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

This review (2014) examines the role of serotonergic transmission in Hallucinogen persisting perception disorder (HPPD), a rare perceptual disorder caused by LSD, and other classical hallucinogens, as well as MDMA. The disorder may be a result of a misbalance of inhibitory-excitatory activity in low-level visual processing caused by interneurons expresses 5-HT2A receptors, whose activity would normally suppress afterimages through inhibitory GABA release.


Introduction: Hallucinogen persisting perception disorder (HPPD) is a drug-induced condition associated with inaccurate visual representations. Since the underlying mechanism(s) are largely unknown, this review aims to uncover aspects underlying its etiology.

Methods: Available evidence on HPPD and drug-related altered visual processing was reviewed…

Results: the majority of HPPD cases were attributed to drugs with agonistic effects on serotonergic 5-HT2A receptors. Moreover, we present 31 new HPPD cases that link HPPD to the use of ecstasy (MDMA), which is known to reverse serotonin reuptake and acts as agonist on 5-HT2A receptors.

Discussion: The available evidence suggests that HPPD symptoms may be a result from a misbalance of inhibitory-excitatory activity in low-level visual processing and GABA-releasing inhibitory interneurons may be involved. However, high co-morbidities with anxiety, attention problems and derealization symptoms add complexity to the etiology of HPPD. Also, other perceptual disorders that show similarity to HPPD cannot be ruled out in presentations to clinical treatment. Taken together, evidence is still sparse, though low-level visual processing may play an important role. A novel finding of this review study, evidenced by our new cases, is that ecstasy (MDMA) use may also induce symptoms of HPPD.”

Authors: Ruud P. W. Litjens, Tibor M. Brunt, Gerard-Jan Alderliefste & Remco H. S. Westerink


This review aims to uncover aspects underlying the etiology of hallucinogen persisting perception disorder (HPPD), which is a drug-induced condition associated with inaccurate visual representations. Moreover, 31 new HPPD cases were presented, which link HPPD to the use of ecstasy (MDMA).

Hallucinogenic drugs can induce a variety of powerful perceptual symptoms, including altered shapes and colors, trails of moving objects, kaleidoscopic images, and less frequently, auditory and olfactory hallucinations. A subgroup of users suffers from persistent perceptual symptoms long after the drug has been used. Estimates of the prevalence of use of hallucinogenic drugs vary greatly between countries. Though it is impossible to determine to what extent hallucinogenic drug use may actually lead to a classification of HPPD, many suggest that there is a consistent number of experimental users exposed to hallucinogenic substances through time.

The psychiatric definition of HPPD is an alteration of perception that persists after the acute effects of certain drugs have worn off. It is included in the DSM IV-TR as ‘Hallucinogen persisting perception disorder (flashbacks)’. The re-experiencing of one or more perceptual symptoms that were experienced while intoxicated with a hallucinogen and that cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

According to the DSM IV-TR, post-hallucinogen perception disorder symptoms typically occur in episodes and can be triggered by entering into a dark environment, acute intoxication with alcohol or marihuana, anxiety, fatigue, different stressors, or by thinking of them (self-induced). In 2003, a thorough analysis of the literature on HPPD and flashbacks was published. It was found that 61% of respondents with extensive drugs histories reported at least one type of recurring visual experience, and 24% reported this on a constant or near-constant basis.

Persistent visual symptoms were encountered less when drugs were administered in controlled research or therapeutic settings, and the incidence of HPPD is suspected within a small proportion of these users.

The visual system consists of photoreceptors, bipolar cells, ganglion cells, and the lateral geniculate nucleus, which receives visual, auditory, gustatory, and sensory information and may be an important region in the subjective experience induced by hallucinogens. The visual system is composed of the lower visual cortex (LGN), the primary visual cortex (V1), and higher brain areas that provide feedback to lower areas.

HPPD is a perceptual disorder, and geometric hallucinations are generally perceived with both eyes and move while maintaining their relative position in the visual field. These hallucinations likely originate in the CNS and not at the level of the eye itself. Trailing is another visual phenomenon that may persist in patients with hallucinogenic psychosis, and may be caused by activity in a population of neurons in the primary visual cortex.

HPPD patients may experience afterimages, which are images that persist in vision after the stimulus has disappeared. Afterimages may be caused by posterior visual pathway lesions or medications, or may arise through a brain mechanism that remains to be elucidated. HPPD symptoms may be caused by a disturbance in lower levels of the visual pathway of the brain, but the thalamus, particularly the lateral geniculate nucleus, deserves consideration.

Hallucinogens affect serotonergic neurotransmission to some extent, including the prefrontal cortex, locus coeruleus, and the raphe nuclei. Psilocin, a metabolite of psilocybin, may inhibit firing of raphe nuclei neurons, but this effect is not essential for the hallucinogenic effects. In line with this, the psychoactive potency of hallucinogens correlates strongly with their affinity for 5-HT2 receptors. The 5-HT2A receptor may be involved in the etiology of HPPD. Serotonergic prescription drugs have been found to induce altered perceptions in patients with HPPD, such as visual trailing and worsening of existing symptoms.

