[RETRACTED] A mechanistic model of the neural entropy increase elicited by psychedelic drugs

This whole-brain simulation study (DMF model) reproduced increased entropy under psychedelics, but also found this to be different (higher/lower) in various parts of the brain, this was correlated with the connections between brain regions, not serotonin (5-HT2a) receptor density.

Abstract

“Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, encoding both acute alterations in consciousness and mediating long-term effects. However, no clear mechanistic explanation for this ’entropic’ phenomenon has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain’s anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.”

Authors: Ruben Herzog, Pedro A. M. Mediano, Fernando E. Rosas, Robin L. Carhart-Harris, Yonatan Sanz Perl, Enzo Tagliazucchi & Rodrigo Cofre

Notes

This paper builds on earlier (fMRI, brain imaging) work by Carhart-Harris et al. (2016) (and many other papers) which mapped the brain under the influence of LSD.

This paper has been retracted on 15 September 2022 due to an error in the script that ran the analysis. At this time, it seems no other appears are affected. An article in Retraction Watch, published on 8 October 2022, details the retraction’s cooperative and open nature.

Summary

INTRODUCTION

Near-death experiences (NDEs) are complex experiential episodes that occur in association with death or the perception that it is impending. They are often characterized by feelings of inner-peace, out-of-body experiences, traveling through a dark region or void, and communicating with sentient ‘beings’.

Commonly described features of the DMT experience include transcending one’s body and entering into an alternative ‘realm’, perceiving and communicating with ‘presences’ or ‘entities’, plus reflections on death, dying and the after-life.

The term near-death experience (NDE) was coined by Raymond Moody more than 40 years ago, and the phenomenology of the classic serotonergic psychedelic experience and NDEs is similar. Ayahuasca, a DMT-containing Amazonian brew, has also been linked to themes of death and dying.

The intensity and quality of a psychedelic experience and the content of a near death experience appear to be sensitive to contextual factors, such as prior psychological traits and state, the environment in which the experience unfolds, and the broader cultural context in which they are embedded.

Near-death experiences have been associated with long-term positive changes in psychological well-being and related outcomes. Similar long-term positive changes have been observed in studies with psychedelic compounds, including reduced death anxiety, pro-ecological behavior, and nature relatedness.

This current study aimed to directly measure the extent to which intravenous DMT given to healthy volunteers in a laboratory setting could induce a near-death type experience as determined by a standard NDE rating scale.

We hypothesized that DMT would induce near-death type experiences, and that age, personality and a propensity toward delusional thinking would correlate with NDEs.

Experimental Design

Thirteen healthy volunteers participated in a fixed-order, placebo-controlled, single blind study, approved by the National Research Ethics Service (NRES) Committee London – Brent and the Health Research Authority (HRA). All subjects gave written informed consent in accordance with the Declaration of Helsinki.

Screening

Participants were recruited via word-of-mouth and received an information sheet detailing all study procedures prior to the screening visits. They were required to abstain from using psychoactive drugs at least 7 days prior to study participation.

Following screening, participants were enrolled for 2 dosing sessions in which DMT and placebo were administered. Questionnaires were completed following each dosing session.

Study Procedures and Participants

Participants rested in a dimly lit room while low volume music was played in the background. EEG recordings were taken before and following administration of DMT and placebo.

Participants received one of four doses of DMT fumarate via intravenous route in a 2 ml sterile solution over 30 s, followed by a 5 ml saline flush lasting 15 s. Placebo was administered during the first dosing session, and DMT 1 week later.

DMT was administered to volunteers in a 30 s injection. Participants reported feeling the subjective effects immediately after the injection or during the flush which came soon after it.

Acute Outcomes

The Near-Death Experience scale was used to determine the degree to which DMT induces near-death type experiences. A total score higher or equal to 7 is considered the threshold for a NDE.

The overlap between drug-induced NDEs and other relevant psychological phenomena associated with psychedelic drugs was also addressed by including the Ego Dissolution Inventory (EDI) and the Mystical Experiences Questionnaire (MEQ).

Correlations with personality trait absorption, delusional thinking and age

The relationship between personality, suggestibility, delusional thinking and age with the magnitude of the NDE scores was assessed using questionnaires completed at baseline. The relationship between age and NDE scores was negatively correlated with delusional thinking.

Pearson-product moment correlations were used to test for relationships between relevant variables and main outcomes (i.e., absorption, delusional thinking and age with NDE scores).

Comparison to ‘actual’ NDE group

To address the degree of overlap between our results and the features typically reported by people who have reported ‘actual’ NDEs, we conducted a separate comparison with a gender and age matched sample of individuals who had completed the NDE scale.

Statistical Analysis

To compare the acute effects of DMT with those of placebo, repeated measures ANOVA and paired t-tests were performed on the NDE scale and the MEQ. The relationship between the DMT state and near-death experiences was also assessed using paired t-tests and Pearson-Product Moment Correlation.

