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

Adapting one's attitudes and behaviours to group norms is central to social interaction, yet the neuropharmacology underpinning social influence processing in humans is poorly understood. Previous neuroimaging work has implicated frontal regions and reward circuitry, including the medial prefrontal cortex (mPFC) and ventral striatum, in responses to mismatches between personal and group opinions. While dopamine and oxytocin have been linked to aspects of social adaptation, the role of the serotonin (5-HT) system—particularly the 5-HT2A receptor—remains unclear. Classic psychedelic lysergic acid diethylamide (LSD) acts at multiple serotonin and dopamine receptor subtypes and is known to alter social cognition and brain connectivity, offering a pharmacological tool to probe 5-HT2A contributions to social influence. Duerler and colleagues set out to test whether LSD modulates behavioural adaptation to group opinion and the neural processes that support it, and whether any LSD effects depend on 5-HT2A receptor stimulation. They used a double-blind, randomised, placebo-controlled, within-subject crossover design to compare placebo, LSD (100 µg), and ketanserin (40 mg, a selective 5-HT2A antagonist) pre-treatment followed by LSD. The main behavioural metric was the Weight of Advice (WOA) score, which quantifies change toward a presented group norm; functional MRI (fMRI) was used to identify brain regions whose activity during social feedback and decision-making was altered by LSD and by ketanserin pre-treatment.

Design and participants: This was a double-blind, randomised, placebo-controlled, within-subject crossover study with three experimental sessions separated by at least two weeks. Twenty-five healthy volunteers were recruited and screened for medical and psychiatric health; one participant was excluded for excessive head motion, leaving 24 subjects (18 males, 6 females; mean age 25.25 years, SD = 3.72) in the analyses. Exclusion criteria included current or past psychiatric disorders, substance dependence, certain medical conditions, left-handedness, poor German, MRI contraindications and prior significant adverse reactions to hallucinogens. Drug conditions and timing: Each participant received, across sessions, (1) placebo + placebo (Pla), (2) placebo + LSD (100 µg oral), and (3) ketanserin (40 mg oral) + LSD (100 µg oral). The pretreatment capsule (placebo or ketanserin) was given 60 minutes before the second capsule (placebo or LSD). The social influence paradigm was administered during fMRI acquisition 330 minutes after the second capsule. Subjective effects were assessed with the 5D-ASC and PANAS questionnaires; the 5D-ASC was administered 720 minutes after dosing to capture retrospective altered-state effects. Behavioural task (Social Influence Paradigm, SIP): While in the scanner participants rated street-art pictures for aesthetic quality on a 0–100 scale (initial rating R1). After each R1, a group rating (FB), presented as the average of 70 prior participants and algorithmically shifted relative to R1, was shown to create three conflict conditions: No Conflict (NC), Low Conflict (LC), and High Conflict (HC). Participants then provided a second rating (R2). Each condition was presented 20 times per session for a total of 60 trials, across two runs. The primary behavioural outcome was the Weight of Advice (WOA) score, defined as the absolute change from R1 to R2 divided by the absolute distance between R1 and FB; WOA ranges from 0 (no adaptation) to 1 (full adjustment), with values >1 indicating movement beyond the group norm. fMRI acquisition and analysis: Events (picture presentation, R1, FB, R2) were modelled as blocks and convolved with a canonical hemodynamic response function. FB and R2 events were categorised into NC, LC, and HC. First-level contrasts computed per subject and treatment included HC > LC, HC > NC and LC > NC for both FB and R2. Group-level contrasts compared Pla, LSD and Ket + LSD using paired t-tests. Analyses focused on five pre-specified regions of interest (ROIs) implicated in social influence: mPFC, lateral orbitofrontal cortex (OFC), inferior frontal gyrus, right nucleus accumbens, supplementary motor area (SMA) and precuneus. Small volume correction (SVC) with 10-mm spheres around published MNI coordinates was applied, and peak-level familywise error (FWE) correction was used at p < 0.05. Behavioural data (R1 and WOA) were analysed via repeated-measures ANOVA with treatment and condition as within-subject factors; significant effects were followed by corrected pairwise comparisons. Exploratory Pearson correlations probed relationships between WOA change (Pla–LSD) and personality measures (NEO-FFI Big Five and Social Responsibility Scale subscales). Results from subjective measures are reported in supplementary material but were summarised as showing ketanserin blocked LSD subjective effects.

Subjective effects: Retrospective measures indicated that ketanserin fully blocked LSD-induced subjective effects assessed with the 5D-ASC and PANAS (detailed figures reported in supplementary material). Initial ratings (R1): A repeated-measures ANOVA showed a significant main effect of treatment on initial picture ratings (F(2,142) = 6.12, p < 0.01). Pairwise comparisons (Bonferroni-corrected) indicated significant differences between LSD and Pla, and between LSD and Ket + LSD; Pla and Ket + LSD did not differ significantly. Weight of Advice (WOA): A treatment × condition repeated-measures ANOVA revealed a significant interaction (F(2,46) = 4.47, p < 0.05). Sidak-corrected contrasts showed that in the Low Conflict (LC) condition participants adapted more under LSD than under Pla (p = 0.01). Within the LSD session, adaptation was greater in LC than in High Conflict (HC) (p = 0.01). There was no significant LC vs HC difference within the Pla condition (p = 0.1). No further significant between- or within-treatment differences survived correction. fMRI—Placebo condition: Under placebo, the HC > LC contrast during feedback elicited greater BOLD in mPFC (MNI x = -3, y = 47, z = 25), SMA, right nucleus accumbens and precuneus (all