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Psychedelics vs. Epilepsy & Seizures: Effective Treatment or Exacerbation? (2023 Review)

Psychedelic compounds, long associated with the fringes of medicine and spirituality, are now at the forefront of a radical shift in neurology and psychiatry.

Decades of clinical trials have begun to unravel the therapeutic potentials of these substances, revealing promising outcomes in the treatment of various psychiatric disorders.

However, a notable gap in this burgeoning field of psychedelic-assisted therapy (PAT) is its exploration for individuals with seizure disorders, a population traditionally excluded from these studies due to safety concerns, despite a lack of evidence suggesting an increased risk of seizures from supervised psychedelic use.


  1. Historical Context: Psychedelic substances such as LSD, psilocybin, MDMA, and ketamine have been used for centuries for their profound effects on consciousness, with modern clinical research supporting their efficacy in treating psychiatric conditions.
  2. Clinical Exclusions: Individuals with seizure disorders, including epilepsy, have been systematically excluded from psychedelic research trials, leaving a significant gap in understanding and potential treatment options for this group.
  3. Emerging Evidence: Case reports and limited clinical data suggest that psychedelics may not increase seizure risk and could offer therapeutic benefits in controlled, clinical settings for those with seizure disorders.
  4. Future Directions: The need for dedicated research, including preclinical and clinical trials, to evaluate the safety and efficacy of psychedelics in individuals with seizures is critical for expanding treatment paradigms.

Source: Frontiers in Pharmacology (2023)

Psychedelics vs. Seizures & Epilepsy (2023 Findings)

A comprehensive review of psychedelic compounds in the context of seizure disorders revealed several nuanced findings, offering insights into the potential roles these substances could play in both exacerbating and alleviating seizure activities under different conditions.

1. Psychedelic Actions & Mechanisms on Neural Circuitry

Classical Psychedelics

  • The review detailed how classical psychedelics like LSD and psilocybin function primarily as agonists at the 5-HT2A receptors.
  • These substances induce alterations in resting-state functional connectivity, particularly increasing inter-network connectivity among the default mode, executive, and salience networks, while reducing intra-network connectivity.
  • This modulation of brain networks is thought to underlie the therapeutic effects seen in psychiatric disorders but also raised questions about their safety in seizure disorders.

Atypical Psychedelics

  • MDMA and ketamine, categorized as atypical psychedelics, have distinct mechanisms.
  • MDMA enhances serotonergic transmission through increased serotonin release and reuptake inhibition, potentially affecting seizure thresholds.
  • Ketamine, an NMDA receptor antagonist, has complex effects on excitatory and inhibitory neurotransmission, with implications for both pro- and anti-convulsant activities.

2. Clinical Safety & Seizure Risks

The review identified a critical gap in current research regarding the safety of psychedelic use in individuals with seizure disorders.

While case reports from recreational settings suggested potential risks, controlled clinical studies provided a more nuanced perspective:

  • MDMA: Reports included cases of seizures following MDMA use, often in combination with alcohol or other drugs, complicating the assessment of MDMA’s direct role in these events.
  • LSD & Psilocybin: Few reports described seizures following LSD or psilocybin use, with some suggesting potential interactions with other medications (e.g., SSRIs) that could elevate seizure risk.
  • Ketamine: Ketamine-assisted therapy showed promise in treating refractory functional seizures, highlighting a potential therapeutic application without worsening seizure activity.

3. Evidence from Case Reports & Studies

Case Reports

Documented instances of seizures following the use of psychedelics predominantly involved unsupervised recreational use, unknown dosages, and often concurrent consumption of other substances.

These reports underscore the difficulty in isolating the effects of psychedelics on seizure activity.

Clinical Studies

Controlled settings provided a contrasting view.

Classical psychedelics appeared safe and tolerable for patients with epilepsy, suggesting that the controlled administration of these substances does not inherently increase seizure risk.

4. Potential Therapeutic Benefits

Despite the primary focus on safety, the review hinted at the therapeutic potential of psychedelics for seizure disorders, particularly in addressing comorbid psychiatric conditions such as depression and anxiety, which are disproportionately prevalent in this population.

This aspect underscores the need for further research to explore the full spectrum of psychedelics’ effects on neurological and psychiatric outcomes in individuals with seizures.

Psychedelics vs. Seizures & Epilepsy (2023 Review)

Ninon Freidel et al. investigated the safety and potential therapeutic effects of psychedelic-assisted therapy (PAT) in individuals with seizure disorders, a population historically excluded from psychedelic research due to concerns over increased seizure risk.

The study sought to bridge a significant gap in the literature by systematically exploring whether classical psychedelics, such as LSD, psilocybin, MDMA, and ketamine, could be safely administered under clinical supervision without exacerbating seizure activity, and potentially even offer therapeutic benefits for seizure-related symptoms and comorbid psychiatric conditions.