All analyses used t-tests and Pearson-Product Moment Correlations. Bonferroni-correction was used for multiple comparisons.

DMT Induces Near-Death Type Experiences

All participants scored above the conventional cutoff for a near-death experience (NDE) following DMT administration, and one participant had a total score of 7 following placebo. Paired t-tests on each of the 16 items comprising the NDE scale revealed that the DMT experience was significantly enhanced.

Ego-Dissolution Inventory (EDI) and Mystical Experience Questionnaire (MEQ)

A paired comparison using the EDI revealed that DMT significantly increased total scores compared to placebo, and the Mystical Experience Questionnaire revealed that all MEQ factors were significantly higher following DMT compared to placebo.

The difference between DMT and placebo scores for the NDE scale, EDI and MEQ were used for correlation analysis. The results revealed that the Mystical and Transcendence of Time and Space factors were most strongly associated with the DMT-induced near-death type experiences.

Correlations With Personality, Delusional Ideation and Age

The personality trait absorption has been associated with NDEs in patient populations, and a correlation between the Tellegen Absorption Scale (MODTAS) and NDE questionnaire was performed. The results showed that baseline PDI scores and NDE scores were positively correlated, but this relationship did not survive multiple comparison correction.

Comparison to ‘Actual’ Near-Death Experiences

A gender/age matched sample of volunteers who reported having gone through an ‘actual’ NDE was analyzed, and the results showed that the total NDE scores induced by DMT are comparable to those given by the ‘actual’ NDE group.

DISCUSSION

This study examined whether DMT elicits similar features to NDEs in a placebo-controlled study. The results revealed that all 13 participants scored above the standard threshold for an NDE.

Near-death type experiences induced by DMT were similar to mystical-type experiences, with the Mystical factor of the MEQ showing the highest relationship with NDE total scores. Additionally, DMT-induced NDE scores were significantly correlated with baseline-measured delusional thinking.

DMT enhanced extrasensory perception, life-review, precognition of future events, increased speed of thoughts and seeing deceased people/relatives, but actual NDEs also feature emotion. These differences may be explained by the very different contexts in which these experiences occur.

The phenomenology of NDEs is still a matter of some investigation, and the temporal sequence of events unfolding during an NDE is highly variable between people. However, four main dimensions are relatively consistent, namely: out-of-body experiences, seeing a bright light, encountering spirits/people, and a feeling of peace.

Personality traits have previously been shown to be associated with response to psychedelics and NDEs. Here, we saw a trend toward absorption predicting DMT-induced NDE, but this relationship did not reach statistical significance.

The reported intensity of NDEs is associated with a tendency to report so-called ‘paranormal’ experiences, and baseline delusional thinking is strongly associated with NDE scores. This could be because people with higher than average delusional thinking see NDE phenomena as less at odds with their pre-existing belief systems.

We found a strong relationship between scores of DMT-induced near-death type and mystical-type experiences. This relationship may be due to similar items featuring in both scales, or because there are some items that are distinct between the scales.

Recent work has consistently shown that mystical-type experiences are predictive of long-term therapeutic benefit from psychedelics, and similar mechanisms may be at play in relation to improved mental well-being post NDE. The so-called ‘unitive experience’ is recognized in descriptions of the mystical experience, the peak experience, and the ‘oceanic feeling’, and may be the common factor that bridges between these different states and is also responsible for the longer-term psychological benefits associated with them.

Detailed interviewing techniques could improve our understanding of the phenomenology of the DMT and NDE states, and future studies could benefit from adopting a more dynamic sampling approach. This would help refine our understanding of the psychology and associated neurobiology of the psychedelic state.

Under psychedelics, medial temporal lobe activity may be implicated in the processing of content and emotion-rich epochs such as complex imagery, entity encounters, and vivid autobiographical recollections.

Limitations

This study had limitations due to the fact that the dose of DMT was not uniform for all participants, and individuals included in the NDE sample had to give NDE-scale scores above a specific threshold.

The NDE scale may have a liberal threshold for determining NDEs, and thus may warrant revision. However, participants’ mental state had largely returned to baseline by the time they completed the NDE scale, and responses to the different dimensions of the NDE scale resembled those seen in relation to actual NDEs.

Both psychedelics and near-death experiences appear to be strongly influenced by contextual factors, and it could be argued that significant differences may exist regarding phenomenological features between both experiences. However, the study of such differences might require the use of other methods addressing nuances not explored here.

CONCLUSION

This study aimed to examine the potential overlap between the phenomenology of near-death experiences and those associated with the potent serotonergic psychedelic DMT. Results revealed a strong overlap, with only subtle differences that might relate more to obvious contextual differences than anything to do with the specific inducers themselves.

AUTHOR CONTRIBUTIONS

CT, LR, LW, DE, CM, HC, and SL conducted the research, and RC-H wrote the paper.

ACKNOWLEDGMENTS

The authors would like to thank all study participants, the NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, and the Beckley Foundation for their support.