## REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

R. L. Carhart-Harris and K. J. Friston

Pharmacological Reviews, 2019,  71, 316–344

https://doi.org/10.1124/pr.118.017160

Significance Statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . 317
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . 317
II. The REBUS Model . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .  . . . . . . .. . . 322
A. The Basic Neuropharmacology of Psychedelics . . . . . . . . . . . . . . . . . . . . . . . . . . 322
1. Interim Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . .  . . . . 323
B. Rhythms, Networks, and the Relaxation of High-Level Priors. .. . . . . . . . .. . . . 324
1. Interim Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . .  . . . 325
C. Plasticity and the Dissolution of (High-Level) Priors under Psychedelics . .  . . 325
D. Behavioral Evidence of Relaxed Priors under Psychedelics. . . . . . . . . . . . . . .  . 326
E. Comparisons with Other Altered States and Traits . . . . . . . . . . .  . . . . . .  . . . . . 328
1. Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. … .  . . 328
2. Hallucinogen-Persisting Perceptual Disorder . . . . . . . . . . . . . . . . . . . . . . .  . . . . 329
3. Autism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . 329
4. Other Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . 329
5. Meditative States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . 330
F. Psychedelics and Insight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 330
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . 330
2. The Mechanics of Insight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
3. Criticality and Optimality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
4. Therapeutic and Epistemic Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . 334
5. Are Psychedelic-Induced Insights Trustworthy? . . . . . . . . . . . . . . . . . . . . . . . . . . 335
G. What to Do About the “woo”?29 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
H. The Anarchic Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
I. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  .. . . 337
III. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . 339
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   . . 340

### Abstract

This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity— psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavilyweighted highlevel priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives.

Significance Statement : Psychedelics are capturing interest,with efforts underway to bring psilocybin therapy to marketing authorisation and legal access within a decade, spearheaded by the findings of a series of phase 2 trials. In this climate, a compelling unified model of how psychedelics alter brain function to alter consciousness would have appeal. Towards this end, we have sought to integrate a leading model of global brain function, hierarchical predictive coding, with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis. The resulting synthesis states that psychedelics work to relax high-level priors, sensitising them to liberated bottom- up information flow, which, with the right intention, care provision and context, can help guide and cultivate the revision of entrenched pathological priors.

### I. Introduction

Psychedelic (mind-manifesting) drugs such as d-lysergic acid diethylamide (LSD) and psilocybin are capturing people’s imagination and permeating popular culture on a scale not seen since the 1960s (Hanks, 2010; Keshavan and Sudarshan, 2017; Bayne and Carter, 2018; Pollan, 2018). For those involved in research with these compounds, it seems likely that they will influence psychology and psychiatry in amajor way in the coming decades—but there is still much that is uncertain. In the present climate of rapid development, a compelling unified model of the brain mechanisms of psychedelics would hold significant value.

In this work, we propose such a unifying model. We call this relaxed beliefs under psychedelics (REBUS)1 and the anarchic brain or “REBUS” for short. The model takes inspiration from two formulations of brain function, namely: 1) the free-energy principle2 (Friston, 2010) and 2) the entropic brain hypothesis3 (Carhart-Harris, 2018a). The free-energy principle furnishes a unified description of the behavior of autopoietic or living (i.e., self-producing and maintaining) systems—that explains their development, processing, and behavior based on their inherent tendency to resist disorder and minimize uncertainty. This description of (self-evidencing) systems appeals to their inherent drive to optimize internal probabilistic representations—and sampling—of their environments (Friston, 2010). Hierarchical predictive coding forms a major part of the free-energy principle and, thus, the REBUS model also (see Fig. 1 and also the Supplemental Glossary for disambiguation of terms).

The entropic brain hypothesis proposes that within upper and lower bounds, i.e., a critical zone (Hilgetag and Hutt, 2014), the entropy of spontaneous brain activity indexes the richness (i.e., the diversity and vividness) of subjective experience, within any given state of consciousness, and that psychedelics acutely increase both (Carhart-Harris et al., 2014; Carhart- Harris, 2018a). Crucially, both the free-energy and entropic brain formulations rest on quantifiable measures from information theory that are apt for empirical study.

The entropic brain hypothesis and free-energy principle are inter-related, not least because of their shared appeal to information theoretical metrics, closely linked to classic (Shannon) entropy. In its most basic information-theoretical form, entropy is a dimensionless measure of uncertainty about a dynamical phenomenon (Ben-Naim, 2007). The entropic brain measures the uncertainty of neuronal fluctuations across time, whereas free-energy measures the uncertainty of beliefs encoded by neuronal fluctuations. The entropic brain hypothesis proposes that a principal action of psychedelics is to increase the entropy of spontaneous brain activity, and that such effects are mirrored at the subjective level by an increase in the richness of conscious experience, assuming that the brain and mind are flip sides of the same coin, i.e., a position commensurate with so-called “dual aspect monism” (Solms and Turnbull, 2003).

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