  • The research utilized a comprehensive literature review, extracting data from public databases including PubMed, Google Scholar, and ResearchGate.
  • Search terms encompassed a wide range of keywords related to epilepsy, psychedelics, and seizures, such as “psilocybin,” “LSD,” “MDMA,” “ketamine,” “seizures,” “chronic seizures,” and “acute seizures.”
  • The screening process involved two steps: initial screening based on titles and abstracts, followed by a full-text review to confirm eligibility.
  • The inclusion criteria were explicit mentions of classical and/or atypical psychedelics in the context of acute and/or chronic seizures and case reports and/or clinical trials involving the use of these substances in any seizure disorder.


  • The study reviewed the actions of classical psychedelics, which primarily act as agonists of 5-HT2A receptors, and atypical psychedelics like MDMA and ketamine.
  • Different psychedelics have distinct mechanisms of action, including serotonergic and dopaminergic pathways for MDMA and NMDA receptor antagonism for ketamine.
  • The research identified case reports and controlled studies that support the safety and tolerability of classical psychedelics under clinical supervision, even in patients with a history of epilepsy.
  • A total of 11 papers were included in the analysis, with several case reports documenting seizures following recreational use of psychedelics, but few controlled studies indicating safety in a clinical setting.
  • Case reports involving MDMA showed instances of seizures in unsupervised settings, often with unknown dosages and concurrent substance use.
  • Conversely, clinical trials and reports in controlled settings, like the use of LSD in individuals undergoing neurosurgery for epilepsy, did not demonstrate an increased seizure risk, suggesting potential safety under clinical supervision.


  • Sparse Data: The majority of available data were case reports of recreational use, with a lack of controlled clinical trials specifically targeting individuals with seizure disorders.
  • Confounding Factors: Many reports involved concurrent use of other substances or unsupervised settings, complicating the assessment of psychedelics’ direct impact on seizure activity.
  • Generalizability: The findings from case reports and small-scale studies may not be generalizable to broader populations with different seizure disorders.
  • Need for Specific Research: The study highlighted the urgent need for dedicated preclinical and clinical research to more definitively assess the safety and efficacy of psychedelics in this population.

Do Psychedelics Increase vs. Decrease Seizure Risk? (Evidence)

The comprehensive review of available literature, including case reports and controlled clinical trials, presents a nuanced perspective on the relationship between psychedelic use and the risk of seizures.

While the paper outlines instances where psychedelics, particularly when used recreationally or in unsupervised settings, have been associated with the occurrence of seizures, it also acknowledges the lack of substantial evidence directly linking clinically supervised psychedelic use to an increased risk of seizure activity.

1. Psychedelics & Increased Seizure Risk

  • Case Reports: The document highlights several case reports of individuals experiencing seizures following the use of psychedelics such as MDMA, LSD, and psilocybin. These instances often involve factors that could confound the interpretation of psychedelics’ direct effects, including unsupervised use, polydrug use, pre-existing health conditions, and unknown dosages. While these reports suggest a potential risk, they do not conclusively establish psychedelics as a direct cause of increased seizure activity due to the lack of controlled conditions.
  • Potential Mechanisms: The review discusses theoretical mechanisms by which psychedelics might influence seizure susceptibility, such as alterations in neurotransmitter systems that can affect the brain’s excitatory and inhibitory balance. However, it also notes the complexity of these mechanisms and the fact that individual responses to psychedelics can vary widely, making it challenging to predict effects on seizure risk.

2. Psychedelics & Decreased Seizure Risk or Neutral Effects

  • Lack of Evidence in Clinical Trials: Importantly, the paper points out that clinical trials examining the therapeutic use of psychedelics have largely excluded individuals with a history of seizures, leaving a gap in evidence regarding the safety of these substances in this population. However, it also highlights that there is no significant evidence from clinical settings to suggest that psychedelics, when used under controlled conditions, inherently increase the risk of seizures.
  • Theoretical Benefits: Some sections of the review speculate on potential therapeutic effects that psychedelics might have on the neural circuits involved in seizure disorders, such as enhancing neuroplasticity or modulating neurotransmitter systems in a way that could potentially reduce seizure frequency or severity. However, these potential benefits remain theoretical in the absence of targeted research.

Cautious approach to psychedelics for seizures & epilepsy…

The paper suggests a cautious approach to interpreting the relationship between psychedelics and seizure risk.

It acknowledges the potential risks highlighted by anecdotal reports and theoretical concerns but also emphasizes the lack of conclusive evidence for an increased risk of seizures with clinically supervised psychedelic use.

The review calls for more rigorous and targeted research to clarify this relationship, particularly studies that include individuals with seizure disorders in clinical trials of psychedelic-assisted therapy.

This future research is deemed essential for determining whether psychedelics might offer therapeutic benefits without increasing seizure risk, potentially providing valuable treatment options for individuals with epilepsy and other seizure disorders.

Psychedelics in Treating Epilepsy & Seizures (Potential Mechanisms)

The therapeutic potential of psychedelics for epilepsy and seizures may be attributed to several mechanisms, informed by our growing understanding of their complex interactions with brain chemistry and function.

1. Modulation of Serotonergic Systems

Psychedelics such as LSD and psilocybin primarily exert their effects through the agonism of serotonin 2A receptors (5-HT2A).

