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Background: Despite an increasing body of research highlighting their efficacy to treat a broad range of medical conditions, psychedelic drugs remain a controversial issue among the public and politicians, tainted by previous stigmatisation and perceptions of risk and danger. Objective: This narrative review examines the evidence for potential harms of the classic psychedelics by separating anecdotes and misinformation from systematic research. Methods: Taking a high-level perspective, we address both psychological and psychiatric risks, such as abuse liability and potential for dependence, as well as medical harms, including toxicity and overdose. We explore the evidence base for these adverse effects to elucidate which of these harms are based largely on anecdotes versus those that stand up to current scientific scrutiny. Results: Our review shows that medical risks are often minimal, and that many – albeit not all – of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context. Conclusions: This highlights the importance for clinicians and therapists to keep to the highest safety and ethical standards. It is imperative not to be overzealous and to ensure balanced media reporting to avoid future controversies, so that much needed research can continue.

Psychedelic drugs are increasingly being incorporated into therapeutic contexts for the purposes of promoting mental health. However, they can also induce adverse reactions in some individuals, and it is difficult to predict before treatment who is likely to experience positive or adverse acute effects. Although consideration of setting and dosage as well as excluding individuals with psychotic predispositions has thus far led to a high degree of safety, it is imperative that researchers develop a more nuanced understanding of how to predict individual reactions. To this end, the current systematic review coalesced the results of 14 studies that included baseline states or traits predictive of the acute effects of psychedelics. Individuals high in the traits of absorption, openness, and acceptance as well as a state of surrender were more likely to have positive and mystical-type experiences, whereas those low in openness and surrender or in preoccupied, apprehensive, or confused psychological states were more likely to experience acute adverse reactions. Participant sex was not a robust predictor of drug effects, but 5-HT2AR binding potential, executive network node diversity, and rACC volume may be potential baseline biomarkers related to acute reactions. Finally, increased age and experience with psychedelics were individual differences related to generally less intense effects, indicating that users may become slightly less sensitive to the effects of the drugs after repeated usage. Although future well-powered, placebo-controlled trials directly comparing the relative importance of these predictors is needed, this review synthesizes the field's current understanding of how to predict acute reactions to psychedelic drugs.

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