Overall, prevalence of HPPD has been generally considered low (2). However, limited publications suggested that chronic visual disturbances may be relatively common among hallucinogens’ users. It has often been assumed that HPPD may be a severe clinical manifestation of the drug-induced visual changes (3–5). While the probability of flashbacks occurring in the wake of hallucinogen use may vary from 5 to 50% among hallucinogens’ users (6, 7), the probability of an HPPD being manifested is lower (3).

Hallucinogen-persisting perception disorder was first described in 1954 (8). Subsequent observations have been then described (3, 4, 8–12). Horowitz (10) first introduced the term flashbacks, referring to recurrent and spontaneous perceptual distortions and unbidden images. When these “flashbacks” present as recurrent, but without a current acute, or chronic hallucinogen intake, the disturbance is referred to as HPPD. Horowitz (10) classified also three types of visual flashbacks: (a) perceptual distortions (e.g., seeing haloes around objects); (b) heightened imagery (e.g., visual experiences as much more vivid and dominant in one’s thoughts); and (c) recurrent unbidden images (e.g., subjects see objects that are not there). HPPD has been introduced under the diagnosis of Post- hallucinogen Perception Disorder in 1987 within the DSM-III-R (13). Subsequently, the DSM-IV-TR (14) recognized the syndrome as Hallucinogen-Persisting Perception Disorder (Flashbacks) (code 292.89) (15). The disorder was confirmed as nosological entity as well in the DSM-5 (1).

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.) (3) (Table 1), including pseudohallucinations. It has been also associated with a LSD (lysergic acid diethylamide)-like dysphoria, panic attacks, and depressive symptomatology. Visual disturbances may be episodic, stress or substance-induced, or persistent. However, the episodes may last for 5 years or more and the symptomatology is disliked by patients (10). While a flashback is usually reported to be infrequent and episodic, HPPD is usually persisting and long-lasting. Moreover, some HPPD subjects report that adaptation to the dark takes significantly longer compared with the general population (16). Moreover, HPPD has been associated with abnormal results for tests of visual function, suggesting disinhibition in the processing of visual information (4, 16). The subject does not develop any paranoid misinterpretation related to and does not believe that their own visual hallucinogenic experiences currently occur (3). Therefore, it has been supposed that there is involvement of the primary visual cortex, the first cortical area responsible for geometric processing of visual input (17). Further data coming from clinical, psychological, and neurophysiological sources may suggest specific physiological changes in the visual system function implicated in the onset of hallucinations after the intake of psychedelics/hallucinogens (5). Table 1 summarizes all clinical and psychopathological characteristics associated with an HPPD.

The pathogenesis of HPPD is currently unknown, even though it has been frequently reported to be associated with the intake of LSD (4, 16, 41). However, HPPD has also been reported following the consumption of all substances with hallucinogenic properties which possess pharmacological and clinical effects resembling those experienced with LSD by serotoninergic 5-HT2A (42), such as cannabis (18, 43, 44), 3,4-methylenedioxymethamphetamine (MDMA, aka “ecstasy”) (45–47), and the recently marketed novel psychoactive substances (NPS). In fact, the advent of NPS facilitated the onset of new psychopathologies and new clinical manifestations, including cases of HPPD, particularly following the intake of synthetic cannabinoids (SCs) and other new synthetic psychedelics and hallucinogens, which facilitated the reoccurrence of this disorder, by posing a new clinical concern to clinicians (19, 20, 48, 49).

Two types of HPPD have been proposed here, accordingly to Lev-Ran (40). Type-1 HPPD, consistent with the definition of flashback provided by the ICD-10 (50), is characterized by brief reexperiences of altered perception, mood, and/or consciousness, as previously experienced during a hallucinogenic intoxication. Symptomatology may be pleasurable and even controllable. They may appear days to months after the hallucinogen-induced experience. The subject is usually aware of the unreality of their own experience. The perception of time may be altered. Visual perceptions usually comprise perceived increased color intensity, dimensionality, vibrancy, illusory changes, and movements of a perceived object. Type-1 HPPD comprises the flashbacks definition, while type-2 HPPD has been used to indicate the HPPD definition elaborated by Abraham (3) as well proposed in the DSM-5. The symptoms usually include palinopsia (afterimages effects), the occurrence of haloes, trails, akinetopsia, visual snows, etc. Sounds and other perceptions are usually not affected. Visual phenomena have been reported to be uncontrollable and disturbing. Symptomatology may be accompanied by depersonalization, derealization, anxiety, and depression (3).