HPPD may be related to the 5-HT2A receptor, and serotonergic neurotransmission in general. However, hallucinations are not frequently reported in studies with human subjects on MDMA, and there is at least one existing case report of persisting perceptual symptoms linked to MDMA. MDMA is a potent releaser and reuptake inhibitor of 5-HT, dopamine and noradrenaline, and also acts as an agonist at the 5-HT2A receptor. This suggests a central role for serotonergic neurotransmission in HPPD. Our HPPD cases were obtained from an addiction care center in the Netherlands. Most individuals found out about it through the internet.

31 individuals were interviewed with a standard checklist that covered social situation and somatic, motoric, urogentical, gastrointestinal, perceptual, infectious, cardiovascular, and psychiatric symptoms. All patients were diagnosed by a psychiatric physician in addiction medicine according to DSM IV-TR criteria. The included cases display visual symptoms, including visual snow, afterimages, flashes, illusory movement, and increased observation of floaters. Five patients were investigated by an ophthalmologist, but no abnormalities were found.

Patients reported recurring visual symptoms, auditory and sensory symptoms, peculiar sensations in the head, and derealization and depersonalization symptoms. Most patients with HPPD reported to have experienced anxiety or panic in the weeks before or following the use of drugs. Serotonergic drugs stood out in most cases, but it is not clear if the condition can be attributed to ecstasy or whether it has developed as a result of combinational drug use or other factors.

We found no mechanistic links between HPPD and migraine with aura, and the typical visual phenomena of migraine with aura were completely absent in our sample. Moreover, the visual hallucinations associated with migraine with aura are usually of a temporary nature and resolve after the migraine seizure. Patients suffering from occipital or temporal-occipital lobe epilepsy may experience visual hallucinations and epileptic auras, which may include colored round-shaped figures, déjà vu’s, or ictal autoscopia. These phenomena are rarely prolonged without being provoked by new seizures.

Serotonin neurotransmission is involved in low-level visual processing and HPPD, and long-term changes are induced in the functioning of lower visual areas. Serotonergic neurotransmission is abundant in lower visual areas and can both facilitate and inhibit the firing of neurons. Post-mortem studies have shown that 5-HT2A receptors are present in human V1, and that 5-HT2A receptors can both suppress strong responses and facilitate weak neuronal responses in primate V1.

Abraham and Aldridge (1993) proposed that damage to GABA-releasing interneurons may be involved in HPPD. Symptoms such as afterimages and halos may be explained by a lack of inhibition, and visual snow during adaptation to darkness may be a cue that a drop in signal to noise ratio plays a role. A misbalance between excitatory and inhibitory input in the visual system of HPPD sufferers is suggested by computational studies, as well as by fMRI studies with long abstinent MDMA users.

HPPD-like effects may occur as a result of lacking inhibition, an increase in excitation, or a combination of both, and may lead to increased excitation and decreased ability to respond to switching stimuli. In experimental animals, MDMA was shown to be neurotoxic to axons projecting from the raphe nuclei. In human users, SERT levels were drastically reduced, and 5-HT2A receptor densities were reduced, but expression was increased in ex-MDMA users and in rats 30 days after administration of MDMA.

The high comorbidity with other psychiatric conditions in our cases forces us to consider the relationship of these conditions to visual perception. Anxiety may modulate contrast sensitivity in low-level visual processing, and benzodiazepines may be used to dampen anxiety. The way in which anxiety affects visual processing may be related to attentional mechanisms. DP/DR symptoms are often mentioned by HPPD patients, and a survey among individuals with DP/DR symptoms found that hallucinogens, cannabis, and ecstasy were the most commonly mentioned drugs of cause.

Recent studies suggest that visual disturbances occur with some regularity resulting from the use of hallucinogenic drugs and MDMA, and that the 5-HT2A receptor may be a target for both drugs to induce long-term visual changes, such as HPPD. Cannabinoids and ketamine may not cause HPPD symptoms by themselves, but they may sensitize an individual to the development of visual complaints after the use of LSD for example.

Some users reported to be incapacitated by their symptoms, whereas a large group appeared to experience symptoms without impairment. Factors such as genetic polymorphisms in SERT, CYP2D6, and COMT genes may play a role in the development of clinical symptoms and decreased cognitive functioning in MDMA users. The symptoms of HPPD are similar to those of other possible underlying conditions, but without appropriate neurological tests, it is difficult to exclude other conditions.

A misbalance of inhibitory/excitatory signaling in low-level visual processing may be responsible for HPPD-like symptoms.

Geometric hallucinations are patterns that seem to move along with eye movements, while trailing is a series of stationary images along a moving object’s trajectory. Palinopsia is a continuous smear left by a moving object. A damaged interneuron hypothesis is proposed to explain prolonged false visual representations of reality. An alternative hypothesis is an increase in strength of excitatory synapses, such as with LSD and ketamine, or a decrease in serotonin release onto 5-HT2A receptors, such as with MDMA.