Persistent Perception Disorder Induced by Hallucinogens
Original Text
Abstract
Persistent Perception Disorder of Hallucinogens (HPPD) is a rare and therefore poorly understood condition linked to the use of hallucinogenic drugs. The prevalence of this disorder is low; The condition is most frequently diagnosed in individuals with a history of prior psychological problems or substance abuse, but it can occur in anyone, even after a single exposure to triggering drugs. The objectives of the present study are to review all original studies on HPPD to evaluate the following: (1) the possible etiologies suggested; (2) possible hallucinogens involved in the induction of HPPD; (3) the clinical characteristics of HPPD I and II; (4) possible psychiatric comorbidities; and (5) available and potential therapeutic strategies. We searched PubMed to identify original studies on psychedelics and Hallucinogen Persistent Perception Disorder (HPPD). Our research yielded a total of 45 articles, which were analyzed and presented to provide readers with the most up-to-date and comprehensive literature review on the clinical characteristics and treatment options for HPPD.
1. Introduction
Hallucinogens represent a huge group of natural and synthetic agents [ 1 , 2 ] The main characteristics of hallucinogens include being empathogenic and capable of inducing alterations in consciousness, cognition, emotions, and perception. Its main characteristic is to profoundly affect a person's internal processes and perception of the surrounding world. Perceptual distortions are primarily visual, as in the vast majority of induced psychoses [ 3 , 4 , 5 ]. The hallucinogenic properties of many natural products have been known for thousands of years: folk healers, "witch doctors," and shamans used these substances in antiquity for medical, religious, spiritual, ritual, divinatory, and magical purposes. However, Western culture only turned its attention to psychedelics at the beginning of the 20th century, but the turning point is considered to be 1938, the year in which lysergic acid diethylamide, better known as LSD, was synthesized by Albert Hofmann. In the 1950s and 1960s, LSD was considered to have therapeutic potential in the psychiatric field, allowing patients to access unconscious material in therapeutic settings. This was recently reevaluated with uncertain results. After a mass diffusion of hallucinogens in the 1960s and 1970s, current prevalence data [ 6 Studies in the United States highlight that over 180,000 Americans report recent LSD use and 32,000 report recent phencyclidine use. Currently, the ingestion of hallucinogens is associated with shamanic ceremonies, underground therapy workshops, and self-experiments. In these settings, hallucinogenic substances are more commonly used alone, while at rave parties and social events they are often part of a heavy, multi-purpose drug use that frequently includes new psychoactive substances. These compounds, readily available on the Internet without any cultural barriers and sometimes without any peer group advice, have profoundly changed the drug landscape. 7 , 8 , 9 , 10 ]. Its use is becoming widespread, also due to its low cost and attractive marketing strategies. 11 , 12 ] However, significant medical and psychiatric problems have been reported for individuals using these drugs. 13 ], regardless of previous psychiatric history [ 14 ]
This article will focus on a rare and therefore poorly understood aspect of hallucinogen use: the total or partial recurrence of perceptual disturbances that appeared during previous hallucinogenic “trips” or intoxications and have resurfaced without recent use [4]. , 5 ] . These recurring syndromes are defined as "benign flashbacks" or generalized Hallucinogen Persistent Perception Disorder (HPPD). LSD is the model and prototype of the classic synthetic hallucinogen, and is certainly the most explored and investigated substance associated with the etiology of this unique and captivating state [15]. ] . HPPDs do not have a notable prevalence [ 16 and therefore are often not recognized 17 , 18 ].
The classifications used to delineate and define persistent perceptual disorders are now clearer than in the past. 18 ] Two main subtypes of recurrent perceptual disorders related to the use of hallucinogenic substances have been identified and reported [ 18 ]: (1) HPPD I, also described and referred to as Benign Flashback and Flashback Type; and (2) HPPD II, also called HPPD Type II [ 17 , 18 ] HPPD I has a short-term, reversible, and benign course. Although visual images may evoke unpleasant feelings, re-experiencing the first hallucinogenic intoxication may not lead to significant worry, distress, or impairment in individual, family, social, occupational, or other important areas of functioning. 17 , 18 ]. The condition is mild and the prognosis is generally good. Some patients report not being bothered by these phenomena: they may, in fact, consider them as "free trips" similar to psychedelic experiences without consuming a psychoactive substance. Conversely, HPPD II has a long-term, irreversible or slowly reversible, and widespread course. 17 , 19 ] HPPD II involvement is severe and the prognosis is worse. Some patients are unable to adapt to and cope with these recurring, long-duration "trips," and a significant proportion require ongoing treatment. 19 , 20 ]. It should be noted that the distinction between HPPD type I and HPPD type II has not yet been made in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), and is still under debate. HPPD type I is consistent with the diagnostic definition expressed by the International Classification of Diseases, 10 (ICD-10), while HPPD type II corresponds better to the DSM-5 criteria.
