Flashbacks, Hallucinogen Persisting Perception Disorder (HPPD), and Reactivations Following the Use of Classic Psychedelics: Classification and Therapeutic Management.

ObjectiveHallucinogen Persistent Perception Disorder (HPPD) is a condition where the effects of hallucinogenic drugs reoccur long after the acute effects have stopped. No established risk factors or mechanisms for HPPD have been identified. However, reports have suggested a risk phenotype for HPPD due to associations with other perceptual disturbances. With recent increases in therapeutic psychedelic drug use, it is essential to consider the existence of HPPD risk factors. Therefore, exploring potential links between HPPD and other perceptual disturbances, such as tinnitus and migraine with aura, is a necessary first step. This study aimed to investigate the association between HPPD and other perceptual disorders.MethodsOne hundred thirty-eight individuals with HPPD and 116 controls participated in a survey assessing the prevalence of various perceptual disturbances: photosensitivity, phonosensitivity, tinnitus, migraine with aura, vertigo, paraesthesia, and synaesthesia.ResultsThe survey results showed a significant association between HPPD and photosensitivity (OR = 10.65), phonosensitivity (OR = 8.00), and the number of perceptual disturbances (OR = 1.59) in the HPPD group compared to the control group. The study also observed trends of dual prevalence between HPPD and tinnitus, migraine with aura, vertigo, paraesthesia, and synaesthesia. Participants with both HPPD and other perceptual disturbances were likelier to experience additional perceptual disturbances after the onset of HPPD.ConclusionsThese findings suggest a common vulnerability or pathophysiological mechanism among these perceptual disturbances. Given the increasing therapeutic use of hallucinogens, the results of this study provide essential considerations for HPPD risk profiles. Moreover, they may guide future investigations into HPPD's pathophysiology and management options.

Learning Objectives:After participating in this CME activity, the psychiatrist should be better able to:Define hallucinogen persisting perception disorder (HPPD) and describe its diagnostic criteria and subtypes.Evaluate pharmacological and nonpharmacological interventions, including evidence-based and supportive approaches.Hallucinogen persisting perception disorder (HPPD) is characterized by perceptual phenomena that either linger after substance-use cessation or recur as reperceptions or flashbacks. These symptoms may be either mild and transient or long-lasting and severely burdening. Since evidence for pharmacological treatment of HPPD is unclear, we seek to provide treatment advice based on a systematic review of existing medication studies. Our search yielded 31 studies with 87 participants treated for HPPD with different types of medication. Three observational studies reported substantial symptom reduction for regimens with clonidine, clonazepam, and levetiracetam. The other 28 studies, which consist of case reports and small case series, found largely similar results for benzodiazepines, antiepileptics, antidepressants, and alpha agonists. Of those who received these pharmacological treatments, 28% showed full recovery and 61% partial recovery within a year. When HPPD was triggered by lysergic acid diethylamide, benzodiazepines were ineffective. Notably, several studies described HPPD symptom aggravation upon treatment with the antipsychotic agent risperidone. Although not statistically significant, our analysis suggests that HPPD can be treated to good effect with the aforementioned groups of medicines. On the basis of our findings, we provide a list of practice-based treatment methods and make suggestions for further research. In particular, epidemiological studies are needed to investigate the natural course of HPPD. Likewise, randomized controlled pharmacological studies are necessary to evaluate the efficacy of medications in different, well-defined HPPD subgroups.

Objective: An unusual side effect of hallucinogen use is the appearance of hallucinogen persisting perception disorder (HPPD). Despite high rates of prior hallucinogen use among individuals with schizophrenia, there are insufficient data on the clinical characteristics of individuals with co-occurring schizophrenia and HPPD. Methods: Twenty-six hospitalized patients with schizophrenia and prior LSD use (12 with HPPD and 14 without HPPD) were recruited. Participants were clinically assessed using validated tools, and details regarding hospitalizations were retrieved from their medical records. Those patients who also had HPPD completed a questionnaire addressing HPPD-associated perceptual disturbances. Results: Participants were mostly male (n = 22, 84.6%) and had an average age of 32.3 (SD = 7.67). Nearly half (n = 12, 46.2%) met criteria for HPPD. No significant differences were found in sociodemographic and clinical characteristics (including response to antipsychotic medications and adverse effects) between the groups. Nine individuals (75%) in the schizophrenia and HPPD group reported the ability to identify specific precursory cues for the appearance of the HPPD-associated perceptual distortions, and 8 (67%) reported the ability to distinguish HPPD perceptual disturbances from those associated with their psychotic disorder. Conclusions: Very little is known about the co-occurrence of schizophrenia and HPPD or the associated clinical implications. Further research is needed to understand the clinical impact of this comorbidity.

