Adverse Events and Psychedelics: Differences Across Substances and Context

SPECIAL REPORT: PSYCHEDELICS

Following the resurgence of psilocybin research around the turn of the millennium, psychedelics have rapidly advanced from an academically marginal subject to a focus of mental health research. Efforts to incorporate psychedelic-assisted psychotherapies into mental health care have been facilitated by their social destigmatization, financial support of scientific research, and the larger context of a relative lack of other innovation in pharmacotherapies for mental disorders.

Broad and Narrow Senses of Psychedelic

The term psychedelic is used variously. Sometimes it is used very broadly to refer to any psychoactive substance that causes intense disruptions in cognition, affect, arousal, and/or perception––including classic psychedelics such as psilocybin, as well as ketamine, 3,4-methylenedioxymethamphetamine (MDMA), ibogaine, and sometimes even cannabis. The narrower sense of the term is used to refer to a set of classic or serotonergic psychedelics that act predominantly as partial agonists of the serotonin 2A receptor; prominent examples include psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Therefore, clarifying whether one is using the broad or narrow sense of the term psychedelic is crucial to any discussion of psychedelic effects, as these different substances can have very different risks and benefits.

There is momentum for clinical trials on psychedelics in the broad sense. The US Food and Drug Administration (FDA) approved intranasal esketamine as an adjunctive treatment for treatment-resistant depression (TRD) in 2019 and, in January 2025, extended approval for its use as monotherapy. Promising results of several phase 2 clinical trials of psilocybin for major depressive disorder have been published, and the first phase 3 study for this indication announced positive findings for the primary end point in June 2025. Clinical trials of classic psychedelics for various other disorders, including substance use disorders, eating disorders, anxiety disorders, and posttraumatic stress disorder (PTSD), are underway. Importantly, in 2024, an FDA Advisory Committee voted against approval of Lykos Therapeutics’ investigational MDMA-assisted therapy for PTSD, citing concerns about safety, data integrity, and functional unblinding, and requested an additional phase 3 trial. Some predict that psilocybin may soon receive approval as a treatment for TRD as Compass Pathways accelerates its commercialization plans for synthetic psilocybin.

There is great public interest in how psychedelics may be used to treat mental illness and improve well-being, as well as in their risks. Unsurprisingly, patients and their families bring questions to clinicians about the risks and benefits of psychedelics. This will only increase in frequency as access to legalized venues for psychedelic experiences expands. Clinicians may do such patients a disservice by being either uncritically supportive or reflexively antagonistic toward psychedelic use. Clinicians should aim to be clear about which specific substances they are discussing, given the ambiguities around the term and the quite different sets of risks and benefits associated with various substances referred to as psychedelic.

Classic or Serotonergic Psychedelics

Following the first wave of psychedelic research that peaked in the 1950s-1960s, baseless fears that psychedelic compounds could cause cancers, heritable teratogenic mutations, and brain damage were inferred from improperly conducted studies, and this misinformation was more widely promulgated than the corrections.¹ Such failures of scientific communication undermine public confidence in institutional research and knowledge. Clinicians who can speak competently about the current state of the scientific data (and its limitations) regarding the adverse effects of psychedelics will be better equipped to engage with interested patients productively.

In research settings, extensive safety procedures are in place. Medical and psychiatric screening occurs before study enrollment. After a lengthy informed consent process, study therapists then build rapport with participants, review and manage expectations regarding the drug experience, and assist in the acute management and subsequent integration of challenging emotional experiences. Current protocols also specify medical and psychological interventions for participants experiencing acute agitation, disorientation, paranoia, psychosis, severe anxiety, nausea, and blood pressure instability. Such contingencies are not available in recreational use contexts, so the following information about adverse events across substances tested in medical research settings should not be uncritically generalized to recreational settings.

