This scoping review (2022) explores the prevalence, risk factors and pathophysiology of hallucinogen persisting perception disorder (HPPD) among different psychedelics. While HPPD is uncommon, current interest in psychedelic research affords the opportunity to characterize HPPD in its frequency, risk and protective factors, key characteristics, and potential treatments.
“Introduction: Hallucinogen persisting perception disorder (HPPD) affects a subset of persons who use hallucinogens and is defined as the repeated experience of hallucinations and other perceptual disturbances as a result of prior intoxications. As hallucinogens are under development for the treatment of select mental disorders, there is a need to better characterize this disorder.
Areas covered: A scoping review of the literature on HPPD was completed from inception to July 2021. Topics covered in the review herein include treatments for HPPD, prevalence or incidence data on HPPD amongst different classes of hallucinogens, risk factors for HPPD, and data pertaining to the pathophysiology of HPPD.
Expert opinion: HPPD appears to be an uncommon yet serious event associated with prior hallucinogen exposure. The renewed interest in psychedelics for select mental disorders, especially agents with hallucinogenic potential provides the impetus to characterize HPPD in its frequency, risk and protective factors, key characteristics, as well as other clinical and treatment-related factors.”
Authors: Marcus A. Doyle, Susan Ling, Leanna M. W. Lui, Paul Fragnelli, Kayla M. Teopiz, Roger Ho, Joshua D. Di Vincenzo, Joshua D. Rosenblat, Emily S. Gillissie, Danica Nogo, Felicia Ceban, Muhammad Y. Jawad & Roger S. McIntyre
Hallucinogen persisting perception disorder (HPPD) is a condition in which a person experiences hallucinations and other perceptual disturbances after using hallucinogens.
1.1 Defining HPPD
Hallucinogen persisting perception disorder (HPPD) is the repeated reexperience of hallucinations and other perceptual disturbances after previous hallucinogen intoxications, with no alternate diagnosis better explaining the condition.
Hallucinogen persisting perception disorder (HPPD) is categorized into two subtypes: HPPD type I and HPPD type II. HPPD type I individuals report short-term and reversible hallucinatory experiences and perceptual disturbances, whereas HPPD type II individuals report longer-lasting and irreversible hallucinatory experiences and perceptual disturbances.
1.1. DSM-5 Criterion for HPPD
The DSM-5 divides hallucinatory psychotic disorders into three criteria: A through C. A patient must experience perceptual disturbances that occurred during hallucinogen intoxication but ceased after intoxication subsided to be diagnosed with hallucinatory psychotic disorders.
1.2. Psilocybin-assisted psychotherapy for psychiatric disorders
Recent evidence suggests that psilocybin may be useful in treating depression. However, the placebo effect may be underplayed when discussing the potential benefits of the drug.
Psychedelics, including psilocybin, have been associated with certain psychological risks, including acute psychological distress possibly accompanied by dangerous behavior, prolonged psychosis precipitated by hallucinogen use, and HPPD. The current scoping review aims to summarize the literature on HPPD.
2.1. Identifying research question(s)
This scoping review identified the following specific questions to help clinicians who encounter HPPD during their practice.
Drug use is associated with HPPD onset, and there are risk factors associated with this disorder.
2.2. Search strategy
A scoping search was conducted on Ovid MEDLINE, Ovid EMBASE, and Ovid psychINFO from inception to June 16, 2021 using the following search terms: Hallucinogen Persisting Perception Disorder, Post Hallucinogen Perception Disorder, and Acute Hallucinogen-induced Psychosis.
2.3. Study selection
Two independent reviewers screened titles and abstracts of articles identified through a pre-defined search strategy and screened full-text versions of eligible articles according to titles and abstracts.
Adult human subjects (18 years old) with a clinical diagnosis of hallucinogen-induced psychosis (HPPD) or a mental behavior disorder caused by hallucinogens as a reverberation state (ICD-10 or earlier version) are eligible to participate.
