Psychedelic Journal Club: The Risk of Flashbacks

A commentary on the article “Flashback phenomena after administration of LSD and psilocybin  in controlled studies with healthy participants,” by Felix Müller et al., published in Psychopharmacology.

Following psychedelics’ explosive popularity during the 1960s and 1970s, a political and cultural backlash suppressed scientific research into their beneficial uses and harmful effects alike. The subsequent era’s ebbing of knowledge and inquiry fostered misinformation, and pervasive rumors about psychedelics took hold in mainstream thought, becoming entrenched myths (Presti & Beck, 2001). Some of these myths have been debunked, such as the claim that LSD is frequently adulterated with toxic substances like strychnine (Brown & Malone, 1976), or that LSD damages chromosomes and causes birth defects (Dishotsky, Loughman, Mogar, & Lipscomb, 1971), and today we recognize that many psychedelics are among the most physiologically safe drugs known.

“Another myth is that psychedelics reliably cause lasting negative psychological effects or permanent brain damage.”

Another myth is that psychedelics reliably cause lasting negative psychological effects or permanent brain damage. Dire warnings such as “if you take LSD seven times, you become legally insane” proliferated during the era of psychedelic suppression (Presti & Beck, 2001) and nowadays are recognized as misinformation. Studies suggest that dosage and frequency of use of classical psychedelics like LSD and psilocybin are not necessarily linked to adverse outcomes (Nichols, 2016). However, in some cases, psychedelics can cause perceptual effects that outlive the drugs’ acute action.

“Flashbacks” are commonly feared aftereffects of psychedelic use. The stereotypical flashback experience is described as a temporary reversion to a state of mind experienced during psychedelic use, including mood alterations, perceptual distortions, and even hallucinations, long after the drug should be out of one’s system. Fears of flashbacks are exaggerated, and rumors and misperceptions are easily propagated in an environment of suppressed information. But in rare cases, recurring perceptual distortions and illusions follow psychedelic use. In the current Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013), the standard diagnostic reference manual for psychiatry, the experience of flashback-type effects is categorized as Hallucinogen Persisting Perception Disorder, or HPPD for short. HPPD is characterized as a distressing, temporary or chronic persistence of altered perceptual experiences after the acute effects of a psychedelic (a.k.a. hallucinogen) have worn off.

Despite the official status of HPPD as a diagnosable psychiatric disorder, little is known about the condition. There have been anecdotal reports and case studies, but its prevalence is largely unknown. There has been little research into its etiology, and there is no consensus about why using psychedelics would lead to lasting perceptual changes (Halpern, Lerner, & Passie, 2018). Moreover, anecdotal reports and survey studies suggest that the diagnostic criteria laid out in the DSM-5 do not capture the full range of psychedelic aftereffects. For example, the DSM-5 emphasizes visual perceptual distortions, whereas distortions in other sensory domains have been reported (Vis, Goudriaan, ter Meulen, & Blom, 2021).

A recent study by Felix Müller and colleagues examined the documented adverse events of six different psychedelic clinical trials to assess the prevalence of HPPD in psychedelic users (Müller et al., 2022). In each study, adverse events, including the occurrence of flashback effects, were recorded after each drug session and at end-of-study visits. If flashbacks occurred, participants were asked to describe their quality, quantity, and degree of interference with daily life. Further, participants who did report flashbacks during the study were surveyed again approximately 30 months after their end-of-study visit to determine the long-term recurrence rates of perceptual distortions. Altogether, the researchers analyzed reports from 142 human subjects who had participated in studies of double-blind, placebo-controlled administration of LSD or psilocybin. In the pooled dataset, 90 participants received LSD at either 0.1 or 0.2 mg doses, 24 received psilocybin at either 15, 25, or 30 mg doses, and 28 received both drugs.

Researchers found that 7.8% of subjects experienced some degree of flashback effects after LSD, 8.3% after psilocybin, and 14.3% after both. Most flashbacks were limited to the week following drug administration. In 53.8% of people who reported flashbacks, the effects only occurred once. One participant reported approximately 30 visual flashback experiences within a 7-month period following drug administration but was the only participant in the dataset who reported flashbacks recurring between their end-of-study visit and the follow-up interview. None of the flashback reports reached the diagnostic criteria for HPPD. Surprisingly, in 76.9% of cases, subjects reported their flashbacks as neutral or positive.

