Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives

This comprehensive literature review (2018) examines the clinical features and treatment options for psychedelic-induced Hallucinogen Persisting Perception Disorder (HPPD), which entails tracers and trailing phenomena among its most resistant symptoms. Although the prevalence is low and hard to assess reliably, the condition is more often diagnosed in individuals with a history of previous psychological issues or substance misuse, and most reported cases were triggered by LSD.

Abstract

Introduction: 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.

Methods: 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).

Results/Discussion: 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.

Authors: Giovanni Martinotti, Rita Santacroce, Mauro Pettorruso, Chiara Montemitro, Maria Chiara Spano, Marco Lorusso, Massimo Di Giannantonio & Arturo G. Lerner

Summary

Review

Hallucinogen Persisting Perception Disorder (HPPD) is a rare condition linked to hallucinogenic drugs consumption. This study analyzed 45 original studies about HPPD and provided readers with the most updated and comprehensive literature review about the clinical features and treatment options for HPPD.

  1. Introduction

Hallucinogens are natural and synthetic agents that can induce alterations of consciousness, cognition, emotions, and perception. They were used by healers, “brujos”, and shamans for thousands of years, but the attention of western culture was drawn to psychedelics only in 1938.

LSD was considered to have a therapeutic potential in the psychiatric field in the 1950s and 1960s, but this has been recently re-evaluated with uncertain results. Nowadays, hallucinogens are most commonly used in shamanic ceremonies, workshops of underground therapy and self-experiences.

This paper will focus on a rare aspect of hallucinogen consumption: benign flashbacks, or pervasive Hallucinogen Persisting Perception Disorder (HPPD). These syndromes are frequently unrecognized.

Two subtypes of hallucinogenic substance-use related persisting perceptual disturbances have been identified: benign Flashback (HPPD I) and severe HPPD II (HPPD II). HPPD I is a short-term, reversible and benign course, while HPPD II is a long-term, irreversible and pervasive course. The distinction between HPPD type I and HPPD type II is still debated, but HPPD type I matches the ICD-10 criteria better.

HPPD has been linked to the consumption of a number of psychoactive substances, including Magic Mushrooms, muscimol, San Pedro cactus, Mescaline, ketamine, dextromethorphan, MDMA and MDA, and cannabis.

This study reviews all the original studies about HPPD and evaluates the possible etiologies, hallucinogens, clinical features, comorbidities, and therapeutic strategies.

  1. Materials and Methods

We searched PubMed for original studies on psychedelics and Hallucinogen Persisting Perception Disorder (HPPD). We included 25 papers that met our inclusion/exclusion criteria, and therefore, included them in the qualitative synthesis.

3.1. Suggested Etiologies

LSD consumers may develop chronic disinhibition of visual processors and dysfunction in the function of the central nervous system. This dysfunction may be linked to an intense current generated by LSD, which may destroy or dysfunction cortical serotonergic inhibitory interneurons. The Lateral Geniculate Nucleus (LGN) is associated with visual perception pathways and may be involved in HPPD. Environmental triggering by specific situations or stimuli may also be involved in flashback experiences.

According to the literature, the majority of HPPD cases have been induced by LSD or phencyclidine (PCP). Two cases have been reported with the use of synthetic cannabinoids, MDMA and PCP.

3.3. Clinical Features

According to DSM-5, Hallucinogen Persisting Perception Disorder (HPPD) is the recurrence of perceptive disturbances that firstly develop during intoxication. The main group of symptoms reported by Criterion A of the DSM-5 are visual disturbances.

A latent period may antecede the onset of returning visual occurrences, and HPPD I and II may re-emerge with or without any recognized or perceived precipitator. They may be continuous, intermittent, or sudden, and their differential diagnosis is based on prognosis rather than clinical presentation.

Prior substance users can voluntarily elicit or produce visual disturbances, and after HPPD II onset, hallucinogenic events tend to occur more frequently.

3.4. Mental Illnesses Comorbid with HPPD

Recent studies suggest that hallucinogenic perceptual disorder is associated with depressive and anxiety traits, and severe mental illnesses such as Major Depressive Disorder, Bipolar Disorder, and Schizophrenia Spectrum Disorders. However, hallucinogenic perceptual disorder is not necessarily accompanied by any prominent additional psychiatric disorder.