A wide range of psychoactive substances have been identified and linked to the development of this condition, including Magic Mushrooms (psilocybin)[ 21 ] and muscimol ( Amanita muscaria (L.) Lam.) [ 22 ]; cactus San Pedro and Peyote (mescaline) [ 16 , 23 ]; ketamine 24 ]; dextromethorphan [ 25 ]; MDMA and MDA 26 ]; and cannabis and synthetic cannabinoids [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ] This condition has also been associated with the consumption of Ayahuasca, Datura stramonium. L., Salvia divinorum Epling & Játiva and Tabernanthe iboga (L.) Nutt., which contains ibogaine [ 17 , 18 ] It is therefore clear that HPPD is not strictly associated with the consumption of psychedelics, but several hallucinogenic substances may be correlated with its onset.
The aim of the present study is to review all original studies on HPPD to evaluate (1) the possible etiologies suggested; (2) possible hallucinogens involved in the induction of HPPD; (3) the clinical characteristics of HPPD I and II; (4) possible psychiatric comorbidities; and (5) available and potential therapeutic strategies.
2. Materials and methods
We searched PubMed to identify original studies on psychedelics and Hallucinogen Persistent Perception Disorder (HPPD). The following search terms were used: “Hallucinogen Persistent Perception Disorder” OR “Hallucinogen Persistent Perception Disorder”. The search was conducted on September 15, 2017, and resulted in 46 records. We included all original articles (open or double-blind trials, prospective or retrospective observational studies, and case reports) written in English. We included all studies that describe perceptual distortions in patients with a prior history of substance use. Reviews, commentaries, letters to the editor, and studies involving adolescents were excluded. All authors agreed to the inclusion and exclusion criteria. We excluded 17 records by reading the titles and abstracts ( Figure 1 ).
3. Results
3.1. Suggested etiologies
HPPDs are poorly understood due to the enormous variety and variability of recurrent sensory disturbances and the multiple distinct subtypes. 17 , 18 ]
The main neurobiological hypothesis is that LSD users may develop chronic disinhibition of visual processors and dysfunction in the function of the central nervous system (CNS). 4 , 34 , 35 , 36 ] This disinhibition may be linked to an intense current generated by LSD [ 37 which can lead to destruction or dysfunction 18 ] of cortical serotonergic inhibitory interneurons with acid outlets Gamma-aminobutyric acid (GABAergic), involved in sensory filtering mechanisms of unnecessary stimuli [ 34 , 35 , 36 , 38 ]. The effectiveness of some treatment options in an individual with HPPD, such as α agonists 2 Presynaptic adrenergic agonists, selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, and mood stabilizers would confirm this neurobiological hypothesis (see Section 3.2 ). Reverse tolerance or sensitization that arises after exposure to LSD may explain recurrent occurrences after withdrawal of the stimulus. 39 ] However, HPPD-type experiences, such as flashbacks, moments of derealization, and hyperintense perceptions, are reported in healthy populations and individuals not exposed to LSD. 40 ]. Moving from biochemical receptor interactions to macroscopic areas, a temporary or permanent deficiency in the Lateral Geniculate Nucleus (LGN) has been hypothesized [ 4 , 41 , 42 , 43 ] The LGN, located in the thalamus, is associated with visual perception pathways. 41 , 42 , 43 ] Recent research has highlighted a brain dysfunction in patients with visual snow, located primarily in the right lingual gyrus [ 44 ], perhaps implying LSD involvement. Halpern et al. [ [40 ] suggested that HPPD may be due to a subtle overactivation of predominantly neural visual pathways that worsens anxiety in predisposed individuals after ingesting arousal-altering drugs, including non-hallucinogenic substances. According to Holland and Passie, environmental triggering by specific situations or stimuli or other elements related to the original experience may be involved in flashback experiences. 45 ]
3.2. Substances that induce HPPD
Different substances have been associated with visual and perceptual disturbances ( Table 1 ).
Table 1
Substances that induce Hallucinogen Persistent Perception Disorder (HPPD).
| Authors | Cases ( n ) | Substances that Induce Perceptual Disturbances | Trigger tips |
|---|---|---|---|
| Zobor, 2015 29 ] | 1 | marihuana | |
| Gaillard, 2003 46 ] | 2 | marihuana | |
| Lerner, 2014 47 ] | 2 | Cannabis (Synthetic) | |
| Anderson, 2017 48 ] | 1 | Marijuana and MDMA | Stress |
| Brodrick, 2016 49 ] | 1 | marijuana and LSD | |
| Coppola, 2017 50 ] | 1 | Cannabis (Synthetic, JWH-122) | marijuana use |
| Lerner, 2003 51 ] | 16 | LSD | |
| Lerner, 2002 20 ] | 1 | LSD | |
| Lerner, 2000 52 ] | 8 | LSD | |
| Gaillard, 2003 46 ] | 1 | LSD | alcohol consumption |
| Lev-Ran, 2017 53 ] | 40 | LSD | Sexual or intentional relationship |
| Hermle, 2012 54 ] | 1 | LSD | Stress |
| Lerner, 2014 19 ] | 2 | LSD | |
| Abraham, 2001 35 ] | 38 | LSD | dark environment |
| Litjens, 2014 [ 26 ] | 31 | LSD | |
| Lerner, 2015 55 ] | 1 | LSD | |
| Baggott, 2011 56 ] | 104 | LSD | |
| Lev-Ran, 2015 57 ] | 37 | LSD | |
| Lev-Ran, 2014 58 ] | 12 | LSD | Situation and mental states |
| Lerner, 1997 59 ] | 2 | LSD | |
| Abraham, 1996 34 ] | 3 | LSD | |
| Espiard, 2005 [ 21 ] | 1 | PCP | marijuana use |
| Lauterbach, 2000 [ 60 ] | 1 | Risperidone |
MDMA: 3,4-methylenedioxy- N -methylamphetamine; LSD: lysergic acid diethylamide; JWH-122: 4-methyl-1-(naphthalenyl)(1-pentyl-1H-indol-3-yl)-methanone.