The classic or serotonergic psychedelics refer to substances such as psilocybin, LSD, DMT, and 5-MeO-DMT. Psilocybin is currently the most studied and is in phase 3 studies for TRD. High doses of these substances reliably cause intensely altered states of consciousness with diverse but characteristic affective, cognitive, and perceptual qualities during their period of acute subjective effects (approximately 6 hours, 12 hours, and 15 minutes for psilocybin, LSD, and DMT, respectively). They can induce acute subjective effects involving feelings of unity, insight, awe, and tranquility, among others²; however, it is not uncommon for intensely negative, dysphoric, disorienting, or otherwise challenging experiences to also occur during the serotonergic psychedelic experience (or “trip”).³ Changes persisting from days to weeks after the acute effects range from positive effects on well-being and improvement of mood and anxiety disorders to negative effects such as fear, anxiety, perceptual disturbances, depression, and paranoia.⁴ Classic psychedelics have very low addiction potential and minimal physiological toxicity.⁵ There are no confirmed cases of fatal overdose due to their direct pharmacological effects.

LSD was used extensively as a psychotherapeutic aid by private psychiatrists in the 1950s. Some of these practitioners reported rare instances of prolonged psychoses with disorganized behavior, persistent perceptual distortions, and suicidal tendencies in the weeks following LSD treatments. However, it is important to note that such treatment regimens often involved extremely high and extremely frequent doses––dosing paradigms that are not currently used.^6,7

In contemporary studies involving the administration of classic psychedelics such as psilocybin, LSD, DMT, or 5-MeO-DMT in controlled and supportive settings, serious adverse events (ie, those that are potentially life-threatening or cause permanent disability) do occur. A meta-analysis of 214 studies with such safety measures in place reported that 0.3% of study participants with a preexisting psychiatric disorder who were administered psilocybin, LSD, DMT, or 5-MeO-DMT experienced a serious adverse event within 48 hours, and this figure rose to 4% during long-term follow-up.⁸ Delayed-phase serious adverse events during the follow-up periods included suicidal ideation, suicidal behavior, nonsuicidal intentional self-injury, adjustment disorder, and worsening depression. Conversely, no serious adverse events among participants without psychiatric disorders were identified. Participants with psychiatric disorders were also more likely to experience an adverse event within 48 hours of drug administration that warranted some form of medical treatment (2.3% and 0.2% for those with and without psychiatric disorders, respectively). These differences may have multifactorial explanations, but they do raise concern that individuals with any psychiatric disorders are more likely to experience serious complications from psychedelics. Interestingly, persistent perceptual disturbances such as hallucinogen persisting perception disorder, a complication of major concern in the late 20th century, have not been reported by contemporary studies but continue to be reported in recreational settings.

The most commonly reported acute adverse events⁸ included symptoms such as headache, anxiety, nausea, fatigue, and dizziness. Acute serious adverse events in outpatient studies involved one case of acute transient anxiety and delusions for LSD. Inpatient LSD studies in those with severe mental illness also reported acute serious adverse events, such as mania psychosis, in 11 out of 517 (2.1%) participants.

Importantly, however, these meta-analytic results reflect studies with participants meeting strict exclusion criteria encompassing medical comorbidities, substance use disorders, bipolar disorder, schizophrenia-spectrum illness, paranoid or borderline personality disorders, and investigator discretion. Therefore, such findings should not be uncritically assumed to generalize broadly, as the context in which psychedelics are taken matters. The same meta-analysis⁸ was limited by the fact that most studies since 2005 did not describe systematic approaches to adverse event assessment, suggesting limitations in the quality of available adverse event data for serotonergic psychedelics. While adverse event data recording and reporting in psychedelic research are above average across medical research,⁸ there remains substantial room for improvement.

