New Insight Into How Psychedelics Work 

Batya Swift Yasgur MA, LSW

April 11, 2022

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

Investigators gathered over 6800 accounts 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 with 40 different neurotransmitter subtypes that had likely induced these experiences.

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

"Hallucinogenic drugs may very well turn out to be the next big thing to improve clinical care of major mental health conditions," senior author Danilo Bzdok, MD, PhD, associate professor, McGill University, Montreal, Canada, said 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 neurotransmitter receptor combinations need to be stimulated to induce a specific state of conscious experience in a given person," said Bzdok, who is also the Canada CIFAR AI Chair at Mila-Quebec Artificial Intelligence Institute.

The study was published online March 16 in Science Advances.

"Unique Window"

Psychedelic drugs "show promise" as treatments for various psychiatric disorders, but subjective alterations of reality are "highly variable across individuals" and this "poses a key challenge as we venture to bring hallucinogenic substances into medical practice," the investigators note.

Although the 5-HT2A receptor has been regarded as 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.

Lead author Galen Ballentine, MD, psychiatry resident, SUNY Downstate Medical Center, Brooklyn, New York, told Medscape Medical News that he was "personally eager to find novel ways to identify the neurobiological underpinnings of different states of conscious awareness."

Psychedelics, he said, offer a "unique window into a vast array of unusual states of consciousness and are particularly useful because they can point toward underlying mechanistic processes that are initiated in specific areas of receptor expression."

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

To explore the issue, 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 prism of 40 receptor subtypes."

Unique Neurotransmitter Fingerprint

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

The researchers constructed a "bag-of-words" encoding of the text descriptions in each testimonial. Using linguistic calculation methods, they derived a final vocabulary of 14,410 words that 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 measurements of their relative binding strengths in 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 transporter (NET)

  • Imidazoline-1 receptor (I1)

  • Sigma receptors (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+)

  • NMDA glutamate receptor

To map receptor-experience factors to regional levels of receptor gene transcription, they utilized human gene expression data drawn from the Allen Human Brain Atlas, as well as the Shafer-Yeo brain atlas.

Via a machine-learning algorithm, they dissected the "phenomenologically rich anecdotes" into a ranking of constituent brain-behavior factors, each of which was characterized by a "unique neurotransmitter fingerprint of action and a unique experiential context" and ultimately created a dimensional map of these neurotransmitter systems.

Data-Driven Framework

Cortex-wide distribution of receptor-experience factors was found in both deep and shallow anatomical brain regions. Regions involved in genetic factor expressions were also wide-ranging, spanning from higher association cortices to unimodal sensory cortices.

The dominant factor "elucidated mystical experience in general and the dissolution of self-world boundaries (ego dissolution) in particular," the authors report, while the second- and third-most explanatory factors "evoked auditory, visual, and emotional themes of mental 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 the D2 receptor.

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

"This data-driven framework identifies patterns that undergird diverse psychedelic experiences such as mystical bliss, existential terror, and complex hallucinations," Ballentine commented.

"Simultaneously subjective and neurobiological, these patterns align with the leading 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 primary sensory cortices," he added.

Forging a New Path

Commenting for Medscape Medical News, Scott Aaronson, MD, chief science officer, Institute for Advanced Diagnostics and Therapeutics and director of the Centre of Excellence at Sheppard Pratt, Towson, Maryland, said, "As we try to get our arms around understanding the implications of a psychedelic exposure, forward-thinking researchers like Bzdok et al are offering interesting ways to capture and understand the experience."

Aaronson, an adjunct professor at the University of Maryland School of Medicine who was not involved with the study, continued: "Using the rapidly developing field of natural language processing (NLP), which looks at how language is used for a deeper understanding of human experiences, and combining it with effects of psychedelic compounds on neuronal pathways and neurochemical receptor sites, the authors are forging a new path for further inquiry." 

In an accompanying editorial, Daniel 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 City, call the work "impressive" and "clever."

"Psychedelics paired with new applications of computational tools might help bypass the imprecision of psychiatric diagnosis and connect measures of behavior to specific physiologic targets," they write.

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

Sci Adv. Published online March 16, 2022. Full text, Editorial

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