5-HT2A Agonists: A Novel Therapy for Functional Neurological Disorders?

Functional neurological disorders (FNDs) are common conditions at the interface of neurology and psychiatry that are associated with a poor prognosis and limited, inconsistently effective treatments. Bryson and colleagues describe prevailing theoretical accounts that implicate a disturbance of somatic self-representation and an excessive top-down cognitive influence on sensorimotor processes as central to FND pathophysiology. These models—supported by behavioural studies and functional neuroimaging—help explain clinical features such as loss of motor agency and symptom variability with attentional focus. This paper sets out to synthesise evidence from cellular, neurophysiological and neuroimaging studies of 5-HT2A agonists and to argue that these agents may have unique therapeutic potential in FNDs. The authors propose that because 5-HT2A agonists perturb hierarchical brain dynamics and modulate networks involved in self-related processing, they could weaken pathological higher-order priors and restore more adaptive sensorimotor integration; on that basis the paper argues a clinical trial is warranted.

The extracted text does not present a formal Methods section or a description of a systematic literature search; the paper is a narrative, mechanistic review and theoretical argument rather than a primary empirical study. Bryson and colleagues synthesise findings from cellular neurophysiology, EEG and fMRI studies, and behavioural and clinical observations of FNDs to construct a cross-level account linking 5-HT2A receptor pharmacology to the proposed pathophysiology of FND. Rather than reporting new experimental data, the authors combine prior experimental findings on receptor expression and single-neuron effects, macroscopic imaging/EEG studies of 5-HT2A agonists, and existing neuroimaging and behavioural literature on FNDs. Where relevant, they interpret these data within neurobiological and computational (Bayesian) models of perception and agency to derive testable clinical hypotheses. The extracted text does not detail inclusion/exclusion criteria, search dates, or risk-of-bias assessment because it is not a systematic review.

The paper summarises clinical and mechanistic findings from prior literature relevant to FNDs and 5-HT2A agonists rather than presenting novel results. Clinically, FNDs are defined by neurological symptoms without structural pathology and include presentations such as functional weakness, visual disturbance and movement disorders. Diagnosis rests on normal investigations and characteristic inconsistencies on examination (for example, symptom improvement with diversion of attention). Psychiatric comorbidity may be present but is not required, and conventional treatment options (psychotherapy, physiotherapy) have limited evidence; overall prognosis is often unfavourable and the condition imposes substantial individual and healthcare burdens. Neuroimaging and behavioural studies discussed in the paper implicate disturbances in motor agency, self-monitoring and somatic self-representation. In particular, reduced activation of the right temporo-parietal junction (TPJ) in patients with functional motor symptoms contrasts with normal TPJ activation in feigned weakness, consistent with a mismatch between movement intention and outcome. Behavioural research shows heightened body vigilance and a tendency to resolve ambiguous sensory input in favour of somatic explanations. Corresponding neuroimaging findings include increased activity in nodes of the default mode network (DMN)—notably the ventromedial prefrontal cortex, precuneus and insula—which are involved in introspective and self-related processing. The authors present the leading neurobiological model alongside a Bayesian formulation: both posit that excessively precise higher-order priors (abnormal somatic representations) exert pathological top-down influence over lower-order sensorimotor signals, producing persistent functional symptoms that are reinforced by attentional focus. Summarising evidence on 5-HT2A agonists, Bryson and colleagues report cellular findings that activation of the 5-HT2A receptor increases excitability of pyramidal neurons (with prominent receptor expression in prefrontal and association cortex and a subcellular localisation favouring proximal apical dendrites), and may alter interneuronal synchrony. At the network level, neuroimaging and EEG studies show that 5-HT2A agonists reduce activity and functional connectivity within higher-order networks such as the DMN, an effect that correlates with subjective ego-dissolution. Concurrently, these agents increase global brain connectivity and strengthen functional coupling between lower-order sensorimotor regions and higher-order areas, producing a "flattening" of hierarchical topography. EEG information‑theoretic analyses suggest a shift in effective connectivity: reduced top-down constraint from frontal regions and increased influence from lower-order centro-posterior areas. The paper links these two evidence streams by proposing that 5-HT2A agonists could weaken pathological higher-order somatic priors and enhance bottom-up sensory signalling, thereby reducing abnormal self-representation and the maladaptive influence of cognition on sensorimotor function. The authors note experiential effects commonly reported with these drugs—hallucinations, synaesthesia and ego dissolution—which they interpret as consistent with the described neural dynamics. They also acknowledge safety and ethical concerns related to the hallucinogenic properties and argue these may be mitigated within controlled clinical settings. The extracted text does not report quantitative effect sizes or clinical trial data demonstrating efficacy of 5-HT2A agonists in FNDs.

Bryson and colleagues interpret the converging cellular, neurophysiological and imaging evidence as supporting the plausibility of 5-HT2A agonists as a novel therapeutic approach for FNDs. They argue that these agents target the two processes central to leading models of FND: (1) abnormal self-representation, through diminished activity and connectivity within networks subserving self-related cognition, and (2) pathological top-down constraint over sensorimotor processing, through enhancement of bottom-up connectivity and reduced frontal-to-posterior influence. Positioning their argument relative to earlier research, the authors note that the neuroimaging correlates of ego dissolution and the observed reversal of hierarchical brain dynamics under 5-HT2A agonists provide a mechanistic bridge to the Bayesian and neurobiological models of FND. On this basis they propose that transient perturbation of brain network dynamics by intermittent dosing could weaken excessively precise priors and increase the salience of sensory evidence, producing clinical benefit. The paper acknowledges key uncertainties and limitations: there is no direct clinical trial evidence for efficacy in FNDs reported in the extracted text, and the therapeutic hypothesis rests on mechanistic inference from disparate literatures. Ethical and safety concerns associated with the hallucinogenic effects are recognised, and the authors recommend mitigation via controlled settings. For future research they recommend a carefully designed clinical study in a well-defined, homogeneous patient cohort (for example, refractory functional hemiparesis without psychiatric comorbidity) combined with best-practice physiotherapy and psychotherapy, using intermittent dosing schedules modelled on existing depression trials. The authors state that such a trial would test whether transient perturbation of network activity produces superior symptom recovery compared with non‑drug controls.