According to the literature, we found that most cases of HPPD were induced by LSD or phencyclidine (PCP) (14 studies, 294 patients) [ 17 , 19 , 21 , 26 , 35 , 46 , 51 , 52 , 53 , 55 , 56 , 57 , 58 , 59 ]
Cannabis use has been associated with the development of perceptual distortions in seven patients. 29 , 46 , 48 , 49 , 61 ] In one case, it was associated with 3,4-Methylenedioxymethamphetamine (MDMA) and in another case with PCP [ 48 , 49 ] In two patients, visual distortion followed the consumption of synthetic cannabinoids [ 61 ]
Lauterbach et al. They reported the single case of HPPD induced by the atypical antipsychotic Risperidone [ 60 ]
3.3. Clinical characteristics
According to the DSM-5, Hallucinogen Persistent Perceptual Disorder is the recurrence of perceptual disturbances that initially develop during intoxication. The contents of perception and visual image vary extensively [ 17 , 19 ] The DSM-5 and previous editions of the DSM report a list of the most common symptoms experienced by patients with HPPD, but only a few of these symptoms have been described in the professional literature. The main group of symptoms reported by Criterion A of the DSM-5 are visual disturbances. In fact, as in the vast majority of induced psychoses, visual hallucinations are notably more common than auditory ones. 3 ]. Regardless, all the perceptual symptoms experienced during intoxication may recur after withdrawal of the hallucinogen. We present a list of the main visual disturbances reported in the literature in Table 2 .
Table 2
A representative, but not exhaustive, list of reported visual disturbances.
| Symptom | Description |
|---|---|
| Symptom reported by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) | |
| visual hallucinations | Perceptions in the absence of objects. Perceived false objects are often geometric figures. |
| Altered perception of movement | False perceptions of movement in the peripheral visual fields. |
| flashes of color | |
| Color enhancement | Enhanced color perception |
| Trails or trackers | Lines, stripes, or bands that can be observed after animate and inanimate objects have moved from their previous location. According to the DSM-5, images left suspended in the path of a moving object, as seen in stroboscopic photography. |
| Palinopsia | Positive afterimages that continue to appear in someone's vision after exposure to the original image has ceased. |
| Almost | Colored light surrounding a light source or an object. |
| Micropsy | Misperception of images as being too small |
| Macropsia | Misperception of images as being too large |
| Common symptoms not reported by the DSM-5 | |
| floats | Spots that appear to float in front of the eye. |
| Views | Dots, dots, particles, spots or specks appearing in a dark room. |
| Fractals | Perception of self-similarity or small parts that are seen as having a shape or form equal and identical to the whole. |
| Repetitions | Recurrence of inanimate or moving patterns or motifs |
| sharpness | Non-faded color contrasts |
| pareidolia | An image within an image, such as images of objects or faces in a hazy arrangement. |
| overlaps | Overlapping or superimposed geometric patterns |
| Distorted perception of distance | Objects were seen to be slightly closer or farther away. |
| Monochromatic Vision | The visual perception of distinct colors as a single color with different hues and shades. |
| intense fragmentation | The sensation of disintegration of stationary or moving objects. |
| Recurrent synesthesia | Stimulation of one sensory pathway leads to automatic and involuntary reactions or experiences in a second sensory pathway. |
| Geometric Phosphenes | Seeing light without the light entering the eye. |
| Imaging Phosphenes | Casual and unplanned images formed as non-human (zoopsia) and human faces without geometric patterns or figures caused by closing one eye and pressing it with a finger. |
| Acquired Dyslexia | Difficulty reading despite normal intelligence. |
| Aeropsia or Visual Snow | Virtually seeing air particles |
A latent period may precede the onset of visual occurrences. This latent period can last from minutes, hours, or days to years, and re-emerge as HPPD I or II with or without any recognized or perceived precipitating factor. 17 , 19 ] HPPD I and II episodes can occur spontaneously or can be triggered by identified and unidentified precipitants. 18 ] Episodes can be continuous, intermittent, or sudden. Regarding this point, neither HPPD I nor HPPD II can truly be considered persistent in the strict sense of the word. Furthermore, its differential diagnosis can only be proposed in terms of prognosis and not clinical presentation.
