Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD

This trial (n=15) assessed the effects of LSD on a number of receptors in the brain including the 5HT_1a, 5HT_1b, 5HT_2a, D1 and D2 receptors. Receptor-enriched analysis of functional connectivity by targets (REACT) found that LSD produced differences in functional connectivity when the analysis was enriched with each of the primary serotonergic and dopaminergic receptors. The serotonergic and dopaminergic systems were associated with perceptual effects and perceived selfhood as well as cognition respectively.

Abstract

“Rationale: LSD is the prototypical psychedelic. Despite a clear central role of the 5HT_2a receptor in its mechanism of action, the contributions of additional receptors for which it shows affinity and agonist activity remain unclear.

Objectives: We employed receptor-enriched analysis of functional connectivity by targets (REACT) to explore differences in functional connectivity (FC) associated with the distributions of the primary targets of LSD—the 5HT_1a, 5HT_1b, 5HT_2a, D1 and D2 receptors.

Methods: We performed secondary analyses of an openly available dataset (N = 15) to estimate the LSD-induced alterations in receptor-enriched FC maps associated with these systems. Principal component analysis (PCA) was employed as a dimension reduction strategy for subjective experiences associated with LSD captured by the Altered States of Consciousness (ASC) questionnaire. Correlations between these principal components as well as VAS ratings of subjective effects with receptor-enriched FC were explored.

Results: Compared to placebo, LSD produced differences in FC when the analysis was enriched with each of the primary serotonergic and dopaminergic receptors. Altered receptor-enriched FC showed relationships with the subjective effects of LSD on conscious experience, with serotonergic and dopaminergic systems being predominantly associated with perceptual effects and perceived selfhood as well as cognition respectively. These relationships were dissociable, with different receptors showing the same relationships within, but not between, the serotonergic and dopaminergic systems.

Conclusions: These exploratory findings provide new insights into the pharmacology of LSD and highlight the need for additional investigation of non-5HT_2a-mediated mechanisms.”

Authors: Timothy Lawn, Ottavia Dipasquale, Alexandros Vamvakas, Ioannis Tsougos, Mitul A. Mehta & Matthew A. Howard

Summary

LSD is the prototypical psychedelic and shows affinity and agonist activity for several receptors. We explored differences in functional connectivity associated with the distribution of these receptors.

Introduction

Psychedelic compounds profoundly modulate conscious experience. Legal restrictions halted research into the therapeutic efficacy of psychedelics in the early 1970s, but it has since been re-investigated with modern techniques.

Neuroimaging approaches have demonstrated numerous changes in the brain at rest in response to the LSD experience, including increased cerebral blood flow, reduced functional network integrity, increased global connectivity, and increased sensitivity to perturbation.

LSD stimulates the 5-HT1A/B, 5-HT6, 5-HT7 as well as D1 and D2 receptors, which alter the gain of receptive neuronal populations and thus affect downstream inter-regional communication.

Ketanserin, a non-selective 5HT2A receptor antagonist, reduces both subjective reports and neural measures associated with LSD administration.

Insights into causality, however, remain elusive, as 5HT2a agonism is not sufficient to explain the effects of LSD. Furthermore, actions of LSD at multiple serotonergic and dopaminergic receptors may provide a more complete insight into how these circuits function.

We used receptor-enriched analysis of functional connectivity by targets to map the pharmacodynamic effects of LSD onto the distribution of its primary targets, and then characterised the differences in these whole-brain maps of FC under conditions of LSD and placebo.

Participants

In this work, we employed a subset (15 healthy controls) of a previously published dataset, made publicly available on the OpenNeuro data repository.

Study design, scene and dosing

Participants undertook two scanning days (LSD and placebo) separated by at least 2 weeks, and received either LSD or placebo infused over a 2-min period through a cannula inserted into the antecubital fossa.

MRI acquisition

Three BOLD-weighted eyes-closed fMRI resting-state runs were acquired using a gradient echoplanar imaging sequence on a 3 T GE HDx system. The runs lasted 7 min and the first and third runs included listening to music.

Subjective report of phenomenology

The 11-dimension Altered States of Consciousness (ASC) questionnaire was completed by subjects at the end of the LSD dosing day. The VAS ratings of subjective effects were also measured after each LSD run.

Principal components analysis of subjectively reported experiences

We used principal components analysis to reduce the dimensionality of the data and to determine whether there were multiple related facets to the subjective LSD experience that could be derived and may show relationships with receptor-enriched FC.

Image pre‑processing

The present work makes use of data that had already undergone pre-processing prior to uploading to the OpenNeuro repository.

Population‑based molecular templates

The REACT analysis was performed using receptor density maps from the serotonergic and dopaminergic systems. These receptor atlases were created from molecular and structural high-resolution PET and MRI data of 210 healthy subjects.

Receptor‑enriched analysis of functional connectivity

The serotonergic and dopaminergic functional systems were estimated using REACT using a two-step regression analysis implemented in FSL. The five neurotransmitter templates were simultaneously included in the model as previously described in Dipasquale et al. (2019).

