Trips and Neurotransmitters: Discovering Principled Patterns across 6,850 Hallucinogenic Experiences

This text mining preprint examines language patterns of Erowid trip reports (n=6850) and maps the subjective experience of 27 psychedelic drugs onto 40 neurotransmitter receptor subtypes expressed across the anatomy of the brain. Their analysis links phenomena such as ego-dissolution and other changes of consciousness to the disintegration of higher-order association circuits, which rebalances the highly integrative top-down control over bottom-up sensory signalling from the primary audiovisual cortices.

Abstract

Introduction: Psychedelics are thought to alter states of consciousness by disrupting how the higher association cortex governs bottom-up sensory signals. Individual hallucinogenic drugs are usually studied in participants in controlled laboratory settings.

Methods: Here, we have explored word usage in 6,850 free-form testimonials with 27 drugs through the prism of 40 neurotransmitter receptor subtypes, which were then mapped to 3D coordinates in the brain via their gene transcription levels from invasive tissue probes.

Results: Despite the variable subjective nature of hallucinogenic experiences, our pattern-learning approach delineated how drug-induced changes of conscious awareness (e.g., dissolving self-world boundaries or fractal distortion of visual perception) are linked to cortex-wide anatomical distributions of receptor density proxies. The dominant explanatory factor related ego-dissolution-like phenomena to a constellation of 5-HT2A, D2, KOR, and NMDA receptors, anchored especially in the brain’s deep hierarchy (epitomized by the associative higher-order cortex) and shallow hierarchy (epitomized by the visual cortex). Additional factors captured psychological phenomena in which emotions (5-HT2A and Imidazoline1) were in tension with auditory (SERT, 5-HT1A) or visual (5-HT2A) sensations.

Discussion: Each discovered receptor-experience factor spanned between a higher-level association pole and a sensory input pole, which may relate to the previously reported collapse of hierarchical order among large-scale networks. Simultaneously considering many psychoactive molecules and thousands of natural language descriptions of drug experiences our framework finds the underlying semantic structure and maps it directly to the brain. These advances could assist in unlocking their wide-ranging potential for medical treatment.”

Authors: Galen Ballentine, Samuel Freesun Friedman & Danilo Bzdok

Summary

ABSTRACT

Psychedelics alter states of consciousness by disrupting how the higher association cortex governs bottom-up sensory signals. We studied 6,850 free-form testimonials with 27 drugs and found that the underlying semantic structure and mapping of drug experiences can assist in unlocking their wide-ranging potential for medical treatment.

INTRODUCTION

Humans have been drawn to consume hallucinogenic substances to deliberately alter states of consciousness for thousands of years. These drug-induced mental states can be highly variable across individuals and may depend on one’s life history, world view, and the setting of the experience.

Clinical studies have shown that drugs can affect high-level thought, and these drugs have been closely linked to experiential phenomena such as ‘ego dissolution’.

The ‘classical psychedelics’ alter perception of self and the world by acting primarily on the 5-HT2A receptor. However, non-traditional psychedelic-like drugs such as ketamine, MDMA, ibogaine, and salvia divinorum act on similar neurotransmitter receptors and may therefore have a similar effect.

Hallucinogens are compounds that temporarily modify conscious awareness. They cause both unique and convergent effects on subjective perception, and new research avenues are needed to illuminate the common denominator.

Hallucinogens are thought to mediate psychological effects through functional coupling shifts between large-scale brain networks, resulting in a flood of minimally filtered processing of interoceptive and exteroceptive sensory information and a concomitant disintegration of ordinary self-awareness.

The mechanism of hallucinogenic drug action depends on multiple parameters, including functional activity at receptors and neuroanatomical distribution of these receptors throughout the cortex.

In this study, we have linked 6,850 real-world experience samples to hallucinogenic drug affinity for neurotransmitter receptor subclasses. This allows us to explore overarching principles that may encapsulate how specific sets of receptor bindings are linked to specific drug-induced alterations of subjective awareness.