However, HPPD I usually begins with "auras" of alertness, minor feelings of self-detachment, mild bewilderment, and mild depersonalization and derealization. 17 , 18 ] On the other hand, the onset of HPPD II can be unexpected and detonate abruptly with explosive “auras,” deep feelings of self-detachment, acute depersonalization-derealization [19] ] .
The frequency of recurrence of perceptual distortions is lower for HPPD I than for HPPD II [ 18 ] Previous substance users may voluntarily induce or produce visual disturbances with or without known triggers. 4 , 17 , 18 ] Following the onset of HPPD II, hallucinogenic events tend to occur more frequently, and their duration and intensity increase. Subjects may experience a partial or total loss of control.
3.4. Mental illnesses comorbid with HPPD
Recent observations have reported a co-occurrence with depressive traits [ 20 ] and anxiety [ 51 ] and serious mental illnesses, such as Major Depressive Disorder [ 23 Bipolar Disorder 23 , 62 ] and Schizophrenia Spectrum Disorders [ 17 , 58 ] However, the onset of HPPD I and HPPD II is not necessarily accompanied by any additional prominent psychiatric disorder, thus representing an independent condition. 17 , 18 ]. In particular, the onset of HPPD II is often associated with clear negative mood and affect. Anxiety and depressive symptoms can worsen new episodes. Anxiety can also develop into a panic attack. Anticipatory anxiety can precede future visual aberration events, and avoidance behavior can limit and restrict regular normal functioning. 17 , 18 ]. Recently, a comprehensive study by Halpern presented and evaluated 20 individuals who reported symptoms similar to HPPD type 2. Dissociative symptoms have been consistently associated with HPPD, suggesting that HPPD is, in most cases, due to a subtle overactivation of predominantly neural visual pathways that worsens anxiety in predisposed individuals after ingesting arousal-altering drugs, including non-hallucinogenic substances. The authors report that many reported perceptual symptoms were not first experienced while intoxicated and are partially associated with pre-existing psychiatric comorbidity, attenuating the direct role of hallucinogens in the etiopathology of the disorder [40]. ] .
Only two observational studies and one case report have evaluated psychotic patients with comorbid HPPD [ 57 , 58 , 60 ] ( Table 3 ). Two cross-sectional observational studies compared schizophrenic patients with prior LSD use who developed HPPD (SCZ+HPPD, 49 patients) with those who did not (SCZ, 57 patients), for a total of 106 patients [57]. , 58 ] . No differences were found between the two groups with respect to demographic characteristics, age of onset of psychosis, age of onset of drug use, and type of substances abused. 57 , 58 ] As expected, patients with SCZ+HPPD reported more distressing and horrific LSD experiences (“bad trips”) ( p < 0.05) [ 57 ]. Interestingly, the positive subscale of the Positive and Negative Syndrome Scale (PANSS) did not differ between the two groups. Conversely, patients with SCZ+HPPD had lower scores on the negative subscale of the PANSS, on the general psychopathology subscale of the PANSS, and on the total PANSS scores ( p < 0.05) [ 57 ] Furthermore, 67% of schizophrenic patients with comorbid HPPD were able to distinguish between perceptual distortion and psychotic hallucinations. 58 ], and 9 out of 12 patients were able to identify precursor cues to perceptual distortion (substance-induced cues, situational cues, and mental cues) [ 58 ] Lauterbach et al. [ 60 ] reported a case of HPPD comorbid with psychosis, in which visual distortions were induced by antipsychotic treatment. Interestingly, the patient did not report any history of prior substance abuse. 60 ] The patient was treated with Risperidone, Clonazepam, and Trazodone, and she reported visual disturbances similar to HPPD, in particular, illusions, after three subsequent increases in the dose of Risperidone [60] ] .
Table 3
Observational studies and case reports comparing schizophrenic patients with HPPD (SCZ+HPPD) and schizophrenic patients without HPPD (SCZ) (* p > 0.05, ** p < 0.05).