This action can lead to altered cortical activity and changes in perception, mood, and cognition.

The serotonergic system plays a role in the modulation of seizures, and the activation of 5-HT2A receptors could potentially stabilize neuronal activity, reducing the likelihood of seizure occurrence.

2. Enhancement of Neuroplasticity

Recent studies suggest that psychedelics may promote neuroplasticity—the brain’s ability to form new connections and pathways.

This increased plasticity could help in “rewiring” neural circuits that are involved in the pathophysiology of epilepsy, potentially leading to a reduction in seizure frequency and severity.

3. Reduction of Inflammation

Some research indicates that psychedelics might have anti-inflammatory effects on the brain.

Since inflammation is a known contributor to epileptogenesis (the development of epilepsy), reducing inflammation could mitigate the risk of seizure development and progression in susceptible individuals.

4. Psychological Effects

For patients with psychogenic non-epileptic seizures (PNES), the therapeutic effects of psychedelics on mental health disorders could indirectly benefit seizure management.

By addressing underlying psychiatric conditions such as depression, anxiety, or PTSD, psychedelics could reduce the frequency of PNES episodes.

Safe Trials of Psychedelics for Seizure Disorders & Epilepsy

The exploration of psychedelics as a treatment for seizure disorders and epilepsy necessitates a cautious, evidence-based approach to ensure safety and efficacy.

Based on the review of case reports and controlled studies, several potential strategies emerge for safely incorporating psychedelic-assisted therapy (PAT) into treatment paradigms for seizure disorders.

Patient Selection

Patients with well-controlled epilepsy, who have not responded to conventional treatments for comorbid psychiatric conditions such as depression or anxiety, may be suitable candidates.

Those with a history of stable seizure patterns and under continuous neurologist supervision could be considered for PAT, ensuring any potential changes in seizure frequency or intensity are closely monitored.

Psychedelic Selection

Among the psychedelics, ketamine shows promise due to its use in controlled clinical settings and documented cases of treating refractory functional seizures without exacerbating seizure activity.

LSD and psilocybin, while having less direct evidence in the context of seizure disorders, have been explored in clinical settings with attention to their impact on brain connectivity and psychiatric symptoms, suggesting potential utility under rigorous clinical supervision.

Clinical Considerations

Supervision: Ensuring that psychedelic use occurs in a controlled, clinical setting under the supervision of experienced medical professionals is paramount. This approach includes detailed pre-screening for psychological vulnerabilities, careful dosing, and comprehensive monitoring during and after administration.

Comprehensive Care: Psychedelic therapy should be integrated into a broader treatment strategy that includes ongoing neurological care, psychiatric support, and possibly psychotherapy to address underlying psychological issues.

Potential Worsening of Seizures & Epilepsy with Psychedelics

Despite the promising mechanisms by which psychedelics could aid in treating epilepsy and seizures, not all patients may respond positively, and in some cases, psychedelics could potentially exacerbate seizures.

Individual Variability in Drug Response

The response to psychedelic therapy is highly individual, depending on genetic makeup, the underlying neurobiology of the patient’s epilepsy, and concurrent medications.

This variability can lead to differing outcomes, where some may experience therapeutic benefits, while others may not see any improvement or could potentially experience worsening of symptoms.

Risk of Lowering Seizure Threshold

Although the modulation of serotonergic systems by psychedelics can have therapeutic effects, there is also a risk that these substances could lower the seizure threshold in some individuals, particularly at higher doses or in combination with other medications that affect seizure susceptibility.

Potential for Psychological Distress

Psychedelic experiences can sometimes lead to psychological distress or exacerbate underlying psychiatric conditions, indirectly influencing the frequency and severity of psychogenic seizures.

Patients with a history of severe mental illness or those particularly sensitive to the effects of psychedelics may be at increased risk.

Interactions with Epilepsy Medications

Psychedelics could interact with antiepileptic drugs (AEDs), affecting their metabolism or efficacy.

Such interactions might compromise seizure control or increase the risk of adverse effects, necessitating careful consideration of drug-drug interactions in patients undergoing psychedelic-assisted therapy.

Takeaway: Psychedelics vs. Seizure Disorders & Epilepsy

The review underscores a cautiously optimistic perspective on the potential of psychedelics for treating seizure disorders, particularly when conventional therapies have failed to provide relief for comorbid psychiatric conditions.

The safety and efficacy of psychedelics like ketamine, LSD, and psilocybin in patients with epilepsy require further investigation through targeted research.

Controlled clinical settings, meticulous patient selection, and comprehensive care integration emerge as critical factors for safely exploring the therapeutic benefits of psychedelics in this unique patient population.

As the body of evidence grows, psychedelics may offer a novel, adjunctive treatment pathway for individuals with epilepsy, promising not only to manage seizures but also to improve overall quality of life by addressing psychiatric comorbidities.

The cautious but forward-looking approach highlighted in this review paves the way for a new chapter in the treatment of seizure disorders, where psychedelics could play a transformative role under the right conditions.


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