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 (51) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (52). Searches were carried out by using PubMed/Medline, Google Scholar, and Scopus. We combined the search strategy of free text terms and exploded MESH headings for the topics of HPPD and NPS as follows: ((Hallucinogen Persisting Perception Disorder [Title/Abstract] OR HPPD [Title/Abstract])) OR ((Hallucinogen Persisting Perception Disorder [Title/Abstract] OR HPPD [Title/Abstract])) and ((novel psychoactive substances [Title/Abstract]) OR (NPS[Title/Abstract])). All articles through August 15, 2017 without time restriction were selected. In addition, the authors performed further secondary searches by using the reference listing of all eligible papers.

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 ad hoc developed data extraction spreadsheet.

The set of keywords initially generated 260 results (Figure 1). A total of 31 papers were excluded because of duplicates; 7 papers were excluded because they did not provide relevant data useful for the aims of our papers (due to the lack of an English abstract). Of the remaining 222 studies, further 186 studies were excluded because they did not meet the inclusion criteria or because they were non-human studies. Of the remaining 36 papers, 6 papers were excluded because they were reviews, letters to editors, or metanalyses; however, 6 papers were not included here due to the lack of an available full text or an abstract useful for collecting relevant data. Finally, a total of 24 papers were included and accounted for in our analysis. Table 2 shows the main characteristics (study design, sample size, main outcomes, and findings) of all studies reviewed here.

An observational study recruited 21 HPPD subjects who were treated with benzodiazepines and/or phenothiazines (3). Among subjects receiving benzodiazepines, eight out of nine reported a reduction in intensity/frequency of visual disorders. Most (11 out of 12) phenothiazine-treated subjects described an exacerbation of HPPD (3). A case series reported three cases of HPPD, treated with risperidone, who presented a worsening of visual perceptions and panic symptomatology (21). Lerner et al. (22) described two LSD-induced HPPD male subjects who reported an improvement of symptomatology following naltrexone (50 mg daily) treatment (22). Another case report described a 22-old-year male who developed HPPD after 8-month discontinuation of LSD (22). The subject significantly improved after sertraline (100 mg/daily) treatment (23). An open-label pilot study recruited eight HPPD drug-free patients who were consecutively treated with 0.025 mg of clonidine, three times a day, for 2 months, in order to evaluate the efficacy of drug in treating persistent visual disturbances associated with the intake of LSD (24). LSD-related flashbacks demonstrated a good response to clonidine (24). A study described two HPPD outpatients who efficaciously responded to clonazepam (25). An HPPD patient with a comorbid depressive symptomatology and a prior history of cannabis, ecstasy and LSD abuse, clinically responded to 6 mg daily of reboxetine (26). An open-label study recruited 16 drug-free patients affected with HPPD with anxiety features for at least 3 months who received 2 mg daily of clonazepam for 2 months (27). Subjects reported a significant relief of anxiety and HPPD symptomatology with only mild symptomatology during the clonazepam treatment, suggesting the efficacy of clonazepam in these cases (27). Espiard et al. (18) presented a case report of an HPPD patient with a previous mixed intoxication with psilocybin and cannabis. Perceptual disorders appeared after a single psilocybin consumption. The subject re-experienced the symptomatology the following day during another cannabis snort. Moreover, symptomatology was recurrent daily with an attenuation after discontinuation until 6 months after he had stopped cannabis. Initially, he received amisulpride (100 mg/daily) treatment, subsequently stopped due to sedative effects. Then he started with olanzapine (5 mg/daily) which caused an exacerbation of symptomatology. Finally, he was treated with risperidone (2 mg/daily). Then, it was coadministered with sertraline (150 mg/daily) for the treatment of persisting dysphoric mood and recurrent anxiety-like symptoms. After 6 months of combination risperidone and sertraline, HPPD disappeared (18). A 33-year-old female developed an HPPD following the recreational use/abuse of LSD for a year at the age of 18 (28). Approximately, 2–3 weeks after the last drug intake, the subject developed persistent visual disturbances (a sort of attenuated flashbacks), like those experienced during an acute LSD intoxication, which lasted for over 13 years, with a little change in intensity and frequency. Despite the patient receiving several psychopharmacological treatments (e.g., sertraline, citalopram, fluoxetine, risperidone, etc.), only a year-long trial of lamotrigine (100–200 mg/day) improved abnormal visual perceptions. In addition, no significant cognitive deficits (i.e., memory functioning, attention span, visual-construction, and frontal-executive functioning) were detected, but an underperformance in the phasic attention. A follow-up after 19 months showed a continued improvement in attention performance. Brain magnetic resonance imaging scans, electroencephalograms, median nerve somatosensory, and visual evoked potential tests were all reported normal (28). A case report described a 36-year-old HPPD subject who experienced persistent visual disturbances after recreational use of LSD, cannabis, alcohol, and cocaine (29). The patient was initially treated with a 3-month course of clonidine without any improvement; then, he was treated with lamotrigine (200 mg daily) for a 7-month period with a significant improvement of his visual disturbances and overall mental well-being (29). A case report described a woman who experienced panic attacks and persistent “re-experience phenomena” characterized with flashbacks to the first trip with LSD. She responded to 0.5 mg daily of risperidone (30). A case report described an HPPD patient with a history of bipolar disorder, a previous consumption of LSD, cannabis, cocaine, and phencyclidine (PCP) (30). The patient, even though treated with lamotrigine, citalopram, and mirtazapine, committed suicide, after the hospitalization (31).