| Authors | To study | Number of patients | Substances | Description of symptoms | Perceptual Onset Disorders | Recurrence of Perceptual Disorders | Treatment |
|---|---|---|---|---|---|---|---|
| Lev-Ran, 2015 57 ] | Observational, cross-sectional, control study |
80 hospitalized SCZ patient with previous LSD use 43 SCZ (DSM-IV-TR) 37 SCZ+HPPD (DSM-IV-TR) Onset of disease: 22.9 SCZ, 23.4 SCZ+HPPD * |
Cannabis: 100% SCZ, 92% SCZ+HPPD * MDMA: 60% SCZ, 46% SCZ+HPPD * Opioids: 26% SCZ, 30% SCZ+HPPD 30% * Cocaine: 16% SCZ, 14% SCZ+HPPD * Initial LSD use: SCZ 17.9y, SCZ+HPPD 19.3y * |
Adverse experience with LSD (bad trip): 28% SCZ, 89% SCZ+HPPD ** PANSS: Positive symptoms: SCZ = SCZ+HPPD ** Negative symptoms: SCZ > SCZ+HPPD ** General psychopathology: SCZ > SCZ+HPPD * * Total score: SCZ > SCZ+HPPD ** |
Ineffective treatment in SCZ+HPPD | Antipsychotic medication | |
| Lev-Ran, 2014 58 ] | observational |
26 patients 14 SCZ (DSM-IV-TR)12 SCZ+HPPD (DSM-IV-TR) The demographic characteristics did not differ between the two groups. |
past use of LSD (100%) Cannabis (100%) MDMA (7%) There are no differences between the two groups in the age of onset of drug use and in the number of incidents of hallucinogen use. |
67% of SCZ+HPPD patients were able to distinguish HPPD symptoms from hallucinations related to a psychotic state. | 9 SCZ+HPPD patients recognized precursor cues to perceptual distortion (7 substance-induced, 5 situational, and 2 mental cues). | 12 patients presented with perceptual distortion (SCZ+HPPD) |
Antipsychotic treatment. There are no significant differences in response to APS and adverse effects between the two groups. |
| Lauterbach, 2000 [ 60 ] | Case report | 1 psychotic patient |
No reports of substance abuse or exposure to hallucinogens. Risperidone Clonazepam Trazodone |
Symptoms similar to those of HPPD: palinopsia, illusions, and visual disturbances. | After treatment with risperidone |
Weekly recurrence. Remission within 48 hours each time. |
3.5. First-line medications
α2 agonists presynaptic adrenergic They are a treatment with a low side effect profile for patients with a prior history of substance-related disorders. Symptom relief has been reported in some patients treated with these drugs. 17 , 18 , 52 , 63 ] The efficacy can be based on evidence that clonidine can increase plasma GABA levels in humans, having an effect similar to benzodiazepines. Clonidine can also decrease the activity of the locus coeruleus, leading to a reduction in adrenergic activity. 64 ], which may be effective in treating PTSD [ 65 ]. Therefore, as with recurring flashbacks related to PTSD, some visual disturbances may be associated with excessive sympathetic nervous activity. Thus, these visual distortions could be improved by clonidine [ 52 , 63 ]
A dosage of 0.75 mg/day of clonidine was evaluated as a treatment option for nine patients with HPPD [ 51 , 59 ] ( Table 4 ). Complete remission was reported in a single patient with flashbacks and anxiety treated with 0.25 mg of clonidine three times daily for two months. 59 ] In the open-label 2-month study in eight patients with HPPD, Clinical Global Impression (CGI) and Patient Severity Perception decreased significantly between baseline and final scores [51] , although two patients dropped out in week 3 and week 5, respectively [ 52 ] Lofexidine (0.2–0.8 mg/day) is an adrenergic agonist. α 2 presynaptic centrally acting sympatholytic that showed similar efficacy in some cases [ 23 , 65 , 66 ]
Table 4
Observational studies and case reports evaluating the clinical presentation.
| Authors | To study | Number of patients | Substances | Description of symptoms | Perceptual Onset Disorders | Recurrence of Perceptual Disorders | Treatment |
|---|---|---|---|---|---|---|---|
| Lev-Ran, 2017 53 ] | Cross-sectional observational study |
40 (27 men); HPPD (DSM-IV-TR) |
Prior use of LSD; Lifelong use of Cannabis |
HPPD I: mean age 25.5 (3.7), times of LSD consumption: 7.1 (4.3), alcohol use; perceptual disturbances triggered by sexual intercourse, dark environments, and looking at stationary or moving objects. | None of the individuals included in the study received medications specifically targeted for the treatment of HPPD. | ||
| HPPD II: mean age 22.1 (2.8), LSD consumption times 24.6 (1.4), use of SCS, stimulants and inhalants; intentionally trigger perceptual disturbances | |||||||
| Zobor, 2015 29 ] | Observational, cross-sectional, control study | Male, 23-year-old | Cannabis, previous 4-year history of heavy consumption (16–20 years) | Visual distortion: visual snow, sperm-like whizzing dot, jittering lights, floaters, photophobia, visual discomfort, positive and negative afterimages, impaired night vision, halos, starburst around lights; | During period of cannabis use | Persistence despite cannabis withdrawal | Node |
| Ophthalmological examination: reduction of phosphene threshold, alteration in the EOG | |||||||
| 4 healthy subjects, mean age 25.5 years | Cannabis: Heavy consumption | Not reported | Not reported | Node | |||
| Lerner, 2014 [ 19 ] | Case report | Male, 24-year-old | Cannabis: Three-year past history of social consumption; | Visual disturbances (halos, color intensification, flashes of colors, distorted perception of distance) | During LSD intoxication | Recurrence one week after completely stopping all substance use: daily visual distortion | Not accepted by the patients |
| MDMA, LSD and cocaine (sporadically); | |||||||
