LSD-induced entropic brain activity predicts subsequent personality change

This counterbalanced, placebo‐controlled within-subjects study (n=19) investigated whether the combination of administering LSD (75µg/70kg) while listening to music can induce changes in entropic brain activity during resting state, and cause subsequent changes in personality structure. Results indicated that acute increases in brain entropy affecting the disintegration of functional connectivity within sensory and higher-order networks were predictive of subsequent increases in trait openness measured two weeks later. This relationship was enhanced by listening to music.

Abstract

“Introduction: Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced‐order, placebo‐controlled study, we investigated biological predictors of post‐lysergic acid diethylamide (LSD) changes in personality.

Methods: Nineteen healthy adults underwent resting-state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO‐PI‐R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5‐min eyes‐closed resting‐state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time series. Mixed‐effects models were used to evaluate drug‐induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2‐week follow‐up.

Results: Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music‐listening scans and when “ego‐dissolution” was reported during the acute experience.

Discussion: These results shed new light on how LSD‐induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality.”

Authors: Alexander V. Lebedev, Mendel Kaelen, M. Lovden, J. Nilsson, Amanda Feilding, David J. Nutt & Robin L. Carhart-Harris

Summary

INTRODUCTION

After several decades of effective prohibition, researchers have begun to re-examine the therapeutic potential of psychedelic drugs, with promising preliminary results.

The dominant approach to psychedelic-assisted therapy involves one or a small number of high-dose sessions that aim to evoke so-called peak experiences, characterized by dissolved ego boundaries and a concomitant sense of oneness or unity.

In healthy individuals, a single session with the shorter-acting LSD-like psychedelic psilocybin can produce lasting increases in the personality trait openness. These increases were greatest in individuals who reported mystical-type experiences in relation to their psilocybin session.

LSD has been shown to have a variety of psychological effects, including desynchronization of cortical activity, increased amplitude of oscillations within limbic structures, and a shift toward more random dynamics within higher-order brain networks.

Inspired by neuroimaging research with psychedelics, an entropic brain hypothesis was recently formulated that proposed that altered states of consciousness lie toward the primary consciousness end of this entropy continuum.

In recent years, there has been a concerted effort to map out the neural correlates of the acute psychedelic state. However, less attention has been paid to how these acute effects of psychedelics relate to more enduring psychological and behavioral changes.

Participants

Twenty healthy subjects aged 30.9 6 7.8 years, 15 males, were recruited via word-of-mouth and underwent standard physical and psychiatric examinations, electrophysiological, blood and urine tests for drugs of abuse and pregnancy.

One subject requested the MRI to be stopped prematurely due to anxiety, but the behavioral data collected was consistent with the group.

Study Design and Procedures

Two sessions with 75 mg of LSD or placebo were scheduled for each participant, with an interval of at least two weeks between each session. Three 7.5-min BOLD resting-state fMRI scans were acquired for each session, with a standardized protocol described in Supporting Information.

Personality Assessment and In-Scanner Subjective Measures

A 240-item revised five-factor personality inventory and a visual analogue scale assessing the intensity of ego-dissolution were administered to evaluate changes in personality after an LSD/placebo session.

For each subject, echo-planar images underwent steps for slice-timing correction, spatial realignment, and registration to standardized MNI space, followed by detrending and band-pass filtering to eliminate biologically non-relevant signals.

The greater a signal’s sample entropy, the lower is its predictability. The entropy maps were parcellated with Yeo’s 17-networks functional scheme and smoothed with a Gaussian kernel.

To evaluate robustness of the effects, we used a multi-scale version of sample entropy, which involves splitting a time series into non-overlapping time-windows and calculating SamEn.

Statistical Analysis

Statistical analyses were carried out using R programming language, version 3.2.2, with nlme package used for mixed-effect modeling. Voxel-wise contrast estimations were accomplished after the ROI-based analyses using SPM12.

A direct comparison of brain dynamics under LSD and placebo was performed using mixed-effects modeling. Minor sound problems were introduced to the models, but generally had little impact on the results.

LSD-induced entropy increases relative to placebo were used to predict personality trait openness 2 weeks after the LSD session.

We introduced ego-dissolution as an additional variable and estimated a full four-way interaction effect between ego-dissolution, personality, state, and music-listening.

A set of analyses was carried out to evaluate the stability of the results after taking into account effects of drug administration order and the impact of previous psychedelic experience on the main contrasts.

Direct Effects of LSD on Sample Entropy

LSD’s effect on brain entropy was well spatially distributed, significantly affecting 11 out of 17 functional systems, and was located in the frontoparietal, medial occipital, posterior and dorsal cingulate regions.

Personality Changes

This study examined changes in trait openness after LSD and found that this trait was significantly affected. No significant changes in openness were observed post-placebo.

Acute Shifts in Brain Dynamics as a Predictor of Changes in Openness

LSD-induced increases in brain entropy showed correlations with subsequent increases in trait openness. Both direct effects of the drug on entropy and change-by-state interactions were predictive of subsequent increases in openness.

Interaction with In-Scanner Measures of Ego-Dissolution

A four-way interaction for openness (DEntropy 2 DOpenness 3 State 3 Ego-dissolution) was significant for the orbitofrontal and superior frontoparietal networks, but not at the global level.

Effects of Drug Order and Previous Psychedelic Experience

Introducing drug order into the models did not eliminate the effects of previous psychedelic experience on openness.

DISCUSSION

LSD exposure was associated with prominent increases in brain entropy, which were predictive of subsequent increases in trait openness measured 2 weeks later.

Psychedelic drugs have been found to enhance associative learning, cognitive performance, extinction of conditioned fear in rodents, and creativity in humans. They are also showing promise in the treatment of drug addiction, depression, and anxiety associated with life-threatening illnesses.

Future research should focus on the neurobiological underpinnings of the long-term effects of psychedelics on outlook and behavior, including the possibility that the profound, transformative nature of the acute psychological experience may drive subsequent personality change. Personality traits reach maturity by adulthood and remain relatively stable until old age. However, major life events can have a significant impact on personality, and a single high-dose of psilocybin can promote sustained positive changes in attitudes and behavior.

Psychological experiences, such as psychedelics, can lead individuals to question their prior assumptions and change their behavior and outlook. If handled with appropriate care, these experiences can promote insights and self-actualization.

Most “classic” psychedelic drugs have agonist properties at the serotonin 2A receptor. This receptor sub-type is thought to be necessary for the occurrence of profound psychological experiences and may also play a role in psychological changes observed in relation to trauma, psychosis and existential crises.

The involvement of 5-HT2ARs in major psychological/behavioral change is supported by findings of 5-HT2AR-mediated enhancements in neural plasticity, associative learning, and cognitive performance in animals, as well as previous and present findings of major personality change in association with psychedelic drugs.

The so-called psychedelic afterglow is a period sometimes lasting several weeks after a high-dose psychedelic experience that is associated with improved mood, liberation from emotional burdens and renewed resilience.

The present study observed that music had a relaxing effect on participants, possibly increasing the likelihood of entropic brain dynamics and associated psychological phenomena. The effects of LSD on personality were not significantly diminished by previous psychedelic use.

The present study discovered that people with more entropic brain activity under LSD showed larger increases in openness in the weeks following their experience. Moreover, the relationship between brain activity and personality change was enhanced when participants listened to music and experienced ego-dissolution.

Our results suggest that psychedelics can open the mind up to change that can be profound and lasting, and stimulate additional questions about what other psychological and/or behavioral traits might be sensitive to psychedelic-induced change.