2.4. Methodological quality scales and checklists
Methodological quality and risk of bias were assessed for each of the study designs included in this review using separate scales and checklists.
Two reviewers completed a NOS scale for case-control studies and an NIH quality assessment tool for before-after (pre-post) studies without a control group. The studies received an overall score and a good, fair, or poor rating.
2.5. Outcomes of interest
The high degree of heterogeneity in the data and among component study designs precluded quantitative analysis, so a qualitative analysis via narrative synthesis was undertaken.
3.1. Search results
A search of Ovid MEDLINE and Ovid EMBASE yielded 188 results, of which 153 were excluded following title and abstract screening. Nine additional studies were excluded following a full-text review, leaving 32 studies in the review.
3.2. Scales and checklists for methodological quality and bias risk
The quality of component studies suffered due to a lack of reported patient details, diagnostic tests used to diagnose HPPD, and reliance on self-report data. Two studies had a case – control study design, and one scored a high-quality NOS rating of 7/9 stars.
3.3.1. Lysergic acid diethylamide
From an aggregate of 30 cases across multiple studies, 20 cases listed LSD as a drug associated with symptom onset in HPPD, and 13 of the 20 cases attributed symptom onset to LSD use alone.
One cross-sectional study surveyed 40 patients with HPPD and reported previous LSD use. Patients with more severe HPPD type-II reported more LSD use.
3.3.2. Natural and synthetic cannabinoids
The most reported drug associated with HPPD is LSD, followed by natural and synthetic cannabinoids. However, a cross-sectional study found that patients with HPPD type-II were significantly more likely to report lifetime synthetic cannabinoid use compared to those with less severe HPPD type-I.
3.3.3. MDMA or ‘ecstasy’
MDMA, or ‘ecstasy’, was the third hallucinogen most commonly associated with HPPD, but no case report associated MDMA use alone with HPPD.
3.3.4. Other drugs associated with HPPD
Psilocybin, phencyclidine, ibogaine, and 5-MeO DiPT have all been associated with HPPD onset. Ibogaine and 5-MeO DiPT were associated with HPPD only when used in combination with other drugs.
3.4. Treatments for HPPD
Table 2 lists drugs used to treat HPPD, as well as the respective articles which have reported its use.
3.4.1. Atypical antipsychotics
Atypical antipsychotics such as risperidone and olanzapine have been reported to improve and worsen symptoms of HPPD in several case reports. Amisulpride has also been used for the treatment of HPPD, but was discontinued due to reports of extreme drowsiness.
Although there are many case-reports, it cannot be determined whether atypical antipsychotics are an effective and safe treatment for HPPD.
3.4.2. Adrenergic α-2 agonists, selective adrenergic reuptake blockers, and β-blockers
A small pre-post study without a control group found that clonidine effectively reduced HPPD symptoms. Two subjects dropped out before the end of the study, but all six that remained had decreased self-reported symptoms and clinician-rated HPPD symptoms.
Other medications used to treat HPPD symptoms include propranolol and reboxetine. Propranolol was not determined to change the severity of HPPD symptoms, whereas reboxetine was determined to reduce HPPD symptoms.
3.4.3. Selective serotonergic reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) have been used to treat hallucinations associated with HPPD, but the effectiveness is mixed.
Sertraline and fluoxetine have been found to be effective for HPPD, both as a monotherapy and in combination with trazodone and lamotrigine.
A pre-post study conducted by Lerner et al. investigated the effectiveness of clonazepam among individuals suffering from HPPD with anxiety features for at least 3 months. Clonazepam significantly decreased CGI scores, self-report scores, and HAM-A scores, but HAM-A scores did not.
Some case reports and one pre-post study describe anticonvulsants as being effective for the treatment of HPPD. Lamotrigine is most effective at reducing symptom severity when administered alone or in combination with other medications.
A pre-post study without a control group investigated the effectiveness of the anticonvulsant levetiracetam at treating HPPD symptoms. 20/27 patients became flashback-free after 1 year of treatment.
