A recent study published in Translational Psychiatry provides evidence that individuals who experience persistent visual distortions after using psychedelic drugs tend to have higher rates of anxiety and physical health conditions. The findings suggest that this phenomenon is part of a complex interaction between mental and physical health, rather than a simple reaction to substance use.
When people consume psychedelic substances like lysergic acid diethylamide, commonly known as LSD, they typically expect visual and perceptual changes to fade once the drug leaves their system. Some individuals experience a condition where these visual distortions persist long after the initial intoxication has ended. This condition is diagnosed as hallucinogen persisting perceptual disorder.
People with this condition might see halos around objects, trailing images, or static-like dots in their vision. These visual phenomena are sometimes colloquially called flashbacks. Recent research tends to divide the condition into two distinct subtypes based on how the symptoms present over time.
Type I is characterized by abrupt, brief alterations in perception that can be experienced positively, neutrally, or negatively. Type II involves chronic, constant visual abnormalities that usually cause significant distress. The constant intrusion of these visual distortions can make people feel trapped and disconnected from reality.
Scientists have not yet identified the exact biological mechanism behind hallucinogen persisting perceptual disorder. Older theories proposed that psychedelic drugs caused toxic damage to the brain’s visual processing pathways. Recent research tends to challenge the idea of permanent toxic brain damage.
Matt Butler, a specialist registrar in psychiatry and doctoral clinical fellow at King’s College London, wanted to investigate the condition on a much larger scale. “HPPD is recognized to affect some people who use psychedelics, and is infrequently reported as a side effect in medical trials of psychedelics,” Butler said. “It can be a debilitating disorder, although the factors that lead to it developing are not completely understood, and previous research has tended to be in small samples.”
Butler noted that patients often struggle to find understanding within the medical community. “People with HPPD are sometimes caught between dismissal that it is ‘all in their head’, and lingering stigma about the disease being caused by irreversible psychedelic-induced brain damage,” he said. “We wanted to use a very large clinical dataset to help us understand the clinical associations of HPPD, which may lead to further hypothesis about how and why it arises.”
Current thinking suggests the condition might relate to a subtle over-activation of the visual processing system. The condition seems to share overlapping characteristics with visual snow syndrome. Visual snow syndrome is a neurological condition where people constantly see tiny, flickering dots in their field of vision, similar to static on an old television set.
To conduct the study, the researchers accessed the TriNetX database. This is a global network of electronic health records containing de-identified medical data from over 150 million patients. By analyzing these medical records, the researchers could look back in time to compare different groups of patients.
The authors identified a specific sample of 25,778 individuals who had been formally diagnosed with hallucinogen persisting perceptual disorder. “We were pleasantly surprised by the numbers we were able to pull out from the clinical database,” Butler said. “At over 25,000 cases, this is the largest study on HPPD by some distance, and suggests, although relatively rare, that HPPD should not be dismissed as a fringe clinical interest.”
To provide proper context, the researchers created three separate control groups for comparison. The first control group consisted of individuals from the general population who had attended routine medical check-ups. The second control group was made up of people who had used psychedelic drugs but did not develop persistent perceptual issues. The third control group included individuals diagnosed with general visual disturbances, serving as a proxy for people with conditions like visual snow syndrome.
The researchers compared the medical histories of these groups using advanced statistical models. They used propensity score matching to ensure the groups were mathematically similar in age, sex, and other basic demographics. They calculated the cumulative incidence of various psychiatric and medical disorders before the patients received their primary diagnosis.
The medical records revealed high rates of pre-existing health conditions in the group with hallucinogen persisting perceptual disorder. Before receiving their diagnosis, 29.2 percent of these individuals had experienced depressive episodes, and 26.2 percent had been diagnosed with anxiety disorders. The researchers also found that 15.9 percent had chronic pain, 14.7 percent suffered from headache syndromes, and 12.3 percent had post-viral fatigue.
Additionally, 6.6 percent of the group had been diagnosed with attention-deficit/hyperactivity disorder, and 6.7 percent had fibromyalgia, a disorder characterized by widespread musculoskeletal pain. When compared to the control group of people who used psychedelics without developing persistent visual issues, the group with the visual disorder had significantly higher rates of anxiety and functional somatic syndromes. Functional somatic syndromes are physical illnesses where patients experience chronic symptoms, like pain or fatigue, that cannot be entirely explained by a standard medical test or structural damage in the body.
