Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants

This study analysed data from participants (n=142) in clinical trials who had received LSD and psilocybin to assess the prevalence of recurring drug-like experiences after administration of these substances. 13 participants (9%) reported recurring drug-like experiences (LSD: 7, psilocybin: 2, both: 4) which were considered mild and perceived as neutral to pleasant. No reports met the criteria for hallucinogen-persisting perception disorder (HPPD).

Abstract

“Background: LSD and psilocybin are increasingly used in phase I trials and evaluated as therapeutic agents for mental disorders. The phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off was described for both substances and especially attributed to LSD. According to the DSM-V, the persisting and distressing manifestation of these experiences is called hallucinogen-persisting perception disorder (HPPD). Data on both conditions is very limited.

Objective: This study aims to provide descriptive data on reoccurring drug-like experiences after the administration of LSD and psilocybin in controlled studies with healthy participants.

Methods and materials: Data from 142 healthy subjects enrolled in six double-blinded, placebo-controlled, randomized cross-over studies were analyzed. In total, 60 subjects received LSD; 27 subjects received LSD, MDMA, and D-amphetamine; 31 subjects received LSD and psilocybin, and 25 subjects received psilocybin and escitalopram. At the end-of-study visit (mean 39.8 days after the last study session, SD 37.2), subjects were asked for any reoccurring drug effects since the initial substance effects had worn off. Those reporting reoccurring perception changes more than 24 h after administration were contacted for follow-up (mean follow-up duration: 31.2 months, SD 28.6).

Results: Thirteen out of 142 subjects reported reoccurring drug-like experiences (LSD: seven, psilocybin: two, both: four). The reported phenomena were predominantly mild and perceived as neutral to pleasant. Flashbacks were mostly of visual nature, lasted for seconds to minutes, and occurred within a week after the last drug administration. Two subjects reported distressing experiences that subsided spontaneously. One subject reported brief and pleasant visual perception changes which reoccurred for 7 months. None of the subjects reported impairment in their daily lives. None of the cases met DSM-V criteria for HPPD.

Conclusion: Reoccurring drug-like experiences after the administration of LSD and psilocybin are a common phenomenon occurring in up to 9.2% of healthy subjects (7.8% for LSD, 8.3% for psilocybin and 14.3% if both substances are administered). Additionally, our work suggests that flashback phenomena are not a clinically relevant problem in controlled studies with healthy participants.”

Authors: Felix Müller, Elias Kraus, Friederike Holze, Anna Becker, Laura Ley, Yasmin Schmid, Patrick Vizeli, Matthias E. Liechti & Stefan Borgwardt

Notes

Reports of drug-induced flashbacks date back to the first era of psychedelic research in the 1950s and 1960s. At the time, research participants reported the reoccurrence of a psychedelic-like state long after the drug’s effects should have worn off. The risk of flashbacks quickly became commonplace in anti-drug campaigns. Now, as psychedelic research has progressed over the last 50 or so years, we have come to regard psychedelics as physically well-tolerated and non-addictive. However, we now know more about the side effects that accompany psychedelics and that people can experience flashbacks as a result of using psychedelics.

According to the World Health Organization, flashbacks are defined as episodic recurrences of drug effects after the acute pharmacological effects have subsided and are characterized as mostly very transient. Moreover, persisting flashbacks that cause clinically significant distress or impairment have been termed hallucinogen persisting perception disorder (HPPD). Despite the recent resurgence in clinical research with psychedelics, data regarding reoccurring drug-like experiences and HPPD remains limited. If psychedelics are to become widely available treatment options, it is important that we unearth the nature of all possible side effects.

The present study aimed to provide data on the prevalence of reoccurring drug-like experiences in modern clinical research with LSD and psilocybin. Data from six double-blind, randomized, controlled trials were analyzed yielding a total of 142 healthy participants who had received LSD (n=60), LSD, MDMA and d-amphetamine (n=27), LSD and psilocybin (n=31) as well as psilocybin and escitalopram (n=25). All participants were asked at the end-of-study visit, on average of 40 days from their last study session, if they had experienced any recurring drug effects since beginning the trial.

Looking back:

• 13 participants reported recurring drug-like experiences (LSD: seven, psilocybin: two, both: four) which were considered mild and perceived as neutral to pleasant.
• The occurrence of flashbacks was limited to the week after drug administration, except for two cases.
• 1.4% of all 142 participants reported distressing experiences related to flashbacks.
• No subjects reported impairment to daily life as a result of these symptoms.
• No reports met the criteria for HPPD.

The present study is one of the first to thoroughly analyse modern clinical research with psychedelics to assess the prevalence of recurring drug-like experiences and HPPD. The results show that these phenomena are relatively common in clinical trials with healthy participants although they tend to be experienced as benign, having little impact on daily life.

The authors do acknowledge limitations to their work including the relatively small sample size as well as the different screening criteria, dosing regimens and substances administered across the studies. Nonetheless, the findings suggest that flashbacks are not a clinically relevant problem in controlled studies with healthy participants.

Summary

LSD and psilocybin are increasingly used in phase I trials as therapeutic agents for mental disorders. However, the phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off has been described for both substances.

Introduction

Several studies have investigated effects of LSD and psilocybin in healthy participants and patients. The most important side effects are mental alterations, namely induction of flashbacks or psychosis.

Recurrent drug effects after intake of hallucinogens have been reported in clinical settings as early as the 1950s, but are still poorly described with little consensus on their cause. Most commonly reported symptoms are changes in vision, but also mood/affect and derealization/depersonalization have been reported.