| Social Alcohol drinking | Disappearance after one year | ||||||
| Female, 25 years old | Cannabis: Three-year past history of social consumption; | Visual disturbances (positive afterimages, color intensification, flashes of colors, trailing phenomena) | During LSD intoxication | Recurrence four days after completely stopping all substance use: daily visual distortion | Not accepted by the patients | ||
| MDMA, LSD (sporadically); | Improvement after one year; | ||||||
| Social Alcohol drinking | Trailing phenomena continued to appear intermittently | ||||||
| Gaillard, 2003 [ 46 ] | Case reports | Female, 18-year-old | Cannabis: Three-year past history of regular consumption | White dots when looking at a white wall or blue sky, “seeing shadows” on the left side, palinopsia, visual vibration upon awakening | During comatosis episode following excessive use of cannabis | Recurrence after stopping all substance use: daily visual distortion | |
| Male, 25-year-old | Cannabis: Two-year past history of regular and heavy consumption | Visual illusion and dyskinetopsia, difficult in depth perception | After two years of consumption | Symptoms persistence and increase after cannabis withdrawal + memory loss, and concentration deficits | |||
| Abraham, 2001 [ 35 ] | Observational | 38 HPPD cases | LSD: first mean use 18.1 (6.0) years; lifetime use 16 times (median) | 7.11 (2.2) different types of visual hallucinations per subject | 21 months after first use | Duration of visual hallucinations: 9.67 (7.68) years | |
| 13.5% subjects experienced symptoms within the first month of use, three subjects after a single use | |||||||
| The majority of subjects reported an intensification of visual hallucinations on emerging into a dark environment | |||||||
| Litjens, 2014 [ 26 ] | Case series | 31 HPPD cases; Web-questionnaire |
MDMA | At least 2 different visual phenomena (visual snow, afterimages, flashes, illusory movement, and increased observation of floaters) with a minimum of one episode of disturbed perception every week (100%); | After a single drug exposure | ||
| Cannabis | |||||||
| LSD | Anxiety or panic in the weeks before or following the use of drugs (71%) | ||||||
| Depersonalization (32%) | |||||||
| assessment | 80% serotonergic drugs | Derealization (39%) | After a period of extensive drug use | ||||
| Lerner, 2015 [ 55 ] | Case report | Male, 26-year-old | Cannabis: a five-year history of occasional consumption; | No distressing macropsia, micropsia, pelopsia and teleopsia, looking at still or moving objects and humans; | LSD intoxication | Recurrence two days after completely stopping all substance use: daily visual distortion | Not accepted by the patients |
| Alcohol: Social Consumption; | |||||||
| LSD: Recreational use | Longer and distressing visual distortion experience with anxiety | ||||||
| Disappearance after one year | |||||||
| Baggott, 2011 [ 56 ] | Observational Web-based questionnaire | 2679 subjects | Median of 5 different drugs used by a single subject | 224 subjects reported having at least one diagnosis associated with unusual visual experiences; | After exposure to LSD | The probability of experiencing constant or near-constant symptoms was predicted by greater past exposure to drugs and exposure to LSD | 104 individuals considered the symptoms harmful enough to seek treatment. |
| 89.5% male, aged 21.6 (3.7) years | 1,487 individuals reported at least one abnormal visual experience; | ||||||
| 587 endorsed at least one experience consistently or almost consistently. |
Benzodiazepines may be useful and effective in eliminating benign HPPD I and improving, but not completely eradicating, the invasive symptoms of HPPD II. 18 , 67 ] The effectiveness of benzodiazepines may be related to their activity on cortical serotonergic inhibitory interneurons with GABAergic outputs. 2 , 4 ] Alprazolam (0.25–0.75 mg/day) has been prescribed with some success and clonazepam (0.5–1.5 mg/day) appears to be the most reliable and effective benzodiazepine, even at low doses [17] , 18 , 51 , 67 ] . Higher doses (4 mg/day) have also been used with good results. 68 ]. Clonazepam can act on serotonergic systems, improving, potentiating, and increasing the transmission [ 17 , 18 , 51 , 67 ], promoting relief and marked improvement [ 51 , 67 ] Clonazepam was evaluated in three case reports and one open-label study by Lerner [ 19 , 50 , 51 ] In the clinical trial, 16 patients with HPPD were treated with a dose of Clonazepam of 2 mg/day [ 51 ] Their symptoms improved significantly after starting treatment, and the improvement persisted during a 6-month follow-up after discontinuation of treatment. 51 ]. The same author reported two cases of cannabis-induced visual disturbances and correlated anxiety features. In both cases, Clonazepam (2 mg/day) was effective in improving symptoms, but non-anxiety focal visual disturbances (trail phenomena in one case and moving black spots in the second case) persisted during and after therapy [19]. ] . More recently, Clonazepam (6 mg/day) has proven effective in improving symptoms of cannabis-induced HPPD [ 50 ] On the other hand, the inherent abuse potential of benzodiazepines may be inconvenient in certain individuals with a history of substance use. 17 , 18 ]. Given the benign nature of HPPD I, the use of benzodiazepines should only be considered for severe cases, in the acute phase, and for a short period of time.