Classic psychedelics like LSD and psilocybin are showing promising effects in treating certain psychiatric disorders. Despite their low toxicity and lack of an addictive potential, in some individuals, psychedelics can be associated with persisting psychological harms. Hallucinogen Persisting Perception Disorder (HPPD) is one of those complications, a rare disorder characterized by enduring perceptual symptoms without impaired reality control. While the phenomenological aspects of HPPD have been characterized, the neuropsychological consequences have remained understudied. This study probes the neuropsychological profiles of eight individuals with HPPD, utilizing a comprehensive test battery. Performance is benchmarked against normative data and compared with two control groups, each comprising eight matched subjects—with and without prior psychedelic use. The assessment of individual performances revealed below average results in tests of visual memory and executive function in some subjects. No significant differences were observed in alpha-adjusted comparisons with controls, whereas unadjusted analyses were suggestive of impaired executive functions among HPPD patients. Together, these preliminary results underline the need for further focused research into the neuropsychological dimensions of HPPD.

Interest in using psychedelic drugs to treat psychiatric disorders is growing rapidly. While modern controlled clinical trials show a favorable safety and efficacy profile, it remains unclear if the risk of side effects would increase with broader use in more heterogeneous populations. To address this, we investigated the frequency and baseline predictors of delusional ideation, magical thinking, and "hallucinogen persisting perception disorder" (HPPD)-related symptoms following psychedelic use in a self-selected naturalistic sample. Using a prospective cohort study, symptoms were assessed in ( ) participants at one week before a planned psychedelic experience, and at two and four weeks afterward. Across the sample, delusional ideation was found to be reduced one month after psychedelic use ( ) with no changes detected in magical thinking. These findings were in seeming opposition to positive correlations between lifetime psychedelic use at baseline with magical thinking ( , ) and delusional ideation ( , ), suggesting that schizotypal traits, instead of being caused by, may merely correlate with psychedelic use. Importantly, over 30% of the sample reported HPPD-type effects at the 4-week endpoint, although rarely perceived as distressing (< 1% of the population). Younger age, female gender, history of a psychiatric diagnosis and baseline trait absorption predicted the occurrence of HPPD-like effects. This is in line with prior studies showing a high prevalence of HPPD-like symptoms in psychedelic users, which, however, appear to remain at a subclinical severity in most cases, explaining the comparatively lower prevalence of HPPD diagnoses.

Hallucinogen Persisting Perception Disorder (HPPD) is considered rare in hallucinogen users although there are conflicting reports about its incidence and prevalence. HPPD may be more common in those with trait neuroticism. In this study, we invited hallucinogen and other drug users to complete an online questionnaire about their use of hallucinogens, their experience of HPPD symptoms, and their trait neuroticism and mental health symptoms. We received 802 responses with 415 of these containing adequate data for further analysis. 39.7% of responders reported symptoms corresponding to Type I HPPD, and 4.3% reported symptoms corresponding to Type II HPPD. We found no significant difference between neuroticism scores for participants with or without HPPD. Individuals with Type II HPPD were more likely to report mental health symptoms including anxiety, obsessional thoughts, paranoia, hypochondria and panic attacks (p < .05). We also found that individuals with Type II HPPD were more likely to report the use of 25I-NBOMe, dextromethorphan, nitrous oxide and benzodiazepines (p < .05). 47.3% of participants had never tested their drugs, making the attribution of HPPD severity to specific drugs difficult. Further work into the development of HPPD is required, particularly with the rise of hallucinogens as potential treatments for depression and other mental illnesses.

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.

Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases

Objective: The purpose of the present study was to obtain patient information across a wide geography about medical history, drug use, symptoms, and treatments of individuals diagnosed with hallucinogen persisting perception disorder (HPPD). Methods: The study was an internet survey that yielded 26 HPPD patients from North America (81%), Europe (12%), and South America (almost 8%), predominantly male (73%), white (92%), with a median age of 24.5 (range, 18 to 63) years, who have been living with HPPD from a period of <1 year to well over 10 years. Results: History of preexisting mood disorders was reported (100%). Previous hallucinogen drugs used include lysergic acid diethylamide, psilocybin, 3,4-methylenedioxymethamphetamine, and mescaline in highest frequencies. There is a high percentage of current use of benzodiazepines (34.6%) and dependency (78% of those using). Current marijuana use is present for 19%, of which all claim dependency. All patients reported experiencing long-term and ongoing symptoms such as depersonalization (92.3%), visual snow, floaters, trailing afterimages and anxiety (96.2% for each factor). Suicide ideation was pronounced (over 69%). HPPD treatments included benzodiazepines (50%), neuroleptics (23%), anticonvulsants (35%), and receiving counseling (62%). Conclusions: HPPD is an understudied mental disorder that has a complex and unpredictable nature with overlapping psychiatric, psychological, and neurological symptoms. Controlled, evidence-based clinical studies are needed for improvements in diagnosing and treating HPPD. There is concern for patients’ well-being, particularly concerning high reported suicide ideation and dependency on drugs currently used (even if they are prescribed). Improved education for health care professionals and patients is also needed.

Hallucinogen Persisting Perception Disorder (HPPD) is a rare, and therefore, poorly understood condition linked to hallucinogenic drugs consumption. The prevalence of this disorder is low; the condition is more often diagnosed in individuals with a history of previous psychological issues or substance misuse, but it can arise in anyone, even after a single exposure to triggering drugs. The aims of the present study are to review all the original studies about HPPD in order to evaluate the following: (1) the possible suggested etiologies; (2) the possible hallucinogens involved in HPPD induction; (3) the clinical features of both HPPD I and II; (4) the possible psychiatric comorbidities; and (5) the available and potential therapeutic strategies. We searched PubMed to identify original studies about psychedelics and Hallucinogen Persisting Perception Disorder (HPPD). Our research yielded a total of 45 papers, which have been analyzed and tabled to provide readers with the most updated and comprehensive literature review about the clinical features and treatment options for HPPD.

Hallucinogen persisting perception disorder (HPPD) is rarely encountered in clinical settings. It is described as a re-experiencing of some perceptual distortions induced while intoxicated and suggested to subsequently cause functional impairment or anxiety. Two forms exist: Type 1, which are brief "flashbacks," and Type 2 claimed to be chronic, waxing, and waning over months to years. A review of HPPD is presented. In addition, data from a comprehensive survey of 20 subjects reporting Type-2 HPPD-like symptoms are presented and evaluated. Dissociative Symptoms are consistently associated with HPPD. Results of the survey suggest that HPPD is in most cases due to a subtle over-activation of predominantly neural visual pathways that worsens anxiety after ingestion of arousal-altering drugs, including non-hallucinogenic substances. Individual or family histories of anxiety and pre-drug use complaints of tinnitus, eye floaters, and concentration problems may predict vulnerability for HPPD. Future research should take a broader outlook as many perceptual symptoms reported were not first experienced while intoxicated and are partially associated with pre-existing psychiatric comorbidity.

Hallucinogen persisting perception disorder (HPPD) is characterized by visual disturbances that resemble psychedelic intoxication and linger after use has ceased. The most common substances precipitating HPPD, lysergic acid diethylamide (LSD) and psilocybin, are posited to do so via damage to serotonergic neurons involved in vision. Mr. N is a 37-year-old with a history of alcohol, cannabis, LSD, cocaine, and nicotine use disorders who described visual distortions that resolved when he drank heavily or received benzodiazepines for withdrawal. He did not appear psychotic. Over 20 years after his last LSD use, he continued to experience illusions of halos around objects, moving walls, and figures appearing cartoonish. He understood that his perceptual disturbances were not reality based. During hospitalization for suicidal ideation, laboratory tests, head computed tomography (CT), and electroencephalogram (EEG) studies offered no explanation for his visual disturbances other than HPPD. The visual distortions remitted with scheduled clonazepam treatment, although chemical dependency treatment programs were hesitant to accept him while on a benzodiazepine. This case emphasizes the importance of diagnostic clarification when patients present with perceptual disturbances that do not fit typical psychotic presentations. Our discussion will distinguish misperceptions from hallucinations and review the pathophysiology of HPPD. Last, we will discuss management strategies for patients with co-occurring HPPD and substance use disorders. It is necessary to discern the correct cause of visual disturbances in order to provide proper treatment. The risks and benefits of long-term benzodiazepine use must be weighed when deciding whether to prescribe them for patients with comorbid HPPD and alcohol use disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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 select hallucinogens are under development for the treatment of selectmental 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 among different classes of hallucinogens, risk factors for HPPD, and data pertaining to the pathophysiology of HPPD. Expert opinion Hallucinogen persisting perception disorder appears to be an uncommon yet serious event associated with prior hallucinogen exposure. The renewed interest in psychedelics as potential treatment options 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.

