This review (2021; n=97) finds that hallucinogen-persisting perception disorder (HPPD) encompasses more characteristics than currently recognized by the DSM-5. The most common (of the 64 unique) symptoms were 76% Alice in Wonderland syndrome (AIWS) characteristics (distorted perception and disorientation), 50% non-visual symptoms, and 38% perceptual symptoms not liked to earlier states under the influence.
“Hallucinogen-persisting perception disorder (HPPD) features as a diagnostic category in the DSM-5, ICD-11, and other major classifications, but our knowledge of the phenomenology of the perceptual symptoms involved and the changes in consciousness during the characteristic “flashbacks” is limited. We systematically evaluated original case reports and case series on HPPD to define its phenomenology, associated (psycho)pathology, and course. Our search of PubMed and Embase yielded 66 relevant publications that described 97 people who, together, experienced 64 unique symptoms of HPPD. Of these, 76% concerned symptoms characteristic of Alice in Wonderland syndrome, over 50% non-visual symptoms, and 38% perceptual symptoms not clearly linked to prior intoxication states. This is in contrast with the DSM-5 diagnostic criteria for HPPD. Even though less than half of the patients showed a protracted disease course of over a year, a third achieved remission. However, in patients with co-occurring depression (with or without anxiety) HPPD symptoms persisted longer and treatment outcomes were more often negative. Thus, unlike the acute stages of psychedelic drug intoxication, which may be accompanied by altered states of consciousness, HPPD is rather characterized by changes in the content of consciousness and an attentional shift from exogenous to endogenous phenomena. Since HPPD is a more encompassing nosological entity than suggested in the DSM-5, we recommend expanding its diagnostic criteria. In addition, we make recommendations for clinical practice and future research.”
Authors: Pieter J. Vis, Anneke E. Goudriaan, Bastiaan C. Ter Meulen & Jan D. Blom
The literature on psychedelic substances almost always maintains that these agents produce “altered states of consciousness”, but it is not always clear whether this is “heightened”, “lowered”, or “narrowed” consciousness. In this paper we seek to understand what happens to consciousness in hallucinogen-persisting perception disorder (HPPD), a condition characterized by perceptual distortions, hallucinations, and other experiential phenomena reminiscent of prior substance use.
HPPD is an underreported condition caused by illicit drug use, and the prognosis is poor. Two subtypes of HPPD are distinguished based on their severity and comorbidity, with type-1 HPPD causing minor impairment in daily and occupational functioning and type-2 HPPD causing significant impairment.
Although the exact proportion of those experiencing HPPD seeking professional help is unknown, only a small group manages to procure the help they need. This is at least partly due to a lack of knowledge of HPPD among general practitioners and medical specialists.
A systematic review of the literature on Alice in Wonderland Syndrome (AIWS) has been conducted. The review discusses the relationship between the use of specific types of drugs and the nature, severity, and course of AIWS symptoms, the associated (psycho-)pathology, and how AIWS symptoms fit in with current paradigms of “altered consciousness”.
We carried out a systematic literature search in PubMed and Embase up until January 1, 2021, using the search terms “hallucinogen-persisting perception disorder”, “post-hallucinogen perception disorder”, and related terms. We excluded papers on perceptual symptoms that occurred following the discontinuation of therapeutics.
Data were extracted from each paper to determine age, sex, psychiatric history, further relevant medical history, suspected triggers, frequency and duration of drug use, lifetime drug use, latency period until HPPD onset, and visual and other perceptual phenomenology.
We used the MAQ-HPPD to assess the methodological quality of the collected cases and to minimize the risk of bias. The score was based on the weighted scoring system and the maximum score was 12.
A search of Embase and PubMed yielded 1,627 articles of potential relevance. 147 articles were read in full, and 99 were excluded, leaving 66 case studies and case series.
A majority of studies scored low on the ascertainment of causality, because they did not provide adequate information in terms of psychiatric and general medical history, psychiatric assessment, neurological/general physical examinations, and/or additional diagnostic details.
97 patients were reported on, 73% were male and 25% female, the average age was 24 years, and 33.3% had a psychiatric history. The most frequently mentioned comorbid disorder was substance-use disorder.
The substances that were identified most frequently as triggers of HPPD were LSD, cannabis, and MDMA. In 6.2% of cases HPPD developed after the use of combinations of two or more substances, but the trigger was unknown.
Phenomenology of the HPPD Symptoms Reported on
97 individual case reports were reviewed, and 64 unique manifestations of HPPD were found. Of these, 67% were metamorphopsias, 52.6% were “other perceptual phenomena”, 46.4% were visual hallucinations, 26.8% were “other visual phenomena”, and 8.4% were “entoptic phenomena”.
The relationship between HPPD symptoms and psychiatric comorbidity was varied. On average, patients with psychiatric comorbidity reported more complex HPPD symptoms, and 22.3% of patients did not report any psychiatric comorbidities.
The latency period between substance use and the onset of symptoms was documented in 59.8% of the cases, and the symptoms started relatively early in 63.8% of the cases. The symptoms were intermittent with longer intervals between their occurrence in 36.4% of the cases. 74.2% of patients with HPPD had a positive outcome, with 29.8% attaining full and 33.3% partial remission, and 14.4% having a worsening of their symptoms.
