The “Endless Trip” among the NPS Users : Psychopathology and Psychopharmacology in the Hallucinogen-Persisting Perception Disorder. A Systematic Review, Laura Orsolini et al., 2017

The “Endless Trip” among the NPS Users : Psychopathology and Psychopharmacology in the Hallucinogen-Persisting Perception Disorder. A Systematic Review

Laura Orsolini, Gabriele Duccio Papanti, Domenico De Berardis, Amira Guirguis, John Martin Corkery and Fabrizio Schifano

Frontiers in Psychiatry, 2017, Vol. 8, article 240

doi: 10.3389/fpsyt.2017.00240


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, methylenedioxy-methamphetamine (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.

Keywords : hallucinogen-persisting perception disorder, novel psychoactive substances, hallucinogens,
hallucinations, flashbacks, palinopsia



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 (1):

(A) 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);

(B) the symptoms in criterion (A) cause clinically significant distress or impairment in social, occupational, or other important areas of functioning;

(C) 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 (2). Moreover, other causes of visual disturbances should be investigated and excluded, such as anatomical lesions, brain infections, epilepsy, schizophrenia, delirium state, or hypnopompic hallucinations (2). Furthermore, an association between the first intake, frequency, and quantity of drug taken and the likelihood of developing an HPPD has not been demonstrated, as has been the onset of the disorder following a single hallucinogenic experience (3).


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).

Historical Background

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 (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).