The effectiveness of lamotrigine and levetiracetam for the treatment of HPPD is inconsistent across studies, and may be affected by concomitant medications.
3.4.6. Opioid antagonists
Three case reports report on the effectiveness of opioid antagonists at treating HPPD. Two case reports found that naltrexone, naloxone, and buprenorphine were effective, but one case report found that EMDR therapy was more effective.
3.5. Risk factors and prevention
There are no recognized risk factors for HPPD, but a number of factors have been associated with the development of HPPD. Some studies have found an association between the number of doses of a hallucinogen taken and the development of HPPD, while others have found no association.
It remains to be determined what dosing of hallucinogens is most commonly associated with HPPD onset, but a majority of patients who could attribute their symptoms to one ‘trip’ reported that the dose was unusually strong, and a majority of patients with schizophrenia reported a negative experience during LSD intoxication.
Hallucinogen use, cannabis use, and atypical antipsychotics have all been reported to either exacerbate HPPD symptoms or promote relapse of HPPD symptoms. The evidence regarding the treatment of HPPD with antipsychotics is mixed, with some evidence suggesting antipsychotics may exacerbate symptoms in some cases.
3.6. Is HPPD something clinicians should be concerned about?
Due to a lack of random sampling and reliance on self-reported data in observational studies investigating hallucinogen use, the prevalence of hallucinogen-induced psychosis is incompletely understood.
The synthetic hallucinogen LSD was found to be the most common precipitator of HPPD symptoms, which have also been reported in the extant literature. The etiology of HPPD remains to be determined, but evidence implicating the serotonergic system in the etiology stems from case reports.
Evidence implicating the GABAergic system in HPPD includes case reports, a pre-post study without a control group, as well as EEG recordings from HPPD patients. These findings are consistent with a GABAergic pathophysiology and the effectiveness of benzodiazepines in the treatment of HPPD.
A separate theory regarding the molecular mechanisms underlying HPPD posits that it is similar to post-traumatic stress disorder (PTSD), and that clonidine, an agonist for -2 adrenergic receptors, is effective at treating HPPD symptoms.
Although both SCZ and HPPD often give rise to hallucinations, the two disorders have different etiologies and share some similarities, as well as differences, such as the brain areas which these experiences tend to overactivate.
Two articles compared clinical and demographic characteristics between SCZ and HPPD. The SCZ and HPPD group claimed they could distinguish HPPD hallucinations from SCZ hallucinations.
Patients with SCZ and HPPD had lower negative symptoms, general psychopathological scores, and total PANSS scores than patients with SCZ only, suggesting that the underlying mechanisms of SCZ and HPPD might be different.
Atypical antipsychotics, -2 adrenergic receptor agonists, -adrenergic receptor antagonists, serotonin-norepinephrine reuptake inhibitors, SSRIs, benzodiazepines, anticonvulsants, and opioid antagonists have been shown to be effective pharmacotherapeutic agents to treat hallucinogen-induced psychosis.
The current literature on HPPD has not identified risk factors, but several elements have been linked to HPPD symptoms.
This review included articles that contained subjects diagnosed with HPPD according to DSM or ICD criteria, and did not include articles that pre-date the adoption of HPPD by the DSM-IV.
The current review has several limitations, including small sample sizes, missing control or placebo groups, and non-peer reviewed material. It is also difficult to assess how concerned clinicians should be with this disorder.
The current review provides an up-to-date scoping review of literature regarding HPPD. Further research is needed to better characterize the disorder, identify risk factors, and determine effective pharmacological treatments.
- Expert opinion
There has been a recent and significant increase in research into the therapeutic potential of disparate hallucinogenic agents. However, there remains much to be determined regarding the condition of hallucinogen-induced psychosis (HPPD), including the degree to which the type of hallucinogen, dose, frequency of exposure, and/or acute effects moderate risks for HPPD.
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