Effects of external stimulation on psychedelic state neurodynamics, Pedro A.M. Mediano et al., 2020

Effects of external stimulation on psychedelic state neurodynamics

Pedro A.M. Mediano, Fernando E. Rosas, Christopher Timmermann, Leor Roseman, David J. Nutt, Amanda Feilding, Mendel Kaelen, Morten L. Kringelbach, Adam B. Barretti, Anil K. Seth, Suresh Muthukumaraswamy, Daniel Bor, and Robin L. Carhart-Harris

bioRxiv preprint, 2020

doi : 10.1101/2020.11.01.356071



Recent findings have shown that psychedelics reliably enhance brain entropy (understood as neural signal diversity), and this effect has been associated with both acute and long-term psychological outcomes such as personality changes. These findings are particularly intriguing given that a decrease of brain entropy is a robust indicator of loss of consciousness (e.g. from wakefulness to sleep). However, little is known about how context impacts the entropy-enhancing effect of psychedelics, which carries important implications for how it can be exploited in, for example, psychedelic psychotherapy. This article investigates how brain entropy is modulated by stimulus manipulation during a psychedelic experience, by studying participants under the effects of LSD or placebo, either with gross state changes (eyes closed vs. open) or different stimulus (no stimulus vs. music vs. video). Results show that while brain entropy increases with LSD in all the experimental conditions, it exhibits largest changes when subjects have their eyes closed. Furthermore, brain entropy changes are consistently associated with subjective ratings of the psychedelic experience, but this relationship is disrupted when participants are viewing video — potentially due to a “competition” between external stimuli and endogenous LSD-induced imagery. Taken together, our findings provide strong quantitative evidence for the role of context in modulating neural dynamics during a psychedelic experience, underlining the importance of performing psychedelic psychotherapy in a suitable environment.

Additionally, our findings put into question simplistic interpretations of brain entropy as a direct neural correlate of conscious level.

Complexity | Psychedelics | Neuroscience | Consciousness

Psychedelic substances, such as LSD and psilocybin, are known to induce profound changes in subjects’ perception, cognition, and conscious experience. In addition to their role in ancestral spiritual and religious practices, and their recreational use related to introspection and self-exploration, there is promising evidence that psychedelics can be used therapeutically to treat multiple mental health conditions (1–4). However, despite the increasingly available evidence of the neurochemical action of psychedelics at the neuronal and sub-neuronal level (5, 6), the mechanisms associated with their therapeutic efficacy are not yet completely understood.

Some of the factors at play during psychedelic therapy can be related to the Entropic Brain Hypothesis (EBH) (7, 8), a simple yet powerful theory which posits that the rich altered state of consciousness experienced under psychedelics depends on a parallel enriching effect on the dynamics of spontaneous
population-level neuronal activity.* The hypothesis that increased brain entropy — as captured e.g. by Lempel-Ziv (LZ) complexity (8) — corresponds to states of enriched experience has found empirical support in neuroimaging research on psychedelics (9, 10), as well as on other altered states, like meditation (11) and states of “flow” associated with musical improvisation (12). Furthermore, the therapeutic mechanisms of psychedelics are thought to depend on their acute entropy- 24
enhancing effect, potentially reflecting a window of opportunity (and plasticity) mediating therapeutic change (13, 14). Conversely, states such as deep sleep, general anaesthesia, and loss of consciousness have consistently shown reduced brain entropy (15–17).

The effectiveness of psychedelic therapy is thought to depend not only on direct neuropharmacological action, but also on contextual factors — commonly referred to as set and setting. These include the subject’s mood, expectations, and broader psychological condition (set) prior to the “trip”, together with the sensorial, social, and cultural environment (setting) in which the drug is taken. For example, there is direct physiological evidence that (visual) stimuli affect the expression of serotonergic receptor genes (18), and that specific music choices may either enhance or impede therapeutic outcomes (19).

Despite its presumed importance, to our knowledge no previous study has systematically assessed the influence of set and setting on brain activity and subjective experience during a psychedelic experience. This lack of relevant research, combined with the fact that psychedelic therapy is almost exclusively carried out with music listening and eyes closed, exposes a knowledge gap that compromises key assumptions of current psychedelic therapy practice. Here, we provide a first step towards bridging this gap, presenting a systematic investigation of how different environmental conditions can modulate changes in brain entropy elicited by psychedelics in healthy subjects. This work provides a proof of principle that paves the way for future studies with clinical cohorts.