BackgroundHallucinogen persisting perception disorder (HPPD) is characterized by the re-emergence of perceptual symptoms experienced during acute hallucinogen intoxication following drug cessation. The underlying pathophysiology is poorly understood. We report the clinical characteristics and investigation findings of a series of HPPD cases with a literature review of previous case reports. We draw parallels between the features of HPPD and Visual Snow Syndrome (VSS).MethodsRetrospective case series of 13 patients referred from neuro-ophthalmologists. Literature review with 24 HPPD case reports were identified through database search using the terms “hallucinogenic persisting perception disorder” OR “hallucinogen persisting perception disorder.”ResultsLysergic acid diethylamide (LSD), 3,4-Methyl enedioxy methamphetamine (MDMA) and cannabinoid use was common. Cannabinoids and MDMA were mostly used in association with classical hallucinogens. The most frequent symptoms in our patients were visual snow, floaters, palinopsia, photophobia and nyctalopia. In the literature other symptoms included visual hallucinations altered motion perception, palinopsia, tracers and color enhancement. Ophthalmic and neurologic investigations were mostly normal. The majority of patients had ongoing symptoms. Two of our patients fully recovered—one after treatment with benzodiazepine and one without treatment. Twenty-five percent of cases from the literature fully recovered.ConclusionsHPPD presents with heterogeneous visual phenomena on a background of previous classic and non-classic hallucinogen use. Ophthalmic investigations are typically normal. The symptoms of HPPD in our case series overlap with the typical features of Visual Snow Syndrome (VSS). Patients presenting with VSS should be screened for past recreational drug use. The DSM-5 description of HPPD does not include visual snow, nyctalopia, photophobia or floaters. A revision of the diagnostic criteria to include these symptoms may better reflect the typical clinical phenotype. Increased awareness of HPPD as a secondary cause of VSS can avoid extensive investigations. Controlled trials comparing primary and secondary VSS patients are needed to understand the pathophysiology better and optimize treatment for HPPD.

An unique and intriguing characteristic of lysergic acid diethylamide (LSD) and LSD-like substances is the recurrence of some of the symptoms which appear during the intoxication, in the absence of recent intake of hallucinogens. Hallucinogen persisting perception disorder (HPPD) is a condition in which the re-experiencing of one or more perceptual symptoms causes significant distress or impairment in social, occupational or other important areas of functioning and may be extremely debilitating. Benzodiazepines are one of the recommended agents for the treatment of HPPD but it is unclear which of them may be more helpful. The goal of our investigation was to assess the efficacy of clonazepam in the treatment of LSD-induced HPPD. Sixteen patients fulfilled entrance criteria. All complained of HPPD with anxiety features for at least 3 months and were drug free at least 3 months. They received clonazepam 2 mg/day for 2 months. Follow-up was continued for 6 months. They were weekly evaluated during the 2 months of clonazepam administration and monthly during the follow-up period using the Clinical Global Impression Scale, a Self-report Scale and Hamilton Anxiety Rating Scale. Patients reported a significant relief and the presence of only mild symptomatology during the clonazepam administration. This improvement was clearly sustained and persisted during a 6-month follow-up period. This study suggests that high potency benzodiazepines like clonazepam, which has serotonergic properties, may be more effective than low-potency benzodiazepines in the treatment of some patients with LSD-induced HPPD.