The work by Müller and co-authors adds to the evidence that flashback experiences can happen, but rarely (Halpern et al., 2018). A more comprehensive understanding of flashbacks and HPPD, including their etiology and associated risk factors, is needed. Psychedelics are being studied as potential treatments for a range of psychiatric conditions (Lieberman, 2021) and are increasingly available to the public. Before psychedelics become widely available, any associated risks should be well studied and characterized to minimize the chances of another cultural backlash against psychedelics, echoing the repressive policies of the 1970s.

“Psychedelics are being studied as potential treatments for a range of psychiatric conditions and are increasingly available to the public.”

Recent research into developing “non-hallucinogenic psychedelics” hints at new drug therapies that may capture some of psychedelics’ beneficial effects without inducing intense or unpleasant perceptual distortions (Cameron et al., 2021; Cao et al., 2022). These new therapies have only been tested in animal models so far but seem likely to advance to human trials.

A clearer understanding of the risks of HPPD associated with classical psychedelic use will aid in evaluating these novel psychedelic-derived drugs. If, for example, the risk of HPPD is linked to the acute perceptual effects of any given psychedelic, then a novel drug that induces beneficial long-term brain changes without causing hallucinations or perceptual distortions might be preferable to a classical psychedelic. On the other hand, HPPD symptoms may be rooted not in the subjective psychedelic experience but instead in the longer-term brain changes that novel non-hallucinogenic psychedelics are designed to induce. In that case, the expected benefits of this new class of drug may be tempered by the risk of developing a chronic perceptual disorder.

Further research is necessary to clarify the potential for harm. Otherwise, we run the risk that today’s resurgence of psychedelic research and its transformative potential will be struck down by cultural backlash once again, like a flashback reliving of a dark time in scientific history.

Link to Article

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Written by Sean Noah
Illustrated by Sean Noah
Edited by Lauren Wagner and Chris Gabriel

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References

1. American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders (5th ed.). Arlington, VA.
2. Brown, J. K., & Malone, M. H. (1976). Status of drug quality in the street-drug market—an update. Clin Toxicol, 9(2), 145-168.
3. Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., et al. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474-479.
4. Cao, D., Yu, J., Wang, H., Luo, Z., Liu, X., He, L., et al. (2022). Structure-based discovery of nonhallucinogenic psychedelic analogs. Science, 375(6579), 403-411.
5. Dishotsky, N. I., Loughman, W. D., Mogar, R. E., & Lipscomb, W. R. (1971). LSD and Genetic Damage. Science, 172(3982), 431-440.
6. Halpern, J. H., Lerner, A. G., & Passie, T. (2018). A Review of Hallucinogen Persisting Perception Disorder (HPPD) and an Exploratory Study of Subjects Claiming Symptoms of HPPD. Curr Top Behav Neurosci, 36, 333-360.
7. Lieberman, J. A. (2021). Back to the Future — The Therapeutic Potential of Psychedelic Drugs. New England Journal of Medicine, 384(15), 1460-1461.
8. Müller, F., Kraus, E., Holze, F., Becker, A., Ley, L., Schmid, Y., et al. (2022). Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants. Psychopharmacology.
9. Presti, D., & Beck, J. (2001). Strychnine and other enduring myths: Expert and user folklore surrounding LSD. Psychoactive sacramentals: Essays on entheogens and religion, 125-135.
10. Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264-355.
11. Vis, P. J., Goudriaan, A. E., ter Meulen, B. C., & Blom, J. D. (2021). On Perception and Consciousness in HPPD: A Systematic Review. Frontiers in Neuroscience, 15.

Sean Noah

Sean is a postdoctoral researcher at the UC Berkeley Center for the Science of Psychedelics. He studies the link between how psychedelics change neural activity in visual cortex and their effects on visual perception. He received his PhD from UC Davis, where he studied the neural mechanisms of visual attention.