Predicting long-term psychedelic side-effects
Schizotypal traits may not be caused by taking LSD or magic mushrooms
PNAS Nexus
Psychedelic drugs are seeing a surge of interest from mainstream medicine, and initial results suggest that psychedelic-therapy can be a safe and effective treatment for some mental health conditions. However, the side-effect profile is still incompletely understood. In particular, the use of psychedelics has been posited to carry a risk of triggering latent psychotic disorders or persistent visual hallucination, known as Hallucinogen Persisting Perception Disorder (HPPD). In order to better understand the prevalence and risk factors of such side-effects, Katie Zhou and colleagues surveyed 654 people online who were planning to take psychedelics through their own initiative. Of those, 315 people were resurveyed two weeks after their experience and 212 people were resurveyed again four weeks after their experience. The sample was 74% male, and 77% university educated. About one third had been diagnosed with at least one psychiatric condition. The authors found a weak correlation between lifetime psychedelic use and both delusional ideation and magical thinking. However, on average, delusional ideation was slightly reduced one month after psychedelic use. These results suggest that schizotypal traits may not be caused by taking LSD or magic mushrooms, in keeping with the principle that correlation does not imply causation. About a third of individuals surveyed at the four-week mark did have some lingering hallucinatory sensory experiences, such as intensified colors and afterimages. However, the majority of those who experienced this did not report being distressed by it. The strongest predictors of persistent visual aftereffects were the personality trait absorption—the tendency to be easily immersed in sensory or imaginative experiences—and younger age. This corroborates previous findings showing that young people and adolescents may be at a particular risk of HPPD. According to the authors, empirical scrutiny of the potential risks of psychedelics should accompany changes in policy and access to psychedelic drugs.
Journal
PNAS Nexus
Article Title
Prediction of hallucinogen persisting perception disorder and thought disturbance symptoms following psychedelic use
Article Publication Date
22-Apr-2025
Single-dose psychedelic boosts brain flexibility for weeks, peer-reviewed study finds
Groundbreaking research reveals potential for psychedelic compounds to enhance cognitive agility in neuropsychiatric treatment
Genomic Press
image:
Figure 1. Experimental timeline and overview. (A) Experimental timeline. (B) Schematic of the SEQFR2-forward protocol. Mice have to sequentially poke left and then right within 30 s to earn a reward pellet. (C) Schematic of the SEQFR2-reversal protocol. Mice now are required to poke right and then left within 30 s to get a reward pellet.
view moreCredit: Dr. Omar J Ahmed
ANN ARBOR, Michigan, USA, 22 April 2025 – In a groundbreaking research study, University of Michigan researchers have discovered that a single dose of a psychedelic compound can enhance cognitive flexibility—the brain's ability to adapt to changing circumstances—for weeks after administration, potentially revolutionizing treatments for depression, PTSD, and neurodegenerative diseases.
The study, published today in the journal Psychedelics, demonstrates that mice treated with a single dose of 25CN-NBOH, a selective serotonin 2A receptor agonist, showed markedly improved performance in reversal learning tasks compared to control groups when tested 2-3 weeks after treatment.
Key Findings
"What makes this discovery particularly significant is the sustained duration of cognitive benefits following just one psychedelic dose," explains Professor Omar J. Ahmed, the study's senior, corresponding author from the University of Michigan's Department of Psychology. "We observed enhanced learning adaptability that persisted for weeks, suggesting these compounds may induce lasting and behaviorally meaningful neuroplasticity changes in the prefrontal cortex."
Using an innovative automated sequential learning paradigm, researchers measured how effectively mice could adapt to rule reversals—a standard test for cognitive flexibility. The psychedelic-treated mice demonstrated superior adaptability compared to saline controls, with enhanced task efficiency, higher percentages of correct trials, and increased reward acquisition during the reversal phase.
Implications for Brain Science
The results complement existing cellular research showing psychedelic-induced structural remodeling in the prefrontal cortex but uniquely demonstrate sustained cognitive benefits persisting long after the immediate effects of the drug have dissipated.
As interest in psychedelic medicine continues to grow, this research raises intriguing questions about how psychedelics might reshape neural pathways governing flexible thinking. Could these compounds potentially reopen critical periods of brain plasticity? What molecular mechanisms underlie these long-lasting cognitive improvements? How might the timing and frequency of administration affect long-term neuroplasticity?
“The current study focused on the long-term effects of a single psychedelic dose. A key question is what happens with two, three, or even twenty doses taken over several months. Is every additional dose increasingly beneficial for flexible learning or is there a plateau effect or even a negative effect of too many doses? These are important questions to answer next in the quest to make psychedelic medicine more rational and mechanistic,” according to Dr. Ahmed.
Sex Differences and Clinical Potential
Importantly, the study found that both male and female mice showed significant improvements in cognitive flexibility, suggesting the potential broad applicability of psychedelic therapy across biological sexes.
"The most striking aspect of our findings is that these cognitive benefits were measured 15-20 days after a single psychedelic administration," notes Elizabeth J. Brouns, first author of the study. "This suggests that a single dose of a psychedelic isn't just temporarily altering perception, but potentially inducing lasting beneficial changes in brain function."
Methodological Advances
The study's automated behavioral task represents a significant methodological advance for evaluating flexible learning, enabling researchers to efficiently evaluate cognitive flexibility in future investigations of psychedelic compounds. This high-throughput approach could accelerate the development of targeted psychedelic therapies for specific cognitive deficits.
The full Psychedelics peer-reviewed research article, titled “Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration” is available on 22 April 2025 in Psychedelics. The research includes Dr. Tyler Ekins as a co-author and was supported by the National Institutes of Health and the University of Michigan Eisenberg Family Depression Center. The article is freely available online at https://doi.org/10.61373/pp025r.0002.
About the Journal
Psychedelics: The Journal of Psychedelic and Psychoactive Drug Research (ISSN: 2997-2671) is a peer-reviewed medical research journal published by Genomic Press, New York. Psychedelics is dedicated to advancing knowledge across the full spectrum of consciousness altering substances, from classical psychedelics to stimulants, cannabinoids, entactogens, dissociatives, plant derived compounds, and novel compounds including drug discovery approaches. Our multidisciplinary approach encompasses molecular mechanisms, therapeutic applications, neuroscientific discoveries, and sociocultural analyses. We welcome diverse methodologies and perspectives from fundamental pharmacology and clinical studies to psychological investigations and societal-historical contexts that enhance our understanding of how these substances interact with human biology, psychology, and society.
Caption
Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration
Credit
Dr. Omar J Ahmed
Journal
Psychedelics
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration
Article Publication Date
22-Apr-2025
COI Statement
The authors declare no competing financial interest.
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