The subject-specific time series were used as temporal regressors in the second multivariate regression analysis, and the target-enriched spatial maps were estimated for each participant, session and receptor.

Statistical analysis

Subject-specific target-enriched spatial maps derived for LSD and placebo conditions were compared, and linear relationships were tested between delta FC maps (LSD minus placebo) and subjective reports of phenomenology, as characterised by the three PCA-derived ASC sub-score as well as the VAS measures.

Alterations in receptor‑enriched networks (LSD vs placebo)

We found significant increases in FC induced by LSD in the 5HT1a-, 5HT1b-, 5HT2a-, D1- and D2-enriched maps, as well as in the right lingual gyrus, right lateral occipital cortex, right paracingulate and bilateral precentral gyri.

LSD increased FC in the right hippocampus, right thalamus, right superior parietal lobe, left occipital pole, lateral occipital cortices, intracalcarine cortices and the right occipital fusiform, right lingual, middle/superior temporal, angular and pre/post-central gyri.

Correlation with principal components

LSD increased scores in all VAS questions and all sub-scores of the ASC except anxiety. Three principal components explained 83.1% of the variance in the data and were confirmed by Kaiser – Meyer – Olkin Measure of Sampling Adequacy and Bartlett’s test of sphericity.

Principal component 3 captured mostly perceptual aspects of disembodiment, with the strongest loadings for audio-visual synaesthesia, elemental imagery and complex imagery. Two correlations remained significant following TFCE correction.

Correlation with VAS questions

When correlating delta target-enriched FC with VAS responses, only two relationships survived TFCE. These relationships were between 5HT1b-enriched FC in the right intraparietal sulcus and simple hallucinations, and between 5HT1a-enriched FC in the precuneus cortex and complex imagery.

Discussion

The present study offers new insights into the pharmacodynamic response of the brain under LSD. It shows that multiple components of the cortico-striatal thalamocortical loop are under the modulatory influence of both the serotonergic and dopaminergic systems.

The thalamus and striatum show increased 5HT1a-enriched FC, and the striatum reduces its inhibitory control over the thalamus under LSD. This may be driven by dopamine or other serotonergic receptors, though the current analyses did not show altered striatal FC.

The serotonergic system

We found widespread LSD-induced FC differences in functional systems enriched by different serotonergic receptors, but no differences in 5HT1a- and 5HT1b-enriched FC. Using high-resolution atlases derived from 210 individuals, we investigated the expression of candidate serotonergic and dopaminergic receptors under LSD compared to LSD alongside ketanserin. We found that 5HT1a and 5HT1b receptors were significantly correlated with LSD, but 5HT2a and 5HT1b showed only weak correlations.

The superior parietal lobules and precuneus showed increased blood flow during simple hallucinations and complex imagery respectively, suggesting that these receptors may act in concert, with visual experiences relating to the functions of the serotonin system more broadly. Psychedelic-related visual experiences frequently involve the precuneus, which is linked to visuo-spatial imagery, episodic memory retrieval, and self-referential processing. The precuneus and superior parietal cortex are also implicated in clinical hallucinations, and have been shown to be involved in altered higher-level integration of visual and autobiographical information.

The cerebellar vermal lobule X is thought to play a crucial role in the representation of self-motion through the processing of spatial and temporal vestibular information. LSD-induced altered serotonergic FC in this region relates to altered integration of vestibular information into multisensory mechanisms underlying the sense of self-motion.

The dopaminergic system

Differences in D1- and D2-enriched FC were observed between LSD and placebo conditions. These differences were correlated with principal component 2, which had loadings from cognitive aspects of predominantly negative valence.

The right posterior insula has long been implicated in subjective body ownership, and strokes affecting this region can produce anosognosia or somatoparaphrenia. This finding aligns with several meta-analyses of body ownership, agency, multisensory integration and self-awareness.

LSD induces disembodiment and impaired cognition, which may be partly mediated by functional dopaminergic circuits. These regions are associated with modulatory effects of dopamine and contribute to LSD-induced experiences of disembodiment and impaired cognition.

LSD has been shown to have an unusual effect on D2/D3 receptor binding measured using [11C]raclopride PET, which may reflect a 5HT2-mediated sensitisation of D2/D3 receptors. This may mean that experiments blocking the action of LSD on the 5HT2a receptor are also preventing dopamine receptor sensitisation and thus masking the role of dopamine in the effects of LSD.

These findings may be strengthened with data acquired later in the LSD experience, possibly employing pharmacological manipulation of dopamine.

Limitations

This study examined the modulation of receptor-enriched networks under LSD, and correlated subject-specific FC changes with subjective effects. However, the study has some limitations, and a larger sample size may be required to detect relationships within a voxelwise framework.

Conclusion

LSD has complex pharmacology that interacts with diverse neural systems. The dopaminergic system was associated with LSD effects on perceived selfhood and cognition, whilst serotonergic systems were involved in hallucinations.