New insight into how psychedelics work

What causes the dramatic alterations in subjective consciousness experienced during a psychedelic “trip”? A new study maps the anatomical changes in specific neurotransmitter systems and brain regions that may be responsible for these effects.

Investigators collected more than 6,800 testimonies from individuals who had taken one of 27 different psychedelic compounds. Using a machine learning strategy, they extracted commonly used words from these testimonials, linking them to 40 different neurotransmitter subtypes that likely mediated these experiences.

The researchers then linked these subjective experiences to specific brain regions where the receptor combinations are most often found and, using gene transcription probes, created a 3D whole-brain map of brain receptors and subjective experiences. which are related to them.

“Hallucinogenic drugs may very well turn out to be the next big thing to improve clinical care of major mental health conditions,” said lead author Danilo Bzdok, MD, PhD, associate professor, McGill University, Montreal, Canada , in a press release.

“Our study provides a first step, a proof of principle, that we may be able to build machine learning systems in the future that can accurately predict which combinations of neurotransmitter receptors need to be stimulated to induce a specific state. of conscious experience in a given person,” said Bzdok, who also holds the Canada-CIFAR Chair in AI at the Mila-Québec Artificial Intelligence Institute.

The study was published online March 16 to Scientists progress.

“Single Window”

Psychedelic drugs “show promise” as treatments for various psychiatric disorders, but subjective reality alterations are “highly variable from individual to individual” and this “poses a major challenge as we venture to introduce hallucinogenic substances in medical practice,” note the investigators.

Although the 5-HT2A receptor has been considered a “putative essential mechanism” of hallucinogenic experiences, it is unclear whether the experiential differences are explained by functional selectivity at the 5-HT2A receptor itself or ” orchestrated by the vast array of neurotransmitter receptor subclasses”. on which these drugs act,” they add.

Senior author Galen Ballentine, MD, resident in psychiatry, SUNY Downstate Medical Center, Brooklyn, New York, said Medscape Medical News that he was “personally keen to find new ways to identify the neurobiological underpinnings of different states of consciousness.”

Psychedelics, he said, provide a “unique window into a wide range of unusual states of consciousness and are particularly useful because they can indicate underlying mechanistic processes that are initiated in specific areas of receivers”.

The investigators wanted to understand “how these drugs work in order to help guide their use in clinical practice,” Ballentine said.

To explore the question, they undertook “the largest investigation to date into the neuroscience of psychedelic drug experiences,” Ballentine said. “While most studies are limited to a single drug on a handful of subjects, this project integrates thousands of experiences induced by dozens of different hallucinogenic compounds, viewing them through the lens of 40 receptor subtypes .”

Unique Neurotransmitter Fingerprint

The researchers analyzed 6850 experience reports from people who had taken 1 of the 27 psychedelic compounds. The reports were drawn from a database hosted by the Erowid Centeran organization that collects first-hand accounts of experiences with psychoactive drugs.

The researchers constructed a “bag of words” encoding the textual descriptions of each testimony. Using linguistic computational methods, they derived a final vocabulary of 14,410 words which they analyzed for descriptive experiential terms.

To shed light on the spatial distribution of these compounds that modulate neuronal activity during subjective “trips”, they compared normalized measures of their relative binding strengths at 40 sites.

  • 5-HT (5-HT2A, 5-HT2C, 5-HT2B, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT5A, 5-HT6, 5-HT7)

  • Dopamine (D1, D2, D3, D4, D5)

  • Adrenergic (a-1A, a-1B, a-2A, a-2B, a-2C, b-1, b-2)

  • Serotonin Transporter (SERT)

  • Dopamine transporter (DAT)

  • Norepinephrine carrier (NET)

  • Imidazoline-1 (I1) receptor

  • Sigma receivers (s-1, s-2)

  • d-opioid receptor (DOR)

  • k-opioid receptor (KOR)

  • m-opioid receptor (MOR)

  • Muscarinic receptors (M1, M2, M3, M4, M5)

  • Histamine receptors (H1, H2)

  • Calcium ion channel (CA+)

  • Glutamate NMDA receptor

To map receptor experience factors to regional levels of receptor gene transcription, they used human gene expression data from the Allen Atlas of the Human Brainas well as Shafer-Yeo’s Brain Atlas.

Using a machine learning algorithm, they dissected the “phenomenologically rich anecdotes” into a ranking of the constituent factors of brain behavior, each characterized by a “unique neurotransmitter action imprint and unique experiential context” and finally created a dimensional map. of these neurotransmitter systems.

Data-driven framework

A cortex-wide distribution of receptor experience factors was found in deep and shallow anatomical brain regions. Regions involved in the expression of genetic factors were also highly varied, ranging from higher association cortices to unimodal sensory cortices.

The dominant factor “elucidated mystical experience in general and the dissolution of the boundaries of the world of the self (dissolution of the ego) in particular”, report the authors, while the second and third most important explanatory factors “evoked themes auditory, visual and emotional of the mind. expansion.”

Ego dissolution was found to be most associated with the 5-HT2A receptor, as well as other serotonin receptors (5-HT2C, 5-HT1A, 5-HT2B), adrenergic receptors a- 2A and b-2 and to the receiver D2.

Alterations in sensory perception were associated with 5-HT2A receptor expression in the visual cortex, while modulation of the salience network by dopamine and opioid receptors was implicated in the experience of space transcendence, time and self-structure. The auditory hallucinations were linked to a weighted mix of receptors expressed throughout the auditory cortex.

“This data-driven framework identifies patterns that underlie various psychedelic experiences such as mystical bliss, existential dread, and complex hallucinations,” Ballentine commented.

“Simultaneously subjective and neurobiological, these patterns align with the central hypothesis that psychedelics temporarily diminish top-down control of the most evolutionarily advanced regions of the brain, while at the same time amplifying bottom-up sensory processing. from the primary sensory cortices,” he added. .

forging a new path

Commenting for Medscape Medical NewsScott Aaronson, MD, scientific director of the Institute for Advanced Diagnostics and Therapeutics and director of the Sheppard Pratt Center of Excellence, Towson, Maryland, said, “As we try to understand the implications of psychedelic exposure, Forward-thinking researchers like Bzdok et al are offering interesting ways to capture and understand experience.”

Aaronson, an assistant professor at the University of Maryland School of Medicine who was not involved in the study, continued, “Using the rapidly developing field of natural language processing (NLP), which examines how the language is used for a deeper understanding of the human being. experiments, and combining them with the effects of psychedelic compounds on neural pathways and neurochemical receptor sites, the authors forge a new avenue for further investigation.”

In a accompanying editorialDaniel Barron, MD, PhD, Medical Director, Interventional Pain Psychiatry Program, Brigham and Women’s Hospital, Boston, and Richard Friedman, MD, Professor of Clinical Psychiatry, Weill Cornell Medical College, New York, call this work “impressive” and “intelligent.”

“Psychedelics combined with novel applications of computational tools could help circumvent the imprecision of psychiatric diagnosis and link behavioral measures to specific physiological targets,” they write.

The research was sponsored by the Brain Canada Foundation, through the Canadian Brain Research Fund, a grant from the NIH grant, and the Canadian Institutes of Health Research. Bzdok has also been supported by the Healthy Brains Healthy Lives initiative (Canada First Research Excellence Fund) and the CIFAR (Canadian Institute for Advanced Research) Chairs in Artificial Intelligence program, as well as the Research Award and the teaching from Google. Disclosures by other authors are listed on the original article. No disclosures have been listed for Barron and Friedman. Aaronson’s research is supported by Compass Pathways.

Science Adv. Published online March 16, 2022. Full Text, Editorial

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