MDMA

MDMA is an amphetamine derivative that, paired with an exposure-like paradigm, is currently in phase 3 studies for the treatment of PTSD. MDMA is not a classic psychedelic, but rather an entactogen, a term intended to describe the feelings of emotional connection and social receptivity that MDMA and similar amphetamines engender. MDMA can cause enduring positive socioemotional effects by improving social relationships, increasing compassion and empathy, or cause persistent negative changes such as increased paranoia and anxiety.⁹ Compared with serotonergic psychedelics, MDMA has higher abuse potential owing to the reliably pleasurable and reinforcing subjective effects of intoxication. MDMA has a more concerning general medical toxicity profile than the serotonergic psychedelics due in part to its sympathomimetic effects and potential for serotonin toxicity. It can more easily become lethal in an overdose.⁵ Recreational MDMA use frequency correlates with reduced gray matter volume in the hippocampus and memory deficits,¹⁰ and although causality is difficult to establish, neurotoxicity is a significant concern with MDMA, which is not the case for the classic psychedelics.

A meta-analysis¹¹ limited to randomized controlled trials of MDMA reported common adverse events to include anxiety, jaw-clenching, muscle tightness, decreased appetite, nausea, excessive perspiration, feeling cold, restlessness, dilated pupils, uncontrolled eye movements, feeling jittery, noncardiac chest pain, blurred vision, and chills.¹¹ But like the meta-analysis of serotonergic psychedelics,⁸ it identified significant limitations to the quality and transparency of adverse event reporting and overreliance on passive monitoring of spontaneously reported adverse effects.¹¹ Therefore, much remains to be learned about the adverse effects of MDMA-assisted psychotherapy, which may not become apparent until larger trials with rigorous pharmacovigilance occur. Of note, the FDA voted against approval of Lykos Therapeutics’ MDMA-assisted protocol partly on the grounds of concern for systematic under-detection of adverse events, particularly those relating to abuse potential, further highlighting the need for improvement.

Ketamine

Ketamine is a dissociative anesthetic, though it is also called a psychedelic by some. Ketamine has demonstrated robust antidepressant effects in many studies, though the effect is generally short-lived. These antidepressant effects led to the clinical approval of esketamine, a ketamine enantiomer, for TRD. Ketamine is also used off-label in clinical settings for mental health disorders. Like MDMA, ketamine has abuse potential due to its euphoric and dissociative effects. Long-term effects of ketamine may include deficits in memory and worsening cognition.¹² Typical acute adverse effects of ketamine and intranasal esketamine include headache, nausea, anxiety, dizziness, dissociation, elevated blood pressure, and blurred vision.^12,13 Chronic ketamine use is associated with urological toxicity, liver function abnormalities, and dependence.¹⁴

However, studies of clinical ketamine/esketamine application for psychiatric indications have limited adverse event detection due to reliance on passive monitoring and little long-term follow-up.¹² The quality of adverse event reporting for intranasal esketamine studies is also variable; one study reported that nearly 40% of psychiatric and cardiovascular adverse events are not disclosed in publications.¹⁵

Ibogaine

Ibogaine is a naturally occurring plant alkaloid and hallucinogen being explored in some contexts as a treatment for substance use disorders and opioid withdrawal syndrome. Acute subjective effects of ibogaine include vivid visual imagery, and increased insight, reflection and mental clarity, as well as unpleasant effects such as auditory buzzing, auditory hypersensitivity, visual tracers, and dissociation.¹⁶ Based on compelling anecdotes and observational studies, ibogaine is being investigated for its potential to reduce opioid cravings and mitigate opioid withdrawal, as well as the treatment of psychiatric complications of traumatic brain injury, including PTSD, depression, and anxiety.¹⁷ Ibogaine is pharmacologically distinct from classic psychedelics (as are MDMA and ketamine), but its exact mechanism of action remains unclear. Human trials with ibogaine are scarce, and most understanding derives from case series and observational studies. Cardiotoxicity is a unique risk associated with ibogaine and is of particular concern.