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 (32). Only 10% of the sample recruited reported long-term perceptual changes, which they would “rather not have but could live with,” while 1% reported changes that “drove them mad” (32). Of these, 39% reported them following the use of LSD, 11% after psilocybin, 9% after MDMA and cannabis, 4% ketamine, and 1% alcohol. Despite 22% of subjects reported having experienced a “flashback”, only 3% of subjects experienced a “negative” flashback (32). A web-based questionnaire investigated abnormal visual experiences among 3139 hallucinogens’ users (33). Each participant had their drug-use history (i.e., classical serotonergic hallucinogens, including LSD, psilocybin, dimethyltryptamine, etc.; NMDA antagonists, including ketamine and dextromethorphan; MDMA, anticholinergic-containing Datura plants; cannabis; Salvia Divinorum, etc.); psychiatric and neurological history; and their visual experiences investigated. Several drugs with hallucinogenic properties have been statistically associated with unusual visual experiences, even though LSD seemed to be the most frequently reported among the HPPD-like cases (33). Lerner et al. (19) reported two case reports with a prior history of LSD intake, who experienced new visual disturbances, not previously appeared during the first LSD intoxication, after totally stopping substance use (34). A pilot study recruited 26 inpatients affected with schizophrenia and concomitant self-reported past LSD use who presented with HPPD (n = 12) or without HPPD (n = 14) (35). No significant differences in demographic, clinical features, adverse effects, and response to medications have been reported between the two groups. Furthermore, the authors reported that patients with schizophrenia and concomitant HPPD were able to distinguish HPPD symptoms from hallucinations related to their own psychotic state (35). A case-control study recruited a cannabis-user who developed HPPD and four healthy controls in order to evaluate the differences in their ophthalmological state (36). Ophthalmological examination did not report clinically significant abnormal values for the HPPD patient or for any healthy controls, even though the HPPD subject reported a slightly reduced fast oscillation rate, a diminished standing potential of the slow oscillations, and a light peak within normal range resulting in higher Arden ratios (36). Another study by Lev-Ran et al. (37) compared the characteristics of schizophrenic patients with a prior LSD consumption who developed HPPD (n = 37) with those who did not develop HPPD (n = 43). No significant differences in sociodemographic characteristics were reported between the two groups. Individuals with schizophrenia and HPPD showed lower scores for negative symptoms (p < 0.001), general psychopathology (p = 0.02), and total symptoms (p < 0.001), as measured with Positive and Negative Symptomatology Scale (PANSS), as compared with those reported in the group of schizophrenics without HPPD (37). A case report described a patient with a prior history of cannabis, alcohol, and LSD sporadic recreational consumption, who developed LSD-induced “Alice in Wonderland Syndrome” and HPPD after discontinuation of all substances (38). A questionnaire specifically identified prevalence and characteristics of self-reported altered perception experiences in hallucinogens’ users (39). The survey concluded that HPPD may be due to a subtle over-activation of predominantly neural visual pathways which in turn may worsen anxiety after ingestion of arousal-altering drugs (39). A study explored triggers associated with type-1 and type-2 HPPD following the use of LSD, by recruiting 40 outpatients affected with HPPD (40). The findings reported differences in terms of visual disturbances and triggers between the two HPPD types. The most common types of visual disturbances were slow movement of still objects (among type-1 HPPD) and trailing phenomena (among type-2 HPPD). Furthermore, type-1 HPPD subjects were more likely to experience disturbances in a dark environment (40).

A case series described two cases of HPPD induced by SCs (19). A recent case report described a patient with a previous history of heavy daily use of cannabis admitted to an Addiction Treatment Unit who reexperienced visual hallucinations and disturbances, like those who experienced during acute consumption of SC, in the days following SC consumption (20).