Two observational studies and one case report evaluated psychotic patients with comorbid HPPD. In both studies, patients with prior use of LSD who developed HPPD reported more distressing and horrific LSD experience (“bad trips”), but also showed lower scores in the Positive and Negative Syndrome Scale (PANSS) negative subscale, and total scores.

3.5. First-Line Medications

Pre-synaptic 2 adrenergic agonists are effective in treating patients with a previous history of substance-related disorders. They may reduce symptoms of PTSD by decreasing sympathetic nervous activity and elevating plasma GABA levels.

Nine patients with HPPD have been treated with Clonidine at 0.75 mg/die. Lofexidine has shown similar efficacy in some cases, although two patients dropped out at week 3 and week 5, respectively.

Benzodiazepines may be useful in alleviating benign HPPD I and ameliorating pervasive HPPD II symptoms. They may act on cortical serotonergic-inhibitory inter-neurons with GABAergic outputs, improving, enhancing, and augmenting transmission, thus promoting alleviation and a marked improvement. Clonazepam has been evaluated in three case reports and one open-label trial by Lerner . It has been proved to be effective in improving symptoms of cannabis-induced HPPD I, but the intrinsic abuse potential of benzodiazepines might be inconvenient in certain individuals with a past history of substance use.

HPPD patients are sensitive to first-generation antipsychotics at low doses, and may be treated with haloperidol, trifluoperazine, perphenazine, sulpiride, and zuclopenthixol. Some long-acting first-generation antipsychotics may still be useful in co-occurring Psychotic Spectrum Disorders and HPPD II.

The use of second-generation antipsychotics in HPPD patients without comorbid psychotic disorders is debated. However, conflicting evidence exists on the effects of antipsychotic medications in psychotic HPPD patients.

Risperidone, a strong antagonist of both postsynaptic 5-HT2 and D2 receptors, was usually prescribed due to its proven efficiency in the treatment of perceptual disturbances in Psychotic Spectrum Disorders, mainly in Schizophrenic Disorders. However, Risperidone worsens visual disturbances and accompanying anxiety, or does not show any effect.

The use of antiepileptic drugs in HPPD has been prompted by the interpretation of visual oddities and disturbances with sudden paroxysmal onset. Valproic Acid, Carbamazepine, Oxcarbamazepine, Gabapentin, Topiramate, and Lamotrigine may be useful in the treatment of HPPD.

Antidepressant medications may help with co-occurring HPPD II with anxiety and depressive disorders, although Sertraline may worsen as well as improve visual disturbances. Norepinephrine reuptake inhibitors may also be useful, although no data are available until now.

3.6. Second Line Medications

Naltrexone, Calcium Channel Blockers, Beta Blockers, Propanolol, Atenolol, have been used to treat chronic visual imagery in patients with HPPD II. These medications have been shown to improve symptoms.

3.7. Brain Stimulation Treatments

rTMS is a non-invasive brain stimulation approach that acts by modulating specific brain circuits. It has been proposed as a promising therapeutic method for refractory visual hallucinations in schizophrenia.

Kilpatrick and Ermentrout (2012) studied the spatiotemporal dynamics of neuronal networks in HPPD, and concluded that altering parameters controlling the strength of synaptic connections in the network can lead to spatially structured activity suggestive of symptoms of HPPD.

  1. Discussion

The study might have been limited by the search method, which used DSM terminology to exclude simple “flashback phenomena” that are commonly reported in psychopathology.

The main consideration with respect to HPPD is its rare and unpredictable nature. It is more often diagnosed in individuals with a history of previous psychological issues or substance misuse.

Hallucinogen Persisting Perception Spectrum Disorders (HPPSD) are a wide spectrum of disorders, with different subtypes. The use of natural and synthetic cannabinoids appears to be the most frequent trigger, and different medications could be useful and helpful in the treatment of different subtypes of HPPD.

Treatment options for Hallucinogen Persisting Perception Spectrum Disorders (HPPSD) depend on the preceding or subsequent psychopathology. Clinical experience and comprehensive knowledge of these phenomena are vital for successful treatment outcomes.

Study details

Topics studied
Safety

Study characteristics
Meta-Analysis Literature Review