RESULTS

We aimed to illuminate key principles that mediate hallucinogenic states of consciousness by dissecting phenomenologically rich anecdotes into a ranking of constituent brain-behavior factors. The dominant factor elucidated mystical experience, and the second and third most explanatory factors evoked auditory, visual, and emotional themes of mental expansion.

The cortical mappings of factor expression often turned out to be spatially contiguous, respecting well-known anatomical and functional divisions. Moreover, salient brain-behavior effects were often found to be mirrored in homologous brain regions in the left and right hemisphere.

The 5-HT2A receptor was the strongest factor explaining the largest portion of systematic joint variation between receptor affinity profiles and collective experiential terms. This factor was also associated with the drugs DIPT, DOI, and 5-MeO-TMT.

The dominant factor in mystical experiences was mental expansion, described by terms such as universe, space, world, consciousness, breakthrough, existence, earth, dimension, reality, flame, and tunnel. This phenomenon was most closely associated with drugs that preferentially bind to D1, 5-HT7, KOR, 5-HT5A, and Sigma 1.

The joint variation between delineated receptor affinity profiles and experiential term constellations exposed the compounds MDMA, MDA, LSD, 2C-C, and 25-I-NBOMe. These compounds had similar magnitudes of affinity correlation with the emotionally flavored terms.

The opposite extreme of the second factor was associated with auditory sensation, and this experience was preferentially localized to gene co-expression patterns in Heschl’s gyri, as well as the dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, mid-cingulate cortex, and inferior parietal lobe.

The third most important receptor-experience factor was visual terms, including patterns, colors, eye, seeing, watch, and unpleasant physiological processes. These terms were exclusively linked with molecular signaling via affinity to the serotonergic molecular receptors 5-HT2A, 5-HT2C, and 5-HT1A.

The third factor was associated with emotional terms such as depression, depressed, dancing, love(d), friends, loss, happy, and an intermediate time horizon suggested by the terms days, weeks, months, years, as well as some auditory terms.

The fourth most important receptor-experience factor was centered around body load and somatic intensity, and included exteroceptive descriptors such as visuals, whispers, and colors. This factor was most closely associated with tryptamines DMT, 5-MeO-MIPT, and 5-MeO-DMT.

The fourth receptor-experience factor was associated with therapeutic treatment, numb, dream, dizzy, and film, and anatomical references to bladder, leg, and feet. These drugs share the strongest affinity and experiential similarity with this receptor-experience constellation.

The fifth most relevant factor was the terms characterized by levels of comfort and other somatic terms. These terms were strongly linked with drugs that preferentially bind to 5-HT1A, Sigma 1, and NMDA receptors.

The fifth factor, environmental terms, was associated with subjective awareness alterations and was linked preferentially with drug affinity at 5-HT2B, 5-HT5A, 5-HT1E, and 5-HT2C receptors as well as D1 and KOR.

Sixth most relevant factor was euphoric sensations, perceptual impressions, and consistent references to entities and aliens. This factor was most strongly associated with drug affinity at serotonergic, adrenergic, as well as NMDA and Sigma 1 receptors.

The sixth factor was characterized by intense fear, dysphoria, pressure, shit, throwing, horrible, dying, insane, surrender, and a parallel theme of apparent transcendence. This factor was linked to drugs that preferentially bind to serotonin receptors.

Seventh most relevant receptor-experience factor emphasized terms relating to physical context, socio-emotional context, and remember, talking, said, knew and thought. These terms were flagged by drugs that bind serotonergic receptors 5-HT1B, 5-HT1D, 5-HT7, 5-HT2A, 5-HT2C, 5-HT6 along with the D3 receptor.

The seventh receptor-experience factor flagged terms related to therapeutic processes and perceptual and somatic modifiers. This factor was most strongly linked to drug affinity with Sigma 2, NMDA, Imidazoline 1, DAT, and MOR molecular receptors.

Rationale and workflow summary

To overcome limitations of existing brain imaging studies, we sought to link free-form testimonials of drug-induced experience with synaptic binding profiles of hallucinogenic drugs.

