Adverse events in clinical treatments with serotonergic psychedelics a

Clinical research with psychedelics has provided promising positive results for various mental disorders (Andersen et al., 2020; Bahji et al., 2020; Dos Santos et al., 2018; Vargas et al., 2020). However, sample sizes were generally small and rather selective. With the first phase III randomized clinical trials (RCTs) nearing completion (Mitchell et al., 2021) and many trials currently investigating novel applications (Siegel et al., 2021), some compounds seem close to registration.

The use of psychedelics, particularly in uncontrolled circumstances, is associated with acute adverse events (AEs) such as anxiety, panic, dysphoria, paranoia, and/or dangerous behaviors (Barrett et al., 2016; Johnson et al., 2008); such events may contribute to enduring psychological problems (Carbonaro et al., 2016). Although adverse outcomes were mostly described after non-medical psychedelic use, and safety and tolerability have been demonstrated in small clinical trials (Andersen et al., 2020; Dos Santos et al., 2018; Rucker et al., 2018), administration in larger, more heterogeneous patient populations with higher levels of comorbidity may lead to unexpected negative effects. Moreover, adverse drug reactions may lead to non-adherence and discontinuation of treatment (Carvalho et al., 2016), and unresolved and non-integrated difficult experiences may lead to persisting negative outcomes (Grof, 2001; Johnson et al., 2008). It is therefore important to identify the full range of adverse reactions to psychedelic drugs, particularly in vulnerable patients with treatment-resistant mental disorders. The literature on this topic has not been systematically described since 1984 (Strassman, 1984). A 1960 review, based on questionnaires distributed among clinicians representing some 5000 patients (mostly treated with lysergic acid diethylamide (LSD)), concluded that AEs were rare, with some exceptions, mostly in patients with schizophrenia, and that these drugs were generally safe when administered with care (Cohen, 1960). A 1984 review of adverse reactions to psychedelics in different settings found that AEs existed on a continuum; from acute, time-limited panic reactions during administration, through transient psychoses lasting several days, to recurrent flashbacks and chronic undifferentiated psychotic and treatment-resistant cases (Strassman, 1984). Flashbacks were later included in the diagnostic category “hallucinogen persisting perception disorder” (HPPD, which appears in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) but not in the International Statistical Classification of Diseases and Related Health Problems (ICD-10); HPPD is reported occasionally, mostly in the context of frequent non-medical use of serotonergic psychedelics or 3,4-methyenedioxymethamphetamine (MDMA), and may be related with pre-existing psychiatric conditions (Halpern and Pope, 2002; Halpern et al., 2018; Litjens et al., 2014); flashbacks seem to be mostly perceived as mild and neutral to pleasant (Müller et al., 2022). A recent non-systematic, narrative review explored the evidence base for the most frequently mentioned AEs in public discourse, to elucidate which of these harms are based largely on anecdotes versus those that stand up to current scientific scrutiny (Schlag et al., 2022).

Assessing AEs is challenging for multiple reasons; AEs are not always pre-specified, the range of potential reactions can be broad, reporting can be erratic, and terminology is often inconsistent (Golder et al., 2016, 2019) and includes side effects, toxic effects, adverse effects, treatment-emergent AEs (TEAEs), adverse drug reactions, complications and harms, all of which are used interchangeably (Peryer et al., 2021). This is further complicated by the highly variable and context-dependent subjective effects elicited by psychedelics (Breeksema et al., 2020; Carbonaro et al., 2016).

As more patients with mental disorders will probably be treated with psychedelics in the near future, a complete overview of both therapeutic benefits and AEs is needed for balanced benefit-risk assessments and decisions, and for understanding which patients are most likely (not) to profit (Loke et al., 2007). The current paper aims to systematically review any AEs occurring during or after psychedelic treatments with classic/serotonergic hallucinogens (psilocybin, LSD, ayahuasca) and entactogens (MDMA) in patients. Despite relevant pharmacological distinctions, both MDMA and serotonergic hallucinogens are often classified as “psychedelics” and administered under similar therapeutic conditions (Garcia-Romeu et al., 2016; Reiff et al., 2020). AEs of the atypical psychedelics ketamine (Short et al., 2018; Van Amsterdam and Van Den Brink, 2021) and ibogaine (Ona et al., 2022) have recently been reviewed elsewhere.