Do classic psychedelics increase the risk of seizures? A scoping review

Interest in the therapeutic potential of serotonergic or "classic" psychedelics (for example LSD, psilocybin, DMT, mescaline and related compounds) has resurged alongside clinical development programmes for several compounds. While preliminary clinical and preclinical data suggest benefits for mood, anxiety and substance-use disorders, safety data remain limited and heterogeneous. Of particular concern for neurological safety is the possibility that these agents might provoke epileptic seizures, a worry reflected in routine exclusion of people with epilepsy from many psychedelic trials and in early case reports linking LSD and other psychedelics to acute seizures. Soto-Angona and colleagues set out to map the available evidence on whether classic psychedelics increase seizure risk. They performed a scoping review of human and animal studies to characterise reported associations, identify methodological gaps, and inform future research and clinical-trial eligibility decisions. The review deliberately excluded non-serotonergic or dissociative compounds (for example MDMA, ketamine) to focus on mechanisms relevant to serotonergic psychedelics and their potential neurophysiological effects.

The investigators conducted a scoping review following PRISMA-ScR guidance; the protocol was registered on the Open Science Framework. Searches were run in PubMed, Web of Science, Google Scholar, LILACS and Scielo up to November 2022. Keywords combined terms for psychedelics (LSD, psilocybin, mescaline, peyote, San Pedro, DMT, 5-MeO-DMT, ayahuasca, Psilocybe mushrooms and related) with seizure-related terms (epilep*, epileptic seizures, seizures). Language inclusion criteria covered English, Spanish, French, Italian, Portuguese and German. After duplicate removal, titles and abstracts were screened, and full texts examined for eligibility. The team also screened private collections held by the project group. Two researchers performed searches and data extraction independently, with a third resolving disagreements. Studies were eligible if peer reviewed and reporting effects of serotonergic psychedelics on seizures in humans or animals. Extracted fields included author, year, country, article type, substance studied, aims, population, methodology, main results and conclusions. The review included both experimental and observational human studies, case reports, and animal experiments; a flowchart was referenced but not reproduced in the extracted text.

The review identified 16 human studies and 11 animal studies. Across the human literature the pooled sample comprised 11,659 individuals who had taken psychedelics, of whom 83 had a prior history of epilepsy; participant ages ranged from 0 to 83 years. The substances represented included LSD (reported in 10 studies), psilocybin (3), ayahuasca (3), mescaline (2), DMT (1) and LSA (1). Study designs and quality varied widely, with older reports often poorly described. Human findings were heterogeneous. Several early studies administering LSD to people with epilepsy reported no consistent EEG changes after dosing, although a minority described transient "aura-like" phenomena. One report found increased focal epileptic activity on EEG in seven of 11 cases after psilocybin (mean dose 0.16 mg/kg), while another small mescaline study (250–500 mg) in 12 people with prior seizures described one absence seizure about four hours post-dose and variable transient disappearance of spike-wave patterns on EEG one hour after dosing. A large therapeutic survey covering about 4,300 patients and ~49,000 LSD doses recorded a single tonic–clonic seizure in a person without prior epilepsy. Conversely, retrospective poison-centre analyses and emergency-department series reported higher rates after intoxication: one 16-year analysis found seizures in 0.8% of psilocybin-mushroom exposures and 3.6% of LSD exposures, with 15 cases of status epilepticus (0.4%), and other ED-based studies reported seizure rates of approximately 0.4% to 2.4% depending on substance and setting. A large sample of ayahuasca users (n = 8,216, reported outside the set of clinical trials) found 1.3% (n = 106) reporting seizures; a smaller observational ayahuasca study (n = 40) reported one seizure. Case reports emphasised context and co-exposures. Two cases linked seizures to combined ayahuasca and kambo use. Reports also described tonic–clonic seizures after recreational high-dose LSD (one case possibly combined with fluoxetine), and a case of status epilepticus related to posterior reversible encephalopathy syndrome after LSA combined with clomipramine. Self-reported online data indicated that 47% of 62 patients who took lithium with psychedelics reported seizures, whereas none of 34 lamotrigine users reported seizures, although these self-reports lack verification and are subject to bias. Overall, modern controlled clinical trials did not report seizures as adverse events, but they routinely excluded people with epilepsy and screened for concomitant drug use. Animal-model studies (eleven reports) used mice, rats and cats with heterogeneous methods: acute psychedelic administration with proconvulsant stimuli, post-decapitation convulsion models, EEG/ECG assessments, and developmental-exposure studies. Dose ranges varied by species and compound. Some studies reported anticonvulsant effects: LSD, psilocybin and DMT reduced myoclonic or audiogenic seizures in certain paradigms, often in a dose-dependent manner (for example psilocybin interrupted myoclonic activity at 1–4 mg/kg). By contrast, 5-MeO-DMT prolonged latency and duration of post-decapitation convulsions at some doses, although repeated dosing reduced these convulsions. Exposure to ayahuasca during pregnancy increased seizure susceptibility in offspring in one recent study. Most animal studies were conducted before 1990; several had small or unreported sample sizes and varying relevance to electrographic seizures.

Soto-Angona and colleagues interpret the evidence as heterogeneous and of limited external validity, but they note a recurrent pattern: when classic psychedelics are used alone in controlled settings and at therapeutic doses, seizures appear to be rare or unobserved, yet seizures are more frequently reported in cases of intoxication, polydrug use or specific drug interactions. The animal literature is inconsistent, showing both seizure-protective and seizure-promoting effects depending on compound, dose and model; notably, ayahuasca exposure in pregnancy and 5-MeO-DMT showed signals of increased seizure susceptibility in some animal studies. The authors emphasise several important caveats. Methods, definitions and outcome ascertainment differed substantially across studies, with many older reports lacking precise dosing information, EEG confirmation, or sample-size reporting. The term "seizure" itself was used variably and may have included non-epileptic events; some animal models (for example post-decapitation convulsions) probe brainstem or spinal activity rather than cortical electrographic seizures, limiting mechanistic inference. Modern clinical trials' lack of seizure reports may reflect stringent exclusion criteria (people with epilepsy) and control of co-medications rather than absence of risk in real-world settings. Drug–drug interactions emerged as a recurring concern. Case reports and observational data implicate concomitant substances such as kambo and lithium in several seizure events, and self-reports suggested increased seizures with lithium but not lamotrigine; the authors caution that self-reported data and intoxication-series cannot establish causality. They also discuss dose-dependent hypotheses and mechanistic proposals from early literature linking serotonergic modulation, effects in thalamic or geniculate circuits, and downstream monoaminergic influences to seizure susceptibility, but conclude that evidence is inconclusive. In sum, the review concludes that current data broadly indicate classic psychedelics alone do not clearly increase seizure risk in healthy individuals without other interacting substances, but co-exposures and certain contexts may elevate risk. The authors call for cautious interpretation, improved prospective data collection with standardised seizure definitions and EEG confirmation where possible, and careful reconsideration of inclusion and exclusion criteria in future clinical trials to balance safety with inclusivity and ethical considerations.