Each text report was modeled as a histogram of word usages, and each examined drug has documented binding strengths for specific receptor systems.

By invoking a doubly multivariate pattern-learning algorithm, we aimed to deconvolve cross-connections between constellations of neurotransmitter modulations and constellations of experiential terms across 6,850 written reports of psychedelic experience.

Experience samples of psychedelic drug experiences from Erowid resource

Erowid Center is a not-for-profit, member-supported organization that hosts a collection of first-hand accounts of experiences that were elicited by psychoactive drugs. The collection now includes >38,000 testimonials in English language in free-text form from >800 different drugs, plants, and fungi.

The following compounds are believed to have psychedelic-like effects: classical psychedelics, entactogens, dissociative anesthetics, and agonists of the kappa opioid receptor (KOR)32.

Natural language processing pipeline

We constructed a bag-of-words encoding of the text descriptions in each testimonial, removed punctuation marks and special characters, and lower-cased all words for consistency. This yielded a summary matrix with 14,410 unique words indexed in the columns.

We have used the term-frequency inverse-document-frequency (tf-idf) transformation to preprocess the testimonial-word matrix M, which allows us to compute a notion of word frequency in a given testimonial in a way that carefully accounts for its global prevalence in our entire corpus.

A bag-of-words representation was used to encode the semantic aspects of one lived experience with a hallucinogenic drug. This representation was naive about word order and thus ignored event sequences in the experience reports.

We used latent sem anticanalysis (LS A) to automatically search and organize sem anticrepresentations in experience reports. The top k=800 sem anticcomponents were extracted from the wordcount matrix M for further analysis.

LSA is a machine learning technique that can be used to extract the meaning of testimonials by analyzing the similarity of their words.

We have drawn a random sample of 300 testimonials from each particular drug, and applied LSA to these testimonials. The resulting vocabulary is 14,410 words, and the neuroscientific conclusions are the same for all sampling proportions.

Constructing receptor affinity fingerprints

We used normalized measurements of binding strengths to elucidate the spatial distribution of hallucinogenic compounds throughout the cortex during subjective “trips”. We found that 27 drugs bind to 40 different G protein-coupled receptors, molecular transporters, and ion channels.

The binding values for 20 hallucinogenic drugs found in Ray (2010) were collected from new or existing binding assays performed in coordination with the NIMH Psychoactive Drug Screening Program. The affinity vector for ketamine was calculated from additional studies contained in the PDSP database.

Sigma opioid receptors were found to have significant binding values, and a sensitivity analysis showed that they can be differentiated into Sigma 1 and Sigma 2 receptors.

Our study relied on the inhibitory constant (Ki) to compare the spatial concentration of drugs in cortical tissue. Ki values are an optimal proxy for simulating the spatial distribution of drugs during hallucinogenic experiences.

The IC50 value for a drug is the concentration of the drug that reduces the biological activity of the drug to half its maximal activity on a receptor.

Since higher binding affinities are represented by lower Ki values, a negative log10 was performed. The results are normalized so that higher affinities have higher numerical values and potencies are factored out.

A virtual screening of binding affinity profiles for the drugs described by Ray (2010) was previously performed21 using the method introduced by Vidal and Maestros (2010). This analysis found that 39% of hits against 34 targets were predicted based on structural similarity.

Exploring coherent receptor-experience patterns underlying psychedelic episodes

We sought dominant factors – “modes” of joint variation – that provide insight into how semantic components emerging from word usage patterns are inter-linked with receptor binding affinities from 40 neurotransmitter receptor subclasses. The canonical correlation analysis (CCA) algorithm was ideally suited to interrogate the possible existence of such a multi-modal correspondence between two high-dimensional variable sets.

The CCA model describes how to rotate the original data (X and Y) to a new representation (U|testimonials| x h and V|testimonials| x h) that maximizes their linear association.

The set of h mutually uncorrelated factors that explain joint variation between molecular features of receptor pharmacology and experiential features of semantic context were ordered from most to least important.