“This is the largest study on HPPD to date, and we found that there was a strong association between HPPD and psychiatric disorders (particularly anxiety) and what we term functional and somatic disorders,” Butler said. “This suggests a burden of symptom complexity in a patient group who may have high-level treatment needs.”
Butler explained that this connection provides insight into the nature of the condition. “The association with anxiety and functional disorders, which arise due to alterations in how the brain processes information, rather than from identifiable structural damage, may give clues to the underlying disease process in HPPD,” he said. “This requires further research to confirm, but the findings are consistent with models of illness in which symptoms may be reversible, offering reasons for optimism regarding treatment and recovery.”
Butler added that recognizing this connection could lead to real benefits for patients. “Further developments of targeted interventions may benefit this oft-neglected patient group,” he said.
The researchers also wanted to know if certain pre-existing conditions predicted the development of hallucinogen persisting perceptual disorder among psychedelic users. To do this, they used a statistical technique known as a Cox proportional hazards model. They found that psychedelic users with a prior history of anxiety were 1.5 times more likely to develop the visual disorder.
Those with a prior diagnosis of post-viral fatigue were 1.9 times more likely to develop persistent visual symptoms. Looking at the period after the diagnosis was made, the scientists found that people with the visual disorder faced increased health risks. Compared to psychedelic-using controls, they were twice as likely to develop new functional somatic syndromes.
The affected group was also 1.4 times more likely to be diagnosed with new psychiatric disorders. The researchers created exploratory composite outcomes to group together similar illnesses. They noticed a slightly elevated risk for neurodegenerative disorders, such as Parkinson’s disease, in the group with the visual disorder compared to the general population controls.
The absolute risk for developing a neurodegenerative disorder remained very small, affecting only about 2.3 percent of the sample. The researchers noted that this slight increase might be explained by the higher rates of antipsychotic medications prescribed to this patient group. Antipsychotic drugs are known to sometimes cause side effects that mimic Parkinson’s disease.
The group with persistent visual symptoms also had higher odds of developing degenerative visual conditions like glaucoma compared to psychedelic users. They did not have higher odds of these eye conditions when compared to the general population controls.
The authors noted several limitations in their approach that require context. “Many of the associations we identified were substantial,” Butler said. “Nevertheless, this is an associative study, so while we can be relatively confident in the findings given the large sample, we cannot draw any conclusions on causation.”
Because the study relied on electronic health records, it was dependent on the accuracy of clinical coding by healthcare professionals. The database also tends to overrepresent individuals with complex medical needs who frequently visit doctors. “Related to this, the suggestions we make about the underlying causes of HPPD are inferential, and would certainly require confirmation through future research which more directly addresses these hypotheses,” Butler said.
The medical billing codes used to identify psychedelic use lack specific details. The researchers could not determine the exact type of drug used, the dosage, or whether the substances were taken in a recreational or clinical setting. The broad diagnostic codes also prevented the scientists from distinguishing between the brief, transient subtype of the disorder and the chronic, constant subtype.
One potential misinterpretation of these findings is the assumption that hallucinogen persisting perceptual disorder is an imaginary illness. “The equation of HPPD to psychiatric and functional disorders does not in any way mean we are suggesting that HPPD is ‘all in the mind’,” Butler said. “Like all functional disorders, it is real, can be debilitating, and a lack of understanding can lead to some patients being alienated.”
Butler emphasized the physical reality of the condition. “Functional disorders produce symptoms in different ways to other illnesses, but they are just as important to understand and treat,” he said. “And, to reiterate, our findings established associations, not causes.”
Future research should explore the overlapping mechanisms that link persistent visual disorders, anxiety, and somatic symptoms. “An important question might be whether the same factors associated with HPPD in this study can predict who develops symptoms after psychedelic exposure: in other words, what might the risk factors for developing HPPD be?” Butler said. “To answer this question, we need prospective, longitudinal studies.”
A better understanding of how the brain’s attention networks contribute to symptom maintenance could lead to novel therapies. “As we have also seen, future research which more directly looks into the question of the underlying biopsychosocial causes of HPPD would also be hugely beneficial,” Butler said. “As well as this, we would hope one day to be part of efforts to develop novel treatment for HPPD, which may incorporate interventions designed to correct the processing errors which may underlie HPPD.”
The study, “Characterising the clinical associations of hallucinogen persisting perceptual disorder: a retrospective cohort study,” was authored by Matt Butler, Ellen Moore, James J. Rucker, Katharine Lynch-Kelly, Danish Hafeez, Ed Prideaux, Timothy R. Nicholson, Mark Edwards, and Thomas A. Pollak.
