139 hallucinogens’ users | Several hallucinogens (including cannabis, MDMA, psilocybin, LSD, ketamine, |
N/A | LSD appeared to be the most robust predictor of HPPD |
( |
Case reports | 2 HPPD (DSM-5 criteria): M, 24 years, university student F, 25 years, university student |
LSD | N/A | Both cases reported the appearance of visual disturbances that were not originally experienced during LSD intoxication |
( |
Case–control study | 12 inpatients with schizophrenia and HPPD vs. 14 inpatients with schizophrenia without HPPD (DSM-IV-TR criteria) | LSD | N/A | No significant differences have been found between two groups in sociodemographic and clinical features. Individuals with schizophrenia and HPPD reported the ability to identify specific precursory cues for the appearance of HPPD-associated perceptual disturbances |
Cannabis | |||||
MDMA | |||||
( |
Case–control study | 4 HC vs. 1 M, 23 years, HPPD patient | Cannabis | N/A | Cannabinoids may have a direct effect on the retina and retinal pigment epithelium function which may be involved in perceptual disturbances experienced in cannabis-induced HPPD |
( |
Case–control study | 37 inpatients with schizophrenia and HPPD vs. 43 inpatients with schizophrenia without HPPD (DSM-IV-TR criteria) | LSD | N/A | No significant differences found between two groups in sociodemographic features. Individuals with schizophrenia and HPPD reported lower general psychopathology and negative symptoms scores compared with individuals without HPPD |
( |
Case report | M, 26 years, university student who developed AIWS and HPPD (DSM-5 criteria) | LSD | N/A | The patient refused any psychotropic treatment and after 1 year of psychiatric follow-up visual disturbances completely disappeared |
Cannabis | |||||
Alcohol | |||||
( |
Survey | 23 out of 67 completed the survey (2 HC; 19 who reported persisting perceptual disturbances triggered or worsened by past drug use) 6 out of 19 with co- diagnosis of HPPD, 3 with persistent migraine aura, 2 psychotic disorders, 1 PTSD and 3 anxiety disorder, 2 depression, 2 hypochondriasis and 3 dissociative disorders HPPD | Various hallucinogenic and non-hallucinogenic drugs | N/A | Many perceptual symptoms reported were not first experienced while intoxicated and are partially associated with pre-existing psychiatric comorbidity |
( |
Observational study | 40 patients who sought psychiatric consultation for SUD with a previous LSD intake who developed HPPD | LSD | N/A | Subjects with type-2 HPPD significantly more likely reported lifetime use of SC, stimulants and inhalants than type-1 HPPD (who reported more likely alcohol) |
An observational study recruited 21 HPPD subjects who were treated with benzodiazepines and/or phenothiazines (
A web-based questionnaire study investigated users’ perceptions of the benefits/harms of hallucinogens’ intake, including the occurrence and prevalence of flashback phenomena and/or HPPD (
A case series described two cases of HPPD induced by SCs (
Several case reports of reoccurring or prolonged persistent visual perceptual disturbances (HPPD) have been described occurring within a certain time frame after cessation of some hallucinogenic drugs (
The present critical mini review presents several limitations. First, given the paucity of double-blind, placebo-controlled/case-control studies, we included case reports and case series as well, and studies with small sample size which may greatly limit the generalizability of findings reviewed here. Second, methodological strategies (sample size, study design, diagnostic criteria, etc.) may vary greatly in several studies retrieved. Most studies included here investigated HPPD cases following the intake of LSD, even though other isolated cases described incidents following the intake of other serotonergic hallucinogens, and cannabis. Furthermore, most studies here retrieved do not specifically distinguish between the two types of HPPD, as previously discussed, by limiting the complete understanding of the clinical symptomatology and manifestation.
The recent wave of novel substances available on the market, includes several novel cannabimimetics, novel hallucinogens (e.g., NBOMe compounds), and new LSD derivatives (
Furthermore, the pharmacotherapy of HPPD may be different from study to study, as only few studies have been published so far and any recommendations are based almost entirely on non-controlled studies of small patient populations or single case reports (
Serotonin neurotransmission has been hypothesized to be involved in the aetiopathogenesys of both acute and persisting LSD- and SC-induced perceptual disturbances (
Further studies should be implemented in order to better clarify the role of the NPS, particularly the new psychedelics and psychostimulants with LSD-like properties in the pathogenesis and etiology of new HPPD cases.
LO and FS conceived the topic of the manuscript, while LO, AG and GP carried out the main analysis. JC and DB assisted in either screening of the studies or preparation of the attachments. FS served as study reviewer. FS served as senior study reviewer. All the coauthors substantially contributed to the present piece of work before approving it for final submission.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.