We determined the statistical significance of each estimated CCA factor by hypothesis testing in a non-parametric permutation procedure used previously38,40. This yielded h=8 significant CCA factors of receptor-experience correspondence, where explicit correction for multiple comparisons was carried out searching through all estimated CCA factors.

We used gene expression data from six whole postmortem brains of neurotypical donors to anatomically locate significant receptor-experience factors. We then computed the implication of a given receptor-experience factor for each of the 200 Schaefer-Yeo regions.

The degree to which the semantic structure captured by LSA is linked to variation in the receptor expression profile of a specific brain region was determined by mapping factor-specific co-expression of receptor genes to each of the 200 target brain regions.

DNA microarray probes of post-mortem brain tissue have previously been used for genome-wide mapping to build transcriptomic cortical atlases, which have been shown to closely track regional levels of actual protein expression across the cortex.

Scientific computing implementation

Python was selected as the scientific computing engine. The scikit-learn package provided efficient, unit-tested implementations of state-of-the-art machine learning algorithms, and the nilearn library provided efficient execution of brain-imaging data analysis workflows.

DISCUSSION

We studied 6,850 real-world narratives with 27 different drugs to uncover general principles that delineate how drug-induced changes in subjective conscious awareness are anatomically rooted in 40 neurotransmitter receptors. We then mapped differences in transcriptomic proxies of synaptic receptor densities onto cortical regions.

To understand the neurobiological and behavioral effects of hallucinogenic drugs, it is beneficial to consider their action within defined neurotransmitter systems and their transcriptomic gene expression within different anatomical regions. Ibogaine’s action at 5-HT2A, KOR, and NMDA receptors leads to a unique profile of psychological changes.

Ego dissolution is a hallmark of hallucinogenic states of consciousness and may be caused by drugs that bind to the D2 receptor, KOR, 5-HT7, and NMDA receptors.

Previous clinical assessment tools have been designed to accurately detect ego dissolution6,7,55. We found that the leading receptor-experience factor tracks a theme of mental expansion, indicated by the terms consciousness, earth, reality, existence, space, and universe.

Self-disintegration may be linked to weakening of the default mode network’s organizing influence on neural activity in subordinate brain networks, and may be underpinned by simultaneous modulation of KOR, 5-HT7, D2, NMDA, and 5-HT2A.

Electrical stimulation of the inferior parietal default mode network can alter own-body perception, and can even lead to experiences of whole-body displacement. Moreover, changes in within-DMN functional connectivity explain the most global variation in the functional interplay between major brain networks.

Our analysis uncovered hidden relationships between receptor affinities and perceptual themes that confirm prior findings and suggest exciting new directions for future research. The medial temporal lobe, ventromedial prefrontal cortex, dorsolateral prefrontal cortex, and rostral anterior cingulate cortex were all consistently implicated in an array of serotonergic receptors.

Psychedelic trips frequently alter time perception or understanding of time. The leading factor was selectively linked to momentary aspects of hallucinogenic experience, such as eyes and lungs, along with fleeting physiological functions, such as inhaled, exhaled, and breath.

Hallucinogenic states of consciousness can stretch minutes to feel like hours or compress hours into seconds in subjective time perception. The role of the dopamine receptor system in our leading factors appears to co-occur with the immediate time horizon.

The data-driven findings dovetail with experimental evidence in animals, and different types of ‘experience of time’ are potentially linked to different receptor binding constellations.

Conclusion

Hallucinogenic drugs are opening a door into the primary biology of conscious awareness. By fusing three separate windows into cognition, we can see how the chaotic breakdown of the hierarchical functional organization affects the subjective perception of internal sensations and facts of the external world.

Psychedelics may serve as a tool to study the mechanistic receptor basis of how the higher association cortex orchestrates sensory perception.

Study details

Topics studied
Neuroscience

Study characteristics
Survey Qualitative

Participants
6850 Humans

Institutes

Institutes associated with this publication

Erowid
Erowid is the original (1995), and still highly regarded, website that documents drugs and their uses. It provides non-judgmental information. Although great in value, the site can sometimes be difficult to navigate.

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