Patients with HPPD appear to be sensitive to first-generation antipsychotics at low doses, requiring monitoring for extrapyramidal side effects. Haloperidol [ 69 ] and Trifluoperazine [ 70 These were reported as useful. Perphenazine (4–8 mg/day) 17 , 23 ], Sulpiride (50–100 mg/day) [ 23 ] and Zuclopenthixol (2–10 mg/day) [ 17 , 23 In very low doses, they are well tolerated and can be an effective treatment. Some long-acting first-generation antipsychotics may still be useful in the co-occurrence of Psychotic Spectrum Disorders and HPPD II [ 58 ]. In one study, haloperidol was observed to reduce hallucinations, but an exacerbation of flashbacks in the initial phases of treatment was also noted. 1 , 69 ]
The use of second-generation antipsychotics in patients with HPPD without comorbid psychotic disorders is debated. Anderson recently reported the case of a young woman presenting with prolonged and distressing multimodal pseudo-hallucinations, depressive symptoms, and anxiety, who was treated with risperidone for three months without any significant improvement [48]. ] . At the same time, there is conflicting evidence regarding the effects of antipsychotics in psychotic patients with HPPD. One study reported no differences in response to antipsychotic treatment between patients with SCZ and SCZ+HPPD [ 58 ] On the other hand, a more recent study showed the ineffectiveness of antipsychotic medications in a population with SCZ+HPPD [ 57 ]
Risperidone was commonly prescribed due to its proven efficacy in treating perceptual disturbances in Psychotic Spectrum Disorders, particularly Schizophrenic Disorders. LSD appears to function as a partial agonist of postsynaptic serotonin receptors. Therefore, it was expected that Risperidone, which is a strong antagonist of 5-HT receptors, would be effective. 2 and D 2 postsynaptic, if it were convenient. In contrast to this assumption, Risperidone in recommended doses 71] and lower [ 72 either worsens visual disturbances and associated anxiety, or has no effect at all 54 ] Presumably, this occurred due to presynaptic α antagonism. 2 of risperidone and the release of noradrenaline [ 34 ]. Furthermore, risperidone has been associated with the re-experiencing of visual disturbances in some patients suffering from schizophrenia with a history of LSD use. 73 ] A psychotic patient treated with risperidone, clonazepam, and trazodone reported visual disturbances similar to HPPD after three subsequent increases in risperidone dosage. 60 ] At the same time, risperidone proved effective in improving PCP-induced HPPD with anxiety in one patient, while in the same patient olanzapine produced an exacerbation of symptoms. 21 ]
Evidence not included in our systematic review suggested that low doses of atypical antipsychotics may be useful, specifically Aripiprazole (5–10 mg/day)[ 23 ], also because of its effectiveness in substance and alcohol use disorders [ 74 ]
Visual oddities and disturbances with sudden paroxysmal onset were interpreted as visual seizures and led to the use of antiepileptic drugs in HPPD. This consideration helped explain the effectiveness of benzodiazepines and led to the prescription of phenytoin. 75 , 76 ] Currently, phenytoin is not used to treat HPPD due to its problematic side effect profile. Medications such as Valproic Acid (200–600 mg/day), Carbamazepine (200–600 mg/day), Oxcarbazepine (300 mg/day), Gabapentin (300–900 mg/day), Topiramate (25–100 mg/day), and Lamotrigine (50–100 mg/day) may be helpful. 23 ], also due to its effectiveness in substance and alcohol use disorders [ 77 , 78 , 79 ]. In a single case of HPPD symptoms and electroencephalographic (EEG) abnormalities consistent with toxic encephalopathy, visual hallucinations that recurred with any alcohol intake improved but did not disappear with the use of valproic acid (1500 mg/day) [46] ] . Levetiracetam has been shown to reduce some visual symptoms, as well as depersonalization and derealization related to HPPD [ 80 ] Lamotrigine has been shown to be effective in a recent severe case of HPPD with some EEG abnormalities (Anderson et al., 2018). These medications may also be helpful when visual disturbances are accompanied by mood changes and concomitant mood disorders.
Antidepressant medications may help in the treatment of HPPD II concomitant with anxiety and depressive disorders. 17 , 18 , 20 , 51 , 67 ] HPPD II alone does not appear to be an appropriate target. There are questionable and controversial results regarding sertraline, which worsens [ 81 as well as improving visual disturbances. The improvement following prolonged administration of SSRIs was attributed to the downregulation of 5-HT. 2 receptors, providing further evidence to corroborate the serotonergic mechanisms underlying this condition. Other prescribed SSRIs have shown no benefit. Norepinephrine reuptake inhibitors (NRIs), such as Reboxetine, have been tested with some success in LSD-induced HPPD symptoms comorbid with Major Depressive Disorder [ 20 ] Agomelatine, given its unique role in neurotrophic factors [ 74 It may have some benefits in the syndrome, although no data is available to date.
