Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants, Felix Müller et al., 2022

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

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

Psychopharmacology, 2022, 1-11.

doi : 10.1007/s00213-022-06066-z



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 crossover 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 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.

Keywords : LSD · Hallucinogens · Psychedelics · Psilocybin · Flashbacks · Hallucinogen-persisting perception disorder · HPPD



In recent years, several studies have investigated effects of LSD and psilocybin in healthy participants (e.g. Griffiths et al. 2006; Schmid et al. 2015) and patients (e.g. Davis et al. 2020; Gasser et al. 2015). These substances are generally regarded as physically well tolerated and non-addictive (Abraham et al. 1996; Johnson et al. 2008; Nichols 2016; Passie et al. 2008). The most important side effects psychosis (Nichols 2016; Passie et al. 2008).

According to the International Classification of Diseases (ICD-10, F16.7, WHO 2010), flashbacks are defined as episodic recurrences of drug effects after the acute pharmacological effects have subsided and are characterized as mostly very transient.

In clinical settings, recurrent drug effects after intake of hallucinogens have been reported in a study on the use of LSD in psychiatric treatments as early as the 1950s (Sandison et al. 1954). Although these phenomena are therefore known for decades, they are still poorly described with little consensus on their cause (Halpern and Pope 2003; Hermle et al. 2008, 2015; Holland and Passie 2011; Lerner et al. 2014b; Martinotti et al. 2018). Reported incidences vary widely, with estimates between 15 and 75% of all users being affected (e.g. Hermle et al. 2015; Stanton and Bardoni 1972). Most cases were reported after the use of LSD (Halpern and Pope 2003; Lerner et al. 2014b), but flashbacks were also seen after the use of MDMA (Vizeli and Liechti 2017) as well as cannabis (Lerner et al. 2011), amphetamines, tobacco, and alcohol (Lerner et al. 2014b) and rarely after psilocybin (Hermle et al. 2015). Most commonly reported symptoms are changes in vision, a great variety of which have been reported, i.e. afterimages, geometrical patterns, and intensified perception of colours (Abraham and David Abraham 1983; Hermle et al. 2008; Lerner et al. 2014b). Other phenomena comprise changes in mood/affect and derealization/depersonalization (Lerner et al. 2014b). Reports of new symptoms—which were not initially experienced during the acute drug effects—exist, but seem to be rare (Lerner et al. 2014a). Awareness of the illusory nature of the phenomenon is usually present (Hermle et al. 2008; Lerner et al. 2014b).

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V, American Psychiatric Association 2013), persisting flashback phenomena which cause clinically significant distress or impairment can be classified as hallucinogenic persisting perception disorder (HPPD, DSM-V, 292.89). Another classification differentiates between type 1 and type 2 HPPD (Halpern et al. 2018). Type 1 HPPD is consistent with the ICD-10 definition and is characterized by transient recurrences of alterations in perception, mood, or consciousness as experienced during the acute drug effects. These alterations might be perceived as pleasant. In contrast with this, type 2 HPPD is characterized by visual phenomena which are constantly or almost constantly present. These symptoms are mostly experienced as distressing and often accompanied by depersonalization, derealization, anxiety, or depression.

Available descriptions of HPPD stem mostly from case reports of hallucinogen users seeking medical help because of significant distress and impairment of daily life due to the persisting perception changes (Halpern and Pope 2003; Lerner et al. 2014b). In most presented cases, the exact circumstances, involved substances, and dosages are unknown or rely on patient memory (Halpern and Pope 2003; Martinotti et al. 2018; Orsolini et al. 2017). Courses seem to vary widely with onsets from hours to years after drug use, episodes that last from seconds to years, and severity ranging from mild to severe and debilitating (Abraham et al. 1996; Lerner et al. 2014b; Martinotti et al. 2018). Pre-existing psychiatric conditions such as major depression, bipolar disorder, schizophrenia spectrum disorders, polysubstance use (Halpern and Pope 2003; Lerner et al. 2014b; Martinotti et al. 2018) or tinnitus, and migraine (Puledda et al. 2020) are proposed risk factors. However, the condition can arise in healthy individuals after a single hallucinogen use (Abraham et al. 1996; Martinotti et al. 2018). Reported incidences vary widely. A systematic review of the literature concluded that HPPD seems to be rare but that an estimate of the incidence is not possible due to insufficient data (Halpern and Pope 2003). In contrast, the DSM-V reports a prevalence of 4.2% among users of hallucinogens.