According to the DSM-V, hallucinogenic persisting perception disorder is characterized by persistent flashback phenomena that cause clinically significant distress or impairment. Type 1 HPPD is characterized by transient recurrences of alterations in perception, mood, or consciousness.

Hallucinogen-induced perception disorders (HPPD) can occur hours to years after drug use, and can last from seconds to years. Pre-existing psychiatric conditions such as major depression, bipolar disorder, schizophrenia spectrum disorders, polysubstance use, and migraine are proposed risk factors.

Current knowledge about flashback phenomena and HPPD in healthy participants is very limited and mostly based on case reports and naturalistic studies. However, given the renewed scientific interest to use hallucinogenic drugs in clinical trials and as potential therapeutic agents, these phenomena should be investigated more carefully.

Studies included in analysis

This analysis is based on pooled data sets of all available clinical trials involving LSD or psilocybin conducted in Basel, Switzerland, as of April 2021.

In six studies, 142 participants received LSD, 24 participants received psilocybin, and 28 participants received both substances. LSD was administered in doses ranging from 0.025 to 0.2 mg, and psilocybin was administered in doses ranging from 15 to 30 mg. LSD was prepared as gelatine capsules or as solution in alcohol and administered orally. Psilocybin was prepared as gelatine capsules and administered orally.

Inclusion and exclusion criteria of studies

Six studies were conducted on healthy volunteers with age ranges between 25 and 65. Inclusion criteria included understanding the German language, willingness to adhere to the protocol, informed consent, refraining from taking illicit psychoactive substances, and using an effective form of birth control.

Data collection

Subjects were asked at each study session to report any adverse events, including flashbacks. At the end of the study, subjects were asked to describe any flashback phenomena.

Follow‑up

Subjects reporting a flashback at their end-of-study visit were contacted in May 2021 to assess the occurrence of further flashbacks or HPPD.

Hallucinogen‑persisting perception disorder

Based on data collection, subjects were evaluated for HPPD at any time point after administration of the study drugs. The probability of observing zero cases was tested for different incidences of HPPD.

Subject characteristics

One hundred forty-six participants were initially enrolled, but 142 subjects were eventually included. Of these, 30.3% had used hallucinogens, 40.1% had used MDMA, and 34.5% had used other stimulants.

Flashback phenomena at end‑of‑study visit

13 subjects reported flashback phenomena of some sort at the end of the study. Seven subjects experienced flashbacks after the administration of LSD, two after the administration of psilocybin, and four after the administration of both substances. Eleven participants reported visual alterations, which were accompanied by other phenomena in three cases (auditory, cognitive, feeling of disintegration). In almost all cases, phenomena lasted for seconds (69.2%) to minutes (23.1%), and in one case (7.7%) persisted for hours.

Flashbacks were experienced as unpleasant in two cases and as neutral or positive in ten cases. None of the subjects reported impairment of daily life due to these symptoms. The subject who experienced flashbacks after administration of 0.2 mg LSD dropped out of the study after this session, while the subject who experienced flashbacks after administration of 25 mg psilocybin described her study session as “pleasant and uncomplicated”. The subject developed symptoms typical of panic attacks after the described event, which were accompanied by several symptoms that could be seen as further flashback phenomena.

Flashback phenomena at follow‑up

The follow-up took place 31.2 months after the end-of-study visit, and 92% of the subjects responded to the follow-up mail.

One subject reported experiencing flashbacks after the end-of-study visit, while all other subjects did not. The flashbacks lasted for seconds and were experienced as benign.

Hallucinogen‑persisting perception disorder

None of the 142 subjects in our sample met DSM-V criteria for HPPD. The probabilities of observing zero cases of HPPD are very low.

Discussion

This work analyzed data from six clinical trials investigating the effects of LSD, psilocybin, MDMA, amphetamine, and escitalopram in healthy participants. It suggests that flashback phenomena are relatively common, affecting approximately 9% of the subjects. Three participants experienced flashbacks, one of which was repeated over a period of several months, and the other two were experienced as distressing. The flashbacks were experienced as benign, did not impair daily life, and resolved spontaneously within a week of drug administration.

Flashback phenomena are more commonly reported after the use of LSD compared to psilocybin, but in our sample the incidence was comparable (7.8% for LSD and 8.3% for psilocybin). However, the incidence of flashback phenomena in our sample was based on a small sample of 24 subjects.

The etiology of flashback phenomena is unknown. It is possible that subjects in studies with psychoactive drugs are more receptive for phenomena which are at the borderline between normal and abnormal experiences, or that flashbacks are involuntary memories shaped by the unusually distinct experience induced by hallucinogenic drugs.

Some of our cases met the ICD-10 definition for flashbacks, but none of our cases met the DSM-V criteria for HPPD. This result is in line with investigations during the 1960s and 1970s, where no cases of HPPD were seen in a sample of several thousand persons who received LSD in clinical settings. There is no consensus with regard to risk factors for HPPD, but some findings suggest that mental disorders, polysubstance use, and number of exposures to the drug may be associated with HPPD.

This work has several limitations, including a small sample size, varying doses and administered substances, a high proportion of participants having used other illicit drugs before enrolment, and a follow-up occurring at different timespans due to different dates of study completion.

Conclusion

Drug-like experiences after the administration of LSD and psilocybin seem to be a relatively common phenomenon in clinical trials with healthy participants. However, these experiences are usually transient, benign and do not impair daily life.