Exploring psychedelic-assisted therapy in the treatment of functional seizures: A review of underlying mechanisms and associated brain networks

Functional seizures (FS) are a common and disabling subtype of functional neurological disorder (FND) that produce episodic disturbances resembling epileptic seizures, yet are distinct in mechanism and treatment response. Lewis and colleagues highlight the substantial clinical and economic burden of FS, noting elevated rates of post-traumatic stress disorder, anxiety and depression in this population, predominance among women (approximately 75%), and recent incidence and prevalence estimates of 3.1/100,000 and 23.8/100,000 per year, respectively. Current care is hampered by inconsistent diagnosis, delayed or incorrect treatment (including inappropriate antiseizure medications), and limited availability and evidence for first-line psychological therapies such as CBT-informed psychotherapy. Neuroimaging to date has revealed multifocal abnormalities across large-scale networks subserving emotion, attention, interoception, self-agency and motor control, but findings are heterogeneous and have not produced a unified mechanistic account. Motivated by the growing evidence base for psychedelic-assisted therapy (PAT) in several psychiatric conditions, the paper synthesises empirical findings and theoretical frameworks to build a biopsychosocial mechanistic argument for PAT as a potential treatment for FS. The authors adopt a broad definition of psychedelics that includes classic serotonergic compounds (e.g. LSD, psilocybin, DMT/ayahuasca), ketamine, and MDMA, and draw links between these drugs' molecular and large-scale neural effects and the hypothesised pathophysiology of FS. They further propose that FS constitute a clinically well-defined cohort in which to study PAT’s neural mechanisms, and suggest applying a complexity science perspective to reconcile heterogeneous neuroimaging results and to identify candidate biomarkers and analytic strategies for future trials.

The extracted text does not present a formal Methods section describing search strategies, inclusion criteria, or systematic review procedures. Instead, the paper functions as a narrative, integrative review that draws on prior clinical trials, historical case series, individual case reports, cross-sectional surveys, and the human neuroimaging literature to construct a mechanistic argument linking PAT and FS. The authors reference summary material (a Supplemental Table) of clinical trials of PAT for psychiatric indications and integrate older case series (1950s–1960s) and recent individual case reports relevant to FND and FS. Analytical framing is grounded in complexity science. The investigators review molecular, mesoscale and macroscale mechanisms of psychedelic drugs, emphasising convergent pro-plasticity pathways (e.g. BDNF–TrkB–mTOR signalling) and drug-specific receptor actions (5-HT2A partial agonism for classic psychedelics, NMDA antagonism for ketamine, MDMA’s serotonergic effects). They also focus on human fMRI studies of acute and post-acute psychedelic effects and compare these with fMRI findings in FS. Rather than performing meta-analytic pooling, the authors propose an analytic roadmap for future empirical work: (i) applying complex systems metrics to pre/post-treatment neuroimaging in FS patients receiving PAT, (ii) using seizure frequency as a primary, quantifiable clinical outcome to define responders, and (iii) examining dynamic whole-brain properties (for example, state repertoire, switching frequency, entropy, modularity, metastability and criticality) as candidate biomarkers of treatment response. Where procedural details are available from cited case reports, the authors describe a standardised ketamine-assisted therapy (KAT) protocol used in one reported case (three preparatory sessions, three dosing sessions with sublingual and intranasal ketamine, three immediate integration sessions, and extended maintenance psychotherapy).

