Redefining Me to We: How Psychedelics Reshape Social Boundaries

795 

Abstract Submission 

Pablo Mallaroni¹, Samuel Ereira², Katrin Preller³, Natasha Mason¹, Johannes Ramaekers¹

¹Maastricht University, Maastricht, Limburg, ²Queen Mary University of London, London, ³University of Zurich, Zurich, Switzerland

Pablo Mallaroni, PhD candidate  
Maastricht University
Maastricht, Limburg

Samuel Ereira, MD, PhD  
Queen Mary University of London
London

Katrin Preller, PhD  
University of Zurich
Zurich, Switzerland

Natasha Mason, PhD  
Maastricht University
Maastricht, Limburg

Johannes Ramaekers, PhD  
Maastricht University
Maastricht, Limburg

Meaningful social interactions hinge on our ability to flexibly intuit others' beliefs, a capacity rooted in the brain's ability to encode and simulate others' neural belief patterns. Self-other distinction is thus central to social cognition, and its impairment is a transdiagnostic marker of neuropsychiatric disorders. Psychedelics are suggested to ameliorate socio-cognitive functioning by impairing self-referential awareness and heightening social connectedness (Preller and Vollenweider 2019). While this self-other mergence may stem from a 5-HT2A-mediated perturbation of 'social' brain regions such as the medial prefrontal cortex (mPFC), it is unknown how this is enacted at a neurocomputational level (Stoliker, Egan et al. 2022). We hypothesise serotonergic psychedelics elicit persisting changes to self-other mergeance by impeding belief attribution in a manner that is predictable by acute changes in functional connectivity.

Here, we fitted agent-specific reinforcement learning models to data from 21 healthy participants collected in a probabilistic false-belief task (p-FBT) + 24 hours following the administration of 15mg of psilocybin and 20 mg 2C-B in a within-subjects, placebo-controlled trial. The p-FBT requires participants to assess the probability of an event while also estimating a third-party's perspective on the same event (Ereira, Hauser et al. 2020). Importantly, participants are aware that the third-party might have access to information that differs from their own. By fitting Rescorla–Wagner learning models to subject reports, we defined leakage' parameters between belief updates for Self and Other, hypothesising greater leakage to cause beliefs for Self and Other to covary. To understand how acute perturbations in mPFC connectivity may drive aberrant belief updating, we leveraged corresponding 7T resting-state fMRI data collected 90 min after administration. Regions of interest (ROIs) were extracted from a extended theory of mind (ToM) network comprising the mPFC defined by a reverse inference Neurosynth approach (Yarkoni, Poldrack et al. 2011) and were denoised by regressing six head-motion, cerebrospinal fluid, and white matter parameters. Low-frequency signal drifts were filtered using a 128-s high-pass filter. To assess how causal changes may influence our leakage parameter we employed spectral dynamic causal modelling (sDCM), which fits the complex cross-spectral density using a (parameterized) power-law model of endogenous neuronal fluctuations (Daunizeau, David and Stephan 2011). This consequently provides the effective connectivity (EC) between regions, as well as the amplitude of endogenous neuronal fluctuations within each region. Second-level analyses on the extracted ROI EC values were performed using the Parametric Empirical Bayes Method (Morris 1983).

We find that an egocentric model parameter, quantifying the extent to which observations available to the Self erroneously update estimates of the Other's belief, is significantly reduced following the administration of a psychedelic (F(63)=7.44, p=0.008) First-level fMRI analyses derived four empirical ToM ROIs correspondent to the mPFC, Precuneous, L/R Temporal Parietal Junction (TPJ), which exceeded a DCM explained variance of 50%. ROIs exhibited widespread changes in connectivity in a manner that was interrelated with social cognition outcomes.

Overall, our findings suggest psychedelics foster a less self-centred perspective of others' beliefs, further implicating the 5-HT2A receptor in social learning and offering potential mechanisms for symptomatic relief.

Social Cognition ¹

Decision Making

fMRI Connectivity and Network Modeling

Pharmacology and Neurotransmission ²

Pharmacotherapy

Social Interactions

Other - psychedelics, reinforcement learning, serotonin, dynamic causal modelling