3.6. Second-line medications
Naltrexone has generally been used, alone or with other medications, in chronic patients with continuous visual imagery who previously did not respond to other medications. 17 , 18 ]
Calcium channel blockers and beta-blockers may be useful in patients with concomitant HPPD II and anxiety disorders. 18 ] Propranolol at low (20–60 mg/day) and high (240 mg/day) doses, as well as Atenolol 25–50 mg/day, have been used to reduce anxiety associated with visual imagery [18]. , 23 ] . Investigations of patients with HPPD using EEG mapping have shown that HPPD is represented by disinhibition [ 35 in the cerebral cortex 34 ] The logic behind this interesting and novel approach is that enhancing sensory control through dopaminergic enhancers may cause an inhibition of catechol- THE -methyltransferase (COMT), which may improve the symptoms of HPPD.
3.7. Brain stimulation treatments
Currently, brain stimulation treatments have been proposed as a possible therapeutic option to improve the recovery from refractory symptoms in various disorders. 82 , 83 ]. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive brain stimulation approach that works by modulating specific brain circuits. While high-frequency stimulation (>5 Hz) causes depolarization of nerve cells, with long-term potentiation (LTP) effects, low-frequency stimulation protocols (1 Hz) cause long-term depression (LTD) of the target area, with the possibility of inducing localized inhibition of specific disordered networks. According to the cortical hyperexcitability hypothesis regarding its pathogenesis, several case reports suggest that rTMS could be a promising therapeutic method for refractory visual hallucinations in schizophrenia. 84 , 85 ]
To date, no studies have investigated the potential use of rTMS in HPPD. Interestingly, Kilpatrick and Ermentrout (2012) [ 86 They studied the spatiotemporal dynamics of neural networks in HPPD, with peak frequency adaptation. This study reported that altering parameters that control the strength of synaptic connections in the network can lead to spatially structured activity suggestive of HPPD symptoms. Further research is needed to test the potential effectiveness of the rTMS neuromodulatory effect on HPPD. It can be assumed that putative stimulation targets are located in the visual cortical areas, as well as in the occipitotemporal sulcus [ 87 ]. Functional neuroimaging can be beneficial in locating a specific target for stimulation and can avoid wasting time and money on targets that are unlikely to be involved in the pathogenesis.
4. Discussion
It should be noted that a limitation of the study may be represented by the search method: in fact, we decided to limit the literature search to DSM terminology to exclude simple "flashback phenomena" that are commonly reported in psychopathology, and which may not follow the use of hallucinogens. This could have narrowed the results, preventing the inclusion of other studies using the less "technical" ICD terminology on the subject.
The main consideration that must be made regarding HPPD is its rare and unpredictable nature. 16 Current prevalence estimates are unknown, but the DSM-5 suggests 4.2% 88 ] The condition is most frequently diagnosed in individuals with a history of prior psychological problems or substance abuse. 56 ], but it can occur in anyone, even after a single exposure (primarily to LSD, but it has also been reported after the use of other psychedelics) [ 89 ] In many cases, HPPD can also be explained in terms of heightened awareness and preoccupation with common visual phenomena, which is supported by the high rates of anxiety, obsessive-compulsive disorder, hypochondria, and paranoia observed in many patients [90]. ] .
The crucial move towards a comprehensive clinical understanding of Hallucinogen Persistent Perception Spectrum Disorders (HPPSD) [ 23 This refers to the establishment of an accepted operational nomenclature. This broad spectrum of disorders encompasses different subtypes, ranging from HPPD I to HPPD II, according to our hypothetical distinction. Among the numerous triggers capable of precipitating HPPD, prospectively, the use of natural and synthetic cannabinoids appears to be the most frequent. This is consistent with the rapid and widespread diffusion of these new psychoactive compounds, now readily available without specific cultural filters or references. 91 , 92 ]. Distinct substances, with completely different mechanisms of action, can lead to or precipitate the genesis of HPPD, thus suggesting a multifaceted etiology. Thus, it is conceivable that different medications may be useful and helpful in treating different subtypes of HPPD. Trackers and tracking phenomena appear to be the most persistent symptoms. Coexisting psychiatric disorders can present an additional clinical challenge, with the clinical construction of the lysergic psychome as a possible heuristic model. According to this theory, the presence of induced psychopathological phenomena (the psychoma) can trigger a specific reaction from the unaffected part of the mind, attempting to neutralize the psychoma, which is perceived as a "foreign body in the mind". Sure, 93 , 94 ].
Regarding treatment options, a combination of medications may be necessary depending on the underlying or subsequent psychopathology. Given the limited literature on HPPD, a possible hypothesis regarding the pharmacotherapy of choice in relation to different etiologies was not considered. However, the presence of psychiatric and neurological comorbidities could represent a valid criterion for selection. Clinical experience and a broad, comprehensive understanding of these phenomena are vital for successful treatment outcomes.
Controlled clinical investigations are needed primarily to better understand the etiology, mechanisms of action, clinical issues, and pharmacological treatment options for Hallucinogen Persistent Perception Spectrum Disorders (HPPSD).