The review summarises epidemiological, clinical, historical and mechanistic findings relevant to FS and PAT rather than reporting new empirical data. Key clinical and epidemiological points include substantial comorbidity with PTSD, anxiety and depression, a predominance of women among diagnosed individuals (75%), and healthcare costs for FND in the USA estimated at $1.2 billion per year. Historical treatment reports include a systematic review of 1950s–1960s case series of LSD for FND in which 26 patients were described: 69% (n = 18) experienced some improvement and 23% (n = 6) achieved complete recoveries. More recent clinical evidence for psychedelic approaches in FND is limited to case reports and surveys: one intranasal esketamine case for FND with sensory and motor paralysis showed clinical benefit; an intranasal and sublingual KAT case from the authors’ group reported marked reductions in FS frequency and severity together with improvements on the Quick Inventory of Depressive Symptomatology (QIDS) and Work and Social Adjustment Scale (WSAS), ability to taper benzodiazepines, and enhanced trauma processing without seizure provocation. An online, cross-sectional survey of 980 people with FND reported that 15% had used illicit substances including psychedelics and found these to be moderately effective by self-report. Neurobiological findings across the FS literature are heterogeneous but converge on multifocal dysfunction across large-scale networks implicated in emotion, interoception and motor control. Reported abnormalities include variable changes in the right temporoparietal junction (rTPJ), altered cortical thickness, variable hippocampal reactivity, and aberrant amygdala reactivity and connectivity, together with altered insular and motor-cortical coupling. The authors note increased coupling of amygdalar-motor and insular-motor cortices in FND relative to controls, consistent with maladaptive integration of emotional-viscerosomatic and motor systems. Psychedelic neurobiology is summarised across molecular to systems levels. Classic serotonergic psychedelics act primarily via 5-HT2A receptor partial agonism increasing glutamatergic transmission; ketamine acts largely through NMDA antagonism and glutamatergic disinhibition in prefrontal cortex. Despite receptor differences, several compounds converge on BDNF–TrkB–mTOR signalling pathways that promote synaptogenesis and dendritogenesis, conceptualised as pro-plasticity or metaplastic effects. Human fMRI studies of the acute psychedelic state report decreased functional segregation and increased whole-brain integration or entropy, but the precise patterns of inter-network change are inconsistent across studies. The authors report that complexity science–inspired analyses of dynamic brain states (for example, identifying recurring connectivity patterns, their switching frequencies, transition probabilities, and entropy) have been applied to psychedelic data and may reconcile heterogeneity by focusing on state dynamics rather than static averaged connectivity. Finally, the authors propose practical outcome measurement for future trials: seizure frequency as a primary, objective clinical outcome (to categorise responders), with secondary measures of function and comorbid mental health; and pre/post neuroimaging analysed with complex systems metrics (modularity, entropy, metastability, criticality and metrics of state repertoire and switching) to identify pre-treatment predictors and post-treatment markers of therapeutic success.

Lewis and colleagues interpret the assembled evidence as supportive—albeit preliminary—for exploring PAT as a novel intervention for FS. They argue that PAT’s combined pharmacological and psychotherapeutic elements could address both the psychological comorbidities commonly accompanying FS and the distributed neural network dysfunctions implicated in the disorder. The authors emphasise mechanistic plausibility: psychedelics’ pro-plasticity molecular effects and their capacity to transiently induce a more flexible, less constrained mode of large-scale brain dynamics may enable a therapeutically relevant disruption of the maladaptive network patterns that sustain the so-called seizure scaffold. The discussion positions a complexity science perspective as a way to reconcile heterogeneous neuroimaging findings in both FS and psychedelic research. Rather than seeking a single representative connectivity signature, the authors favour characterising how whole-brain network states are traversed over time—metrics such as repertoire of states, switching dynamics, entropy and metastability—and using these to identify common mechanistic features across individuals despite inter-individual variability. They suggest that such an approach could yield pre-treatment imaging characteristics predictive of response and post-treatment changes that serve as biomarkers of successful intervention. The authors acknowledge limitations of the existing evidence base: most clinical data directly addressing psychedelics in FS are limited to case reports, small historical series and self-report surveys, and neuroimaging results are heterogeneous. They therefore refrain from definitive efficacy claims and instead frame their paper as a mechanistic rationale and a methodological blueprint for future empirical work. Practical implications discussed include designing future clinical trials in FS that use seizure frequency as a clear primary endpoint, incorporate rigorous pre/post neuroimaging, apply complexity metrics to identify mechanistic markers, and combine pharmacological dosing with preparatory and integration psychotherapies. Finally, the authors suggest that such work could bridge neurology and psychedelic medicine and, if successful, form the basis for a nascent subspecialty of psychedelic neurology.

The authors conclude that FS represent a clinically well-defined cohort in which to test whether PAT, analysed through a complexity science lens, can produce clinically meaningful and mechanistically informative changes. They argue that shifting the investigational focus from specific network targets to restoring global neural flexibility and diversity may allow PAT to relax compromised top-down inhibitory control, facilitate unlearning of the seizure scaffold, and produce accessible, generalisable treatments across FS phenotypes. A future clinical trial applying the outlined framework could identify predictive and outcome biomarkers, deepen mechanistic understanding of psychedelic action, and potentially expand therapeutic options for treatment-resistant FS and broader FND populations.