Default Mode Network Modulation by Psychedelics: A Systematic Review

Abstract

Psychedelics are a unique class of drug that commonly produce vivid hallucinations as well as profound psychological and mystical experiences. A grouping of interconnected brain regions characterized by increased temporal coherence at rest have been termed the Default Mode Network (DMN). The DMN has been the focus of numerous studies assessing its role in self-referencing, mind wandering, and autobiographical memories. Altered connectivity in the DMN has been associated with a range of neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder, attention deficit hyperactive disorder, schizophrenia, and obsessive-compulsive disorder. To date, several studies have investigated how psychedelics modulate this network, but no comprehensive review, to our knowledge, has critically evaluated how major classical psychedelic agents-lysergic acid diethylamide, psilocybin, and ayahuasca-modulate the DMN. Here we present a systematic review of the knowledge base. Across psychedelics there is consistent acute disruption in resting state connectivity within the DMN and increased functional connectivity between canonical resting-state networks. Various models have been proposed to explain the cognitive mechanisms of psychedelics, and in one model DMN modulation is a central axiom. Although the DMN is consistently implicated in psychedelic studies, it is unclear how central the DMN is to the therapeutic potential of classical psychedelic agents. This article aims to provide the field with a comprehensive overview that can propel future research in such a way as to elucidate the neurocognitive mechanisms of psychedelics.

Keywords: DMN; LSD; Psychedelics; ayahuasca; connectivity; psilocybin.

Figure 1.

Reprinted by permission from [Springer Nature]: Nature [Nature Reviews Neuroscience]. The default mode network in cognition: a topographical perspective, Smallwood et al. (2021). Brain regions of the DMN based on the coherence of their temporal activity, measured at rest. These regions are the posteromedial cortex (PMC), the medial prefrontal cortex (MPFC), angular gyrus (AG), middle temporal cortex (MTC), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG).

Figure 2.

PRISMA flow diagram (Page et al., 2021) for study selection. Although 28 papers were included, 1 paper (Varley et al., 2020) included 1 analysis on psilocybin and 1 on LSD.

Figure 3.

fMRI activity patterns of the various psychedelics on regions of the DMN. (A) Blue BOLD signals represent significant brain deactivations after psilocybin compared with placebo (adapted from Carhart-Harris et al., (2016)). (B) Significant BOLD decreases of the DMN after the ingestion of Ayahuasca (adapted from Palhano-Fontes et al., (2015)). (C) Between-group differences (LSD vs placebo) in the FC between a key DMN node (bilateral hippocampal seed) and the rest of the brain. Orange represents increases in FC between the seed at the parahippocampus, and cyan/blue signifies decreases. Pink is a mask of the parahippocampal gyrus [adapted from Carhart-Harris et al., (2016)]. This figure is used to help visually compare and contrast the heterogeneity of activity patterns between 3 foundational studies, but it should be noted that other neuroimaging studies exist that are not included. Blood-oxygen-level-dependent (BOLD), Default mode network (DMN), Functional connectivity (FC).