Neuropharmacological modulation of the aberrant bodily self through psychedelics

Ho and colleagues frame the bodily self as a continuous, multisensory construct that is central to cognition and vulnerable to disruption in several psychiatric disorders. Earlier work links disturbances in body-related awareness to failures of multisensory integration and updating of internal models; conventional treatments such as SSRIs do not reliably remediate those disturbances. The introduction highlights that classical psychedelics, notably via agonism at the 5-HT2A receptor, produce pronounced alterations of bodily self-awareness and have shown preliminary therapeutic effects in conditions marked by aberrant body experience. This paper sets out to bridge two literatures: theoretical and empirical accounts of the bodily self (including predictive coding and embodied cognition) and the neuropharmacology and phenomenology of psychedelics. Rather than reporting a systematic meta-analysis, the authors adopt a hybrid narrative approach: they review phenomenology, predictive coding models and neuroimaging findings relevant to bodily self disorders, then propose a hypothetical model in which psychedelics remediate such disorders through 5-HT2A receptor-mediated modulation of multisensory and associative networks. The intent is both to synthesise existing evidence and to generate testable hypotheses for future empirical work.

The extracted text does not present a formal Methods section or a systematic search strategy. Instead, Ho and colleagues conduct a narrative, integrative review that combines phenomenological descriptions, predictive coding theory, neuropharmacological data on classical psychedelics, and neuroimaging findings to construct a mechanistic hypothesis. The authors explicitly describe their approach as hybrid: first reviewing literature on the bodily self, embodied cognition, and predictive coding accounts of selfhood; then surveying neuropharmacological and neuroimaging evidence on psychedelics; and finally proposing a speculative model linking 5-HT2A receptor agonism to remediation of bodily self disorders. Because this is a conceptual review rather than an empirical study, no primary participant recruitment, experimental protocol, or statistical analysis plan is reported. Where the authors discuss clinical or experimental protocols (for example, proposed inclusion/exclusion criteria for future trials, washout of SSRIs, or session structure with preparatory and integrative psychotherapy), these are presented as suggested practical considerations rather than methods used in new data collection. The text does not report databases searched, date ranges, explicit inclusion/exclusion criteria for reviewed studies, or formal risk-of-bias assessment.

The review synthesises phenomenological, theoretical and neuroimaging evidence concerning the bodily self and psychedelic effects. Phenomenologically, the bodily self is parsed into a pre-reflective (embodied, first-person) level and a narrative (autobiographical, reflective) level. The authors link disorders to these levels: depression is discussed as an example of disrupted pre-reflective self (manifesting as hyperembodiment, psychomotor retardation and increased bodily self-focus), while anorexia nervosa is used to illustrate disrupted narrative self (allocentric 'body memory' that fails to be updated by egocentric sensory input). Applying predictive coding and the free-energy principle, Ho and colleagues argue that self-representation arises from hierarchical Bayesian inference in which high-level priors are continually recalibrated by precision-weighted interoceptive and exteroceptive prediction errors. Interoceptive predictive coding, mediated in part by insula and anterior cingulate cortex networks, is highlighted as central to maintaining bodily self-awareness; empirical findings cited (from the extracted text) indicate altered interoceptive accuracy in depression and anorexia. Neuroimaging evidence reviewed indicates that classical psychedelics perturb large-scale brain networks implicated in self-related processing. Typical findings summarised include decreased integrity or desynchronisation of high-level association networks (notably the default mode network, DMN), altered salience network (SN) function, increased connectivity in somatomotor and sensory networks, and changes in medial temporal lobe (MTL) circuitry. The authors describe that subjective phenomena such as disembodiment and ego dissolution correlate with altered connectivity in regions including the posterior cingulate cortex (PCC), temporoparietal junction (TPJ), insula and supplementary motor area. Psychedelic effects on thalamic gating and increased bottom-up information flow are also noted. Building on these empirical motifs, the review presents the REBUS model (relaxed beliefs under psychedelics) as a unifying account: psychedelics decrease the precision of high-level priors (via 5-HT2A receptor-mediated excitation of deep-layer pyramidal neurons), allowing previously suppressed bottom-up prediction errors to influence higher-level models. The authors advance a two-part hypothetical therapeutic mechanism: (1) an acute disintegration of associative and somatomotor predictive coding that destabilises rigid pre-reflective self-models, and (2) a subsequent readaptation in which decreased DMN coupling permits restructuring of autobiographical/narrative self-representations during memory reconsolidation. Clinical and translational observations collected from the literature include case reports and small trials suggesting psilocybin and related compounds can evoke vivid autobiographical recall, shift emotional bias towards positive processing (including modulation of amygdala reactivity), and produce sustained subjective benefits in some patients. The review also notes non-serotonergic agents (e.g. ketamine as an NMDA antagonist; salvinorin-A as a KOR agonist) produce related alterations of bodily self-experience, indicating phenomenological overlap across pharmacologies. Finally, the authors collate proposed practical considerations for future clinical protocols (exclusion of psychosis risk, SSRI washout, supervised sessions with preparatory and integrative therapy) and suggest combining psychedelics with bodily-illusion techniques or mind-body practices to potentiate and stabilise therapeutic gains.

Ho and colleagues interpret the converging literature to propose that psychedelics can modulate the bodily self by perturbing hierarchical predictive coding processes. They suggest that 5-HT2A receptor agonism induces an entropic disintegration of associative networks that maintain the pre-reflective self, thereby loosening overly rigid priors; this permits bottom-up signals to reach higher levels and enables potential revision of maladaptive narrative self-representations during a post-acute readaptation phase. Such a two-stage process could plausibly underlie reported therapeutic effects in disorders characterised by aberrant bodily self-awareness. The authors situate these ideas relative to prior work by emphasising consistency with predictive coding and network-level neuroimaging findings, and by noting that phenomenological reports (for example, altered body sensations, vivid autobiographical recall, and changes in emotional valence) align with the proposed mechanisms. They also highlight therapeutic implications: integrating psychedelics with psychotherapeutic support, virtual reality or bodily-illusion interventions, and mind–body practices may help channel the acute destabilisation into enduring, adaptive changes in self-representation. Key limitations are acknowledged. Ho and colleagues characterise much of the mechanistic proposal as speculative and note the absence of a formal, empirical demonstration tying 5-HT2A-mediated network changes directly to clinical remediation of bodily self disorders. The authors also caution against simplistic comparisons between psychedelic states and psychosis, emphasising differing temporal dynamics and persistence of altered priors. Methodological gaps are noted: the need for anatomically and functionally plausible models to localise aberrant coding mechanisms, behavioural tasks to test predictive coding hypotheses, and more data on long-term effects. Finally, they point out that alterations of bodily self-experience are not unique to serotonergic psychedelics and that other pharmacological routes (e.g. NMDA antagonists, KOR agonists) produce related phenomena, complicating claims about specificity.

The authors conclude that classical psychedelics transiently and reversibly alter consciousness in ways that affect bodily self-experience and autobiographical memory, and that these multidimensional effects may be parsed into processes that destabilise pre-reflective self-models and permit restructuring of the narrative self. While proposing 5-HT2A receptor-mediated entropic disintegration of associative networks together with decreased DMN coupling as a plausible explanatory framework, they emphasise that these mechanisms remain largely hypothetical and require empirical testing. Ho and colleagues call for future research integrating computational predictive coding models, targeted behavioural assays and neuroimaging to better characterise how psychedelically induced changes in the bodily self might be harnessed therapeutically for disorders marked by aberrant body-related self-awareness.