Hallucinogen Persisting Perception Disorder (HPPD)

Key Points at a Glance

Key Points of This Disease

• Hallucinogen Persisting Perception Disorder (HPPD) is a rare condition in which visual distortions persist for months to years after discontinuation of hallucinogen use.
• The prevalence among hallucinogen users is approximately 4.2%, and it can occur even after a single use. ¹⁾
• HPPD I involves brief flashbacks, while HPPD II is persistent, recurrent, and can become irreversible.
• The DSM-5 diagnostic criteria consist of three items, requiring establishment of a causal relationship with hallucinogens and exclusion of other disorders.
• First-line medications are clonidine or benzodiazepines, and aripiprazole may also be effective. ¹⁾
• Treatment options are mostly based on case reports, and accumulating evidence remains a challenge.

1. What is Hallucinogen Persisting Perception Disorder (HPPD)?

Hallucinogen Persisting Perception Disorder (HPPD) is a rare clinical condition in which patients who have used hallucinogens in the past continue to experience perceptual distortions for months to years after discontinuing the drug. It was first reported in 1954 and was formally recognized as a clinical syndrome in the DSM-IV-TR in 2000.

According to the DSM-5-TR, the prevalence among hallucinogen users is reported to be approximately 4.2% ¹⁾. In the United States, LSD use increased by about 200% from 0.2% to 0.7% between 2002 and 2018 ¹⁾, raising concerns about a potential increase in HPPD cases with its growing popularity.

HPPD Type I and HPPD Type II

There are two subtypes of HPPD, but the DSM-5-TR does not distinguish between them¹⁾.

HPPD I (flashback type): Characterized by brief, irregularly occurring “flashbacks.” Prodromal “warning signs” may occur before onset. It is non-distressing and follows a relatively benign course.

HPPD II (persistent type): Characterized by persistent or recurrent perceptual abnormalities lasting months to years. It can suddenly appear without warning, with symptoms fluctuating in intensity. It may become irreversible and can be accompanied by anxiety, panic disorder, and depression. Patients experience a partial to complete loss of control.

Epidemiological Background

It is most commonly diagnosed in patients with pre-existing mental disorders or a history of chronic substance abuse, but it can also occur after a single use. Cannabis use among adolescents and school-age children has increased by 245% since 2000, and increased intensity of cannabis use has been reported to be associated with higher odds of hallucinogen use ¹⁾.

Q How likely is HPPD to develop?

A

It is reported to occur in approximately 4.2% of hallucinogen users ¹⁾. However, DSM-5-TR does not indicate a strong correlation between the number of uses and the onset time, and it can occur even after a single use.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Visual symptoms are common to all HPPD patients. There may be an asymptomatic period ranging from minutes to years after the first drug intake before the onset of symptoms.

The main symptoms reported in DSM-5 are as follows:

• Visual hallucinations: Seeing images of acquaintances, objects, etc., that do not actually exist
• Afterimages/trails/tracers: Images remaining behind moving objects
• Palinopsia: Repeated re-experiencing of a seen image
• Halo phenomenon: Seeing rings around light sources
• Color flashes / color enhancement: altered color perception
• Micropsia / macropsia: objects appear smaller/larger than actual size
• Altered motion perception: stationary objects appear to move

Other symptoms reported but not included in DSM-5 diagnostic criteria:

• Visual snow: seeing snow-like noise across the entire visual field
• Geometric photopsia: seeing geometric shapes (e.g., fractals)
• Pareidolia: seeing faces or patterns in random stimuli
• Distorted distance perception: altered depth perception

Other than visual symptoms, synesthesia, dissociation, depersonalization, and derealization have also been reported. Severe anxiety may accompany hallucinations, sometimes developing into panic attacks.

Clinical Findings (Findings Confirmed by Physician Examination)

HPPD I

Onset pattern: Brief flashbacks following a prodromal “warning sign”.

Duration: Short and transient. Occurrence is irregular.

Severity: Relatively benign. Low frequency and non-distressing.

Outcome: Often resolves spontaneously.

HPPD II

Onset pattern: Sudden onset without warning. Continuous, with fluctuations in intensity.

Associated symptoms: Often accompanied by anxiety, obsessive thoughts, paranoia, and panic attacks. High rate of benzodiazepine use ¹⁾.

Severity: Can become severe. May become irreversible.

Outcome: Patients experience a partial to complete loss of control.

Case reports have noted symptom exacerbation in dark environments ¹⁾. Reality testing is preserved, and the absence of thought disorganization and delusions supports a diagnosis of HPPD.

Q How do HPPD I and HPPD II differ?

A

HPPD I involves brief, irregular flashbacks with a relatively benign course. HPPD II is a severe, persistent, and recurrent form that can become irreversible, often comorbid with anxiety disorders and depression. Note that the DSM-5-TR does not formally distinguish between these two subtypes ¹⁾.