Patients with psychiatric comorbidity, such as depression or anxiety, tend to have a longer duration of HPPD and a worse outcome than those with comorbid anxiety only or a formal diagnosis of substance use disorder.
In our review of the literature on HPPD, we found that none of the 97 detailed case reports were characterized by “altered states of consciousness”. Instead, we found multiple changes pertaining to the content of consciousness.
Brief Historical Perspective
The use of psychedelics is probably as long as the history of humanity. However, the knowledge about the long-term effects of these substances is only as old as the use of LSD-assisted psychotherapy in the 1950s.
The notion of “flashbacks” and “endless trips” is intimately tied up with modern scientific notions about biochemistry and neurophysiology. Yet, more substantial evidence for the long-term effects of hallucinogens became available when Cohen and Ditman (1963) published their results of a survey among 62 scientific experts on mescaline and LSD.
Cohen and Ditman (1963) reported that one out of every 550 patients had a persistent psychotic state. This condition was incorporated into the DSM-III-R as “post-hallucinogen perception disorder” in 1987.
The current study may have several implications for our ideas on pathophysiology, as it indicates that the pathophysiology of HPPD depends on central rather than peripheral mechanisms, and that EEG patterns in acute intoxication states show faster alpha frequencies and shorter visually-evoked response times.
Hallucinogens may partly or fully agonize 5-HT2A receptors throughout the brain, and chronic cortical disinhibition resulting from damage to inhibitory interneurons is believed to play an important role in the mediation of HPPD. The 5-HT2 hypothesis is challenged by the fact that HPPD can be triggered by substances with very different working mechanisms. In AIWS, multiple working mechanisms have been suggested, including mechanisms that act on isolated cortical columns and larger neuron populations. HPPD symptoms are likely triggered by multiple receptor systems rather than the serotonergic system alone.
Implications for Classification
The inclusion of HPPD as a diagnostic category in major classifications is important, but the operational criteria used in these classifications fail to do justice to the broad symptomatology of HPPD.
The DSM’s limited inventory of visual disturbances was adapted from a study by Abraham (1983), but other perceptual symptoms and comorbid psychiatric disorders were not considered and to date have not been incorporated into the DSM criteria for HPPD. Studies have described more symptoms of HPPD than are mentioned in the DSM-5, and it is important to include these symptoms in classifications to serve clinical and scientific practice.
The majority of people with HPPD report symptoms that are reminiscent of prior acute trips, but 38.1% also report new perceptual phenomena. This is in contrast with the DSM-5 criterion which states that HPPD involves the “reexperiencing” of one or more perceptual symptoms that were experienced while intoxicated.
Clinical Practice Diagnosis
A diagnosis of HPPD depends on a proper history-taking, an adequate insight into the condition’s wide array of symptoms, a psychiatric and neurological examination, blood work, and a medication review.
HPPD is diagnosed when the symptoms are not caused by neurological conditions or hypnagogia. It is also a differential diagnosis for AIWS.
We found that 63% of patients who received pharmacotherapy had a positive outcome, with 30% achieving full remission. We recommend treating comorbid psychiatric symptoms and disorders, especially depressive disorder, when present, to improve treatment outcomes and shorten symptom durations.
HPPD and Consciousness
Acute intoxication with psychedelics may be accompanied by a lowered, heightened, or narrowed state of consciousness, but our analysis yielded no indications for such changes in HPPD. However, the symptoms of HPPD are often triggered by looking at blank surfaces.
The dual-input model proposed by West (1962) suggests that HPPD patients become aware of their perceptual symptoms when their regular sensory input diminishes, and that this awareness is facilitated by fronto-parietal networks that heighten or at least redirect one’s attention.
Future research should attempt to establish the incidence and prevalence of HPPD in the general population, and a standardized questionnaire should be developed. The diagnostic criteria for HPPD should also be adjusted to reflect the impact of comorbid psychiatric symptoms and disorders. Regarding basic research, further elucidation of the mechanisms of action underlying HPPD is needed, as well as an explanation of the latency period until symptom onset and the risk factors involved. Additionally, awareness of HPPD should be promoted among health professionals, psychedelics users, and those who care for them.
The present review relied on published case reports and case series, and although most of the papers were deemed of high methodological quality, recall bias cannot be eliminated. In terms of outcome, publication bias must have played a role.
Our systematic review of 97 case descriptions of hallucinogen-induced perceptual dysfunction shows that this late-onset complication of hallucinogen use is characterized by 64 unique perceptual phenomena, most of which are perceptual distortions. Comorbid anxiety and depression are associated with a longer duration of symptoms and poorer treatment outcomes. Pathophysiologically, multiple neurotransmitter systems are implicated in HPPD, including the 5HT2 system and an attentional shift toward endogenous perceptual content.
We recommend promoting awareness of HPPD and its full range of manifestations, and rephrasing HPPD in terms of diagnostic terms rather than retrospective outcome analyses.
PV, JDB, AG, BtM contributed to the conception and design of the work, analysis and interpretation of data for the work, drafted and revised the work, gave approval for the final version to be published, and agreed to be accountable for all aspects of the work.
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