The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation

By using the serotonin receptor (5-HT_2AR) antagonist ketanserin, this study (n=22) found that this inhibited the forming of meaningful/personal relevant connections that were made under the influence of LSD (100μg). This confirms the idea that this 5-HT_2AR is crucial for generating meaning.

Abstract

“A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT_2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT_2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution.”

Authors: Katrin H. Preller, Marcus Herdener, Thomas Pokorny, Amanda Planzer, Rainer Kraehenmann, Philipp Stämpfli, Matthias E. Liechti, Erich Seifritz & Franz X. Vollenweider

Notes

The study analysed data from the same participants as Barrett et al. (2017).

This study was supported in part by the Usona Institute and the Heffter Research Institute.

Summary

Subjective Effects of LSD and Role of 5HT2AR

Participants underwent three treatment conditions: placebo + placebo (Pla), placebo + lysergic acid diethylamide (LSD) or ketanserin + LSD (Ket + LSD). The LSD treatment condition resulted in greater scores on 9 of 11 Altered States of Consciousness scales than the Pla and Ket + LSD treatment conditions.

To investigate treatment effects on mood state, we conducted a repeated-measures ANOVA for the Positive and Negative Affect Schedule (PANAS) and found that scores on the positive affect scale were higher in the LSD treatment condition than in the Pla and Ket + LSD treatment conditions.

Effects of LSD on the Fabric of Meaning

Music is a powerful stimulus to elicit self-related processing. We investigated the neuropharmacology of personal relevance processing by testing the influence of LSD with and without ketanserin pretreatment on the processing of music otherwise experienced as personally meaningful, neutral, and personally not meaningful music.

Pre-task Questionnaire

The mean rating for general personal meaningfulness of music was 7.00, with a significant main effect for treatment condition and music condition. Furthermore, meaningfulness ratings significantly differed across music conditions, with songs being rated highest in the meaningful condition and lowest in the meaningless condition.

A comparison of the blood-oxygenation-level-dependent (BOLD) signals in the left SMA and bilateral vlPFC and left dorsomedial prefrontal cortex between LSD and placebo treatment conditions revealed greater BOLD signals after LSD treatment.

After LSD administration that was not preceded by ketanserin, there was significantly greater BOLD signal in the left dorsal anterior cingulate cortex, left middle frontal gyrus, and left superior frontal gyrus.

Listening to meaningless music in the LSD condition increased BOLD signal in the SMA, dACC, and dmPFC compared to Pla and Ket + LSD treatment conditions.

DISCUSSION

In this study, we investigated the role of the 5-HT2AR system in the generation and modulation of subjective psychedelic effects in humans, and found that the 5-HT2AR system was the key mechanism of action in mediating the unique human experience of psychedelic effects induced by the prototypical hallucinogen LSD.

Ketanserin blocked all subjective effects of LSD on the 5D-ASC and PANAS questionnaires. This result indicates that the overall psychedelic effects of LSD are primarily mediated via 5-HT2AR stimulation in humans.

LSD treatment increased the rating of meaningfulness for previously meaningless and neutral music excerpts, and this effect was normalized by pretreatment with ketanserin. This indicates that the 5-HT2AR may be involved in dysfunctional personal relevance attribution observed in psychiatric disorders such as schizophrenia and addiction.

Listening to personally meaningful music was associated with greater activity in the SMA, putamen, middle occipital gyrus, vlPFC, and cerebellum than listening to neutral and personally meaningless music. Furthermore, these areas overlapped with those associated with the ascription of subjective value to music.

LSD increased activation of the SMA and the dmPFC in response to meaningless music, and of the vlPFC and dmPFC compared to neutral music. These results suggest that LSD increases the attribution of meaning to previously not meaningful stimuli, which is important in psychiatric disorders characterized by altered self-processing.

Ketanserin blocked the LSD-induced increase in activation of self-related brain regions in response to previously non-meaningful stimuli. This result indicates that the 5-HT2AR is key in the attribution of self-relevance and meaning to external stimuli.

The results indicate that the PCC is involved in autobiographical memory retrieval and experiential self-reflection. The increase in BOLD signal in the PCC after Ket + LSD administration may be due to dopaminergic R stimulation. The study found that participants treated with LSD had increased attribution of meaning to self-relevant stimuli, but the increase was not reflected in the meaningfulness ratings. A ceiling effect might have masked differences between conditions.

In contrast to a previous study, we did not find significant increases in spiritual experiences in the LSD condition. Moreover, the clinical atmosphere in the magnetic resonance environment may have prevented spiritual experiences.

The current results highlight the key role of the 5-HT2AR subtype of 5-HT Rs in the mediation of the psychedelic effects of LSD in humans, and point to the involvement of the dopamine system in the further modulation of personal relevance.