LSD-induced increases in social adaptation to opinions similar to one’s own are associated with stimulation of serotonin receptors

LSD (100μg) increased social adaptation in a double-blind, randomized, counterbalanced, cross-over study, but only when opinions were similar to one’s own.

Abstract

“Adapting one’s attitudes and behaviors to group norms is essential for successful social interaction and, thus, participation in society. Yet, despite its importance for societal and individual functioning, the underlying neuropharmacology is poorly understood. We therefore investigated its neurochemical and neural correlates in a pharmacological functional magnetic resonance imaging study. Lysergic acid diethylamide (LSD) has been shown to alter social processing and therefore provides the unique opportunity to investigate the role of the 5-HT_2A receptor in social influence processing. Twenty-four healthy human volunteers received either (1) placebo + placebo, (2) placebo + LSD (100 µg), or (3) the 5-HT_2A receptor antagonist ketanserin (40 mg) + LSD (100 µg) at three different occasions in a double-blind, randomized, counterbalanced, cross-over design. LSD increases social adaptation but only if the opinions of others are similar to the individual’s own. These increases were associated with increased activity in the medial prefrontal cortex while participants received social feedback. Furthermore, pretreatment with the 5-HT_2A antagonist ketanserin fully blocked LSD-induced changes during feedback processing, indicating a key role of the 5-HT_2A system in social feedback processing. Our results highlight the crucial role of the 5-HT-system in social influence and, thus, provide important insight into the neuropharmacological basis of social cognition and behavior.”

Authors: Patricia Duerler, Leonhard Schilbach, Philipp Stämpfli, Franz X. Vollenweider & Katrin H. Preller

Summary

Social influence is omnipresent in our everyday life and is deeply rooted in human nature. The brain regions associated with conflict detection, reinforcement learning, and social cognition are involved in adapting to social norms.

Most studies have focused on localizing brain regions implicated in social influence processing, but few have investigated the role of the serotonin (5-HT) system in humans in these processes.

LSD is a classic psychedelic substance that has predominantly agonistic activity at 5-HT2A, -1A/B, -6 and -7 and dopamine (D) D1 and D2 receptors. It has been shown to modulate social behavior and interaction, as well as brain activity and connectivity in areas related to social processing.

In this study, participants underwent functional magnetic resonance imaging (fMRI) while judging the aesthetic quality of art pictures. They were then confronted with a group norm and subsequently re-evaluated their decision.

Based on previous findings32, we hypothesized that LSD increases social adaptation compared to Pla, and that ketanserin would block at least partially LSD-induced changes in social influence processing.

Social influence paradigm. Rating 1 (R1) revealed a significant main effect for treatment and a Bonferroni corrected simple main effect analysis revealed no significant difference between Pla and Ket + LSD treatment conditions.

Results

A repeated measures ANOVA revealed a significant interaction for treatment condition, and a significant difference between WOA scores in the LSD Low Conflict (LC) and the Pla Low Conflict (LC) conditions. There was no significant difference between the LC and HC conditions within the Pla condition.

fMRI data revealed that the mPFC, SMA, right nucleus accumbens and precuneus were activated during feedback processing of the group rating and that the angular gyrus was activated during rating 2 (R2).

Participants showed a strong adaptation to the group norm in the LSD LC condition, which was significantly different from the Pla LC and LSD HC conditions.

Feedback processing in the mPFC is increased in the LSD condition compared to the Placebo condition, and is decreased in the Pla condition compared to the LSD condition.

Placebo vs. LSD condition revealed greater BOLD signal in the mPFC during feedback processing, but significantly increased BOLD signal in the mPFC during LSD condition for the LC > NC contrast.

A repeated measures ANOVA revealed a significant main effect for drug and condition, and a significant interaction for drug & condition. No further within-treatment comparisons reached significance.

Ket + LSD treatment resulted in a higher BOLD signal in the lateral orbitofrontal cortex, inferior frontal gyrus and nucleus accumbens compared to LSD treatment. Furthermore, the HC > NC R2 contrast revealed a significant increase in BOLD signal in the medial OFC and lateral OFC after LSD treatment.

Correlations between personality traits and changes in adaptation to social norms were found. The personality traits Neuroticism and Fulfilling Expectations were negatively correlated, as were beta values and WOA scores within each treatment condition.

Figure 3 shows that fMRI data showed that LSD decreased BOLD signal in the inferior frontal gyrus, Ket + LSD increased BOLD signal in the medial OFC, and Rating 2 contrast in the superior frontal gyrus.

Discussion

This study presents strong evidence that LSD affects social influence processing and social decision-making. It also shows that LSD affects the mPFC in particular during social feedback processing.

LSD increases social adaptation to opinions similar to one’s own. This is in line with previous studies, but extends these findings by showing that LSD increases adaptation to opinions that are similar to one’s own.

LSD induces changes in self-relevance processing, which may explain why opinions in low conflict are given more value. At the same time, the need to adapt to avoid social punishment may be diminished in the LSD condition, explaining a lower adaptation when opinions are in high conflict.

The anterior part of the mPFC has been associated with assigning personal significance to stimuli, and the serotonin system has been implicated in value-based decision-making. LSD alters the computation of value assigned to a group norm via increased processing of self-relevance in the mPFC.

In the HC condition, disagreement with the group norm induces a negative tension state and may induce feelings of social rejection. However, in the LSD condition, the motivation to avoid social rejection or punishment may be diminished, leading to less adaptation when exposed to highly conflicting opinions.

LSD modulates the mpfc during social feedback processing, but not during social decision-making. This suggests that LSD changes the value assigned to other persons’ opinions via alterations in self-relevance processing associated with alterations in activity in the mPFC.

LSD-induced changes in social feedback processing depend on the 5-HT2A receptor system, however, dopamine receptor stimulation may contribute to the effects of LSD. Therefore, social feedback processing and socially influenced decision-making are potentially modulated by two different neurotransmitter systems.

Participants with higher scores in Neuroticism adapt more strongly to social norms after LSD administration. This may be because LSD reduces negative emotion and fear processing, while at the same time enhancing empathy, heightening positive mood and leading to increases in the personality trait openness.

We found that participants with lower scores in Fulfilling Expectations adapted more strongly to social situations after LSD, and that this was negatively correlated with Neuroticism.

Limitations

This study provided empirical evidence for the involvement of the 5-HT2A receptor system in social feedback processing. However, the study did not investigate the effect of ketanserin without LSD on social influence processing and decision-making.

conclusion

LSD increased social adaptation to group opinions that are relatively similar to one’s own via stimulation of 5-HT2A receptors and increased activity of the mPFC. This may have important implications for psychedelic-assisted therapeutic approaches.

Participants were recruited through advertisements placed at local universities and underwent a screening visit before inclusion into the study. They were required to abstain from drinking alcohol and drugs for at least 24 h before the test day and from smoking for at least 60 min before MRI assessment.

The initial study population consisted of 25 participants, of which 24 were included in the statistical analyses. No substantial side effects were recorded during the study, and participants were contacted again three months after the last drug administration.

Participants completed the NEO-FFI61 and SRS62 to assess personality traits. A double-blind, randomized, placebo-controlled, within-subject design was employed with three experimental sessions, each separated by at least 2 weeks.

(1) Placing a placebo and taking Aerosil 1 mg po, (2) taking LSD and taking ketanserin, and (3) taking LSD after taking ketanserin.

Participants were administered placebo or LSD 60 min after pretreatment with the first capsule, and the social influence paradigm was conducted 330 min after second drug administration while undergoing the MRI acquisition.

All participants were familiarized with the Social Influence Paradigm (SIP) before drug administration. They rated pictures of street art according to a pre-study survey. While undergoing fMRI scanning, participants rated pictures according to their perceived aesthetic quality. After receiving feedback of the group rating, participants had to rate their pictures again, but the group rating varied algorithmically as a function of the initial rating provided by the participant.

Each subject completed 60 trials per session, and three parallel versions of the social conflict conditions were presented in a counter-balanced randomized order to the subject across experimental days.

Figure 5 shows an example trial of the social influence paradigm. Participants can confirm or change their initial rating of a street art picture.

Weight of advice (WOA) is the change in judgment between initial and final judgment in relation to the group norm13.

The WOA is calculated from the ratings provided by the participants while conducting the SIP during fMRI scanning. Treatment and condition were entered as within-subject factors in a repeated measures ANOVA.

fMRI data were analyzed to identify brain regions sensitive to social conflict. The influence of our pharmacological intervention was investigated by comparing these contrasts between the treatment conditions LSD > Pla, LSD > Ket + LSD, and Ket + LSD > Pla. We used small volume correction (SVC) to analyze areas sensitive to social influence processing. Five regions were identified to be involved in social influence processing, and search volumes were defined as spheres with a 10-mm radius centered on these previously reported MNI coordinates.

To investigate the relationship between personality traits and the adaptation to the group norm, Pearson correlation analyses were computed between the WOA score and the NEO-FFI Big Five personality traits.

Additional information

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