A systematic review of adverse events of ibogaine in human studies found that QTc prolongation was the most commonly reported acute adverse event, along with other cardiac alterations (tachycardia, hypotension, and electrocardiographic abnormalities such as widened QRS complex), gastrointestinal symptoms (nausea and vomiting), alterations of consciousness, and neurological effects (ataxia, tremors, and seizures).¹⁸ Prolonged adverse events include psychiatric alterations (insomnia, speech alterations, delusions, aggressiveness, irritability, dissociation, and hallucinations), neurological symptoms (psychomotor slowing/agitation, bilateral ptosis, dysarthria, and amnesia), and cardiac alterations such as QTc prolongation.¹⁸

Crucially, and uniquely among the substances mentioned so far, ibogaine has also been associated with fatalities from the pharmacological drug effects (fatalities have occurred in the other psychedelics due to confusion and behavioral interactions with the surrounding environment). One review of 19 ibogaine-associated deaths suggested causes such as ibogaine-induced QT prolongation, comorbid cardiovascular disease, concomitant drug use, and seizures from alcohol and benzodiazepine withdrawal.¹⁹ It is physiologically plausible that magnesium coadministration may mitigate cardiotoxicity mediated by QT prolongation, leading to the incorporation of prophylactic magnesium infusions in some ibogaine studies.¹⁷ In general, as mentioned, the current literature on ibogaine is dominated by case series and observational studies, with inconsistent dosages and nonsystematic reporting of adverse events,¹⁸ and there is greater concern about physiological toxicity compared with other psychedelics.

Concluding Thoughts

This brief survey of adverse effects across the set of substances most commonly referred to as psychedelics should not be considered comprehensive, and there is room for field-wide improvement of adverse event recording and reporting in psychedelic trials and real-world settings.^8,11,12 Adopting enhanced and standardized assessment tools to proactively detect adverse effects is a clear first step.²⁰ Note that with all of these psychedelic experiences, in addition to persisting benefits such as enhanced well-being, persisting psychological difficulties such as anxiety, confusion, dissociation, perceptual effects, and other issues can also occur––and the prevalence of such persisting effects is being quantified in ongoing scientific research.²¹

The benefits and risks of psychedelics suggested by current research cannot be extrapolated directly to recreational settings without careful consideration of set and setting. Relevant factors include drug purity, medical-psychiatric supervision, adjunctive psychotherapy, and abstinence from other intoxicants such as cannabis or alcohol. The safety of these substances for individuals taking psychotropics such as antidepressants or mood stabilizers is also a topic of ongoing investigation, the details of which depend on the specific substance under discussion. Further insights regarding the safety of expanding access to psychedelics may be forthcoming soon, considering legalized avenues for psychedelic access, such as Oregon’s psilocybin service centers.

In our view, the most important takeaway for mental health providers is that although there is a substantial signal for therapeutic benefit from psychedelics, and while serious complications with a clear causal relationship to psychedelics are rare in clinical trials, adverse events do occur across contexts, and those with preexisting psychiatric illness are clearly more vulnerable.^7,22 However, these risks and benefits vary depending on the specific psychedelic under discussion, so it is advisable to think in terms of specific substances rather than the broad set sometimes called psychedelics.

Dr Hinkle is a resident psychiatrist at the Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences. His research interests include clinical applications of psychedelic-assisted psychotherapy.

Mr Choi is a fourth-year medical student at the Warren Alpert Medical School of Brown University and a clinical research coordinator at the Center for Psychedelic and Consciousness Research at Johns Hopkins University.

Dr Yaden is the Roland Griffiths Professor of Psychedelic Research at Johns Hopkins University School of Medicine in the Department of Psychiatry and Behavioral Sciences in the Center for Psychedelic and Consciousness Research. He is a research associate at the University of Oxford and the cofounder of the Hub at Oxford for Psychedelic Ethics (HOPE). He studies brief experiences with the potential for long-term positive impact. His current research at the Yaden Lab focuses on psychedelic experiences, including their risks, benefits, and mechanisms.

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