3. Causes and Risk Factors

Main causative substances

The main substances that cause HPPD are listed below.

Substance	Classification
LSD (lysergic acid diethylamide)	Classic hallucinogen (most common)
Psilocybin (magic mushrooms)	Classic hallucinogen
MDMA (Ecstasy)	Empathogen
Cannabis (Marijuana)	Cannabinoid
PCP (Phencyclidine)	Dissociative anesthetic
25I-NBOMe	Phenethylamine class

HPPD can also be triggered by the concurrent use of other substances (e.g., cannabis)¹⁾.

Risk Factors

• History of mental illness: Pre-existing mental disorders or chronic substance abuse increase the risk of onset
• Frequency of use: Onset can occur even after a single use. DSM-5-TR does not show a strong correlation between frequency of use and timing of onset¹⁾
• Characteristics of young people: Sensation seeking, impulsivity, and emotional dysregulation are positive predictors of hallucinogen use¹⁾
• Association with cannabis: Increased intensity of cannabis use is associated with higher odds of hallucinogen use¹⁾

Dangers of Self-Medication

There have been reported cases of individuals self-medicating with benzodiazepines to reduce HPPD symptoms, leading to overdose¹⁾. If you experience symptoms, always consult a specialist. Self-directed drug use can lead to serious outcomes.

Q Can HPPD develop from cannabis use alone?

A

Cannabis has been reported as a substance that can cause HPPD, and it can also occur when used in combination with other hallucinogens¹⁾. Increased intensity of cannabis use is also associated with higher odds of hallucinogen use.

4. Diagnosis and Examination Methods

DSM-5 Diagnostic Criteria

Diagnosis according to DSM-5 requires meeting all three of the following criteria.

1. Re-experiencing one or more perceptual symptoms that were experienced during hallucinogen intoxication
2. The symptoms cause clinically significant distress or impairment in social or occupational functioning
3. The symptoms are not attributable to an underlying medical condition and are not better explained by other mental disorders or hypnagogic hallucinations

To confirm the diagnosis, it is necessary to establish a relationship between the first use of hallucinogens and the onset of HPPD symptoms.

Differential diagnoses to exclude

The following diseases must be excluded.

• Psychiatric disorders: PTSD, depersonalization/derealization disorder, schizophrenia, hallucinogen-induced psychotic disorder
• Neurological disorders: epilepsy, structural brain lesions, brain infections (encephalitis)
• Others: delirium, hypnagogic hallucinations

Diagnostic considerations

In cases of polysubstance use, several days of inpatient observation may be necessary to differentiate substance-induced psychosis from primary psychosis ¹⁾. Preservation of reality testing, maintenance of linear thinking, and absence of disorganized behavior/speech/delusions are important findings supporting HPPD.

5. Standard Treatment

Because the exact pathophysiology of HPPD is unknown and it is a rare disease, most treatment options are based on case reports ¹⁾. No established guidelines exist.

Pharmacotherapy

The classification and characteristics of therapeutic drugs are shown below.

Classification	Drug	Indications/Features
First-line	Clonidine	Alpha-2 receptor agonist. Also applicable to cases with comorbid substance use disorder.
First-line	Benzodiazepines	HPPD I disappearance, HPPD II reduction. Short-term effect.
Second-line	Naltrexone	Opioid antagonist
Second-line	Calcium channel blockers	Adjunctive use
Second-line	Beta-blockers	Useful for HPPD II with comorbid anxiety disorder
Other	First-generation antipsychotics	Reports of efficacy exist
Other	Antiepileptic drugs	Reports of efficacy exist
Caution	SSRI	Both improvement and worsening have been reported. Efficacy is debated1)
Caution	Second-generation antipsychotics (most)	Most reported as ineffective1)
Attention	Aripiprazole	Exceptionally may be effective among second-generation antipsychotics1)

Mori-Kreiner et al. (2025) administered aripiprazole 5 mg to a 16-year-old male with HPPD type II and reported significant improvement in visual and auditory hallucinations ¹⁾. Although complete remission before discharge was not confirmed, marked symptom reduction was observed.

Non-Pharmacological Therapy

Brain stimulation therapy has been mentioned as an option, but it has not been sufficiently validated or investigated.

Ocular Side Effects of Therapeutic Drugs

The following ocular side effects of drugs used to treat HPPD should be recognized.

• Benzodiazepines: Decreased impulsive motor speed, abnormal smooth pursuit eye movements
• Antipsychotics: Tardive dystonia (including blepharospasm)

Treatment Considerations

Benzodiazepines have only short-term effects and carry a risk of dependence. Cases of overdose due to self-medication have been reported, and they must be used under a doctor’s supervision¹⁾. SSRIs may worsen HPPD symptoms and require caution when used.

Q What medications are used to treat HPPD?

A

Clonidine and benzodiazepines are used as first-line treatments¹⁾. Second-line options include naltrexone, calcium channel blockers, and beta-blockers. Aripiprazole has been reported as potentially effective among second-generation antipsychotics, though exceptionally. However, there are no established guidelines, and all choices are based on case reports.

6. Pathophysiology and Detailed Mechanisms

The exact mechanism of HPPD remains unknown, and the unknown etiology, rarity, and diversity of symptoms pose barriers to research¹⁾. The main hypotheses currently proposed are described below.

GABA-Related Mechanism (Main Hypothesis)

After ingestion of hallucinogens (e.g., LSD), chronic disinhibition in the visual processing system is thought to occur. Specifically, the following pathways are hypothesized.

• Destruction or dysfunction of cortical serotonergic inhibitory interneurons
• Impairment of GABA-mediated inhibitory mechanisms
• Breakdown of the filtering mechanism for unnecessary stimuli
• Resulting sustained hyperactivity of the visual cortex

Reverse tolerance (sensitization) hypothesis

It has been suggested that reverse tolerance (a phenomenon in which the effect is enhanced with repeated use) occurring after LSD exposure may be involved in the long-term recurrence of hallucinations.

Involvement of the lateral geniculate nucleus (LGN)

The lateral geniculate nucleus (LGN) of the thalamus has been suggested to be involved in the pathophysiology of HPPD. The LGN is a relay nucleus from the retina to the visual cortex, and dysfunction here is thought to lead to persistent abnormal visual experiences.

7. Latest research and future perspectives (reports at the research stage)

For patients: Please read this

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Aripiprazole for adolescent HPPD

Over the past decade, reports of adolescent HPPD cases have been scarce, and evidence-based treatment options are lacking¹⁾.

Mori-Kreiner et al. (2025) reported a case of HPPD type II in a 16-year-old male with a history of polysubstance use including LSD, MDMA, psilocybin, cannabis, and benzodiazepines¹⁾. Administration of aripiprazole 5 mg significantly improved visual hallucinations (seeing acquaintances, game consoles, mobile phones) and auditory hallucinations (loud background noise, hyperacusis). Although complete remission was not confirmed before discharge, marked symptom reduction was achieved. Notably, this case also involved self-medication with benzodiazepines for HPPD symptom relief leading to overdose, highlighting the risk of self-treatment in young individuals.

Medical use of hallucinogens and risk of developing HPPD

Research is advancing globally on the medical use of hallucinogens (e.g., psilocybin, MDMA) for treating psychiatric conditions such as depression, PTSD, and addiction. Along with this trend, there is concern that the incidence of HPPD from medical hallucinogen use may increase¹⁾.

Concerns about hallucinogen use and increasing HPPD in young people

Given the rising rates of LSD use among adolescents and the increasing trend of cannabis use in the United States, a potential future increase in HPPD is anticipated ¹⁾. The risk of onset is particularly high in young individuals with sensation-seeking tendencies, impulsivity, and emotional dysregulation, and there is an urgent need to establish evidence-based treatment protocols.

---

8. References

1. Mori-Kreiner A, Aggarwal A, Bordoloi M. Hallucinogen-Persisting Perception Disorder in a 16-Year-Old Adolescent. Psychopharmacology Bulletin. 2025;55(2):94-99.
2. Lerner AG, Rudinski D, Bor O, Goodman C. Flashbacks and HPPD: A Clinical-oriented Concise Review. Isr J Psychiatry Relat Sci. 2014;51(4):296-301.
3. Martinotti G, Santacroce R, Pettorruso M, et al. Hallucinogen Persisting Perception Disorder: Etiology, Clinical Features, and Therapeutic Perspectives. Brain Sciences. 2018;8(3):47.
4. Hadley M, Halliday A, Stone JM. Association of Hallucinogen Persisting Perception Disorder with Trait Neuroticism and Mental Health Symptoms. J Psychoactive Drugs. 2023;1-7.
5. Killion B, Hai AH, Alsolami A, et al. LSD use in the United States: Trends, correlates, and a typology of us. Drug Alcohol Depend. 2021;223:108715.
6. Hughes AR, Grusing S, Lin A, et al. Trends in intentional abuse and misuse ingestions in school-aged children and adolescents reported to US poison centers from 2000-2020. Clinical Toxicology. 2023;61(1):64-71.
7. Desai S, Kulkarni N, Gandhi K, et al. The Link Between Marijuana and Hallucinogen Use Among US Adolescents. The Primary Care Companion For CNS Disorders. 2022;24(5).
8. Parnes JE, Kentopp SD, Conner BT, Rebecca RA. Who takes the trip? Personality and hallucinogen use among college students and adolescents. Drug and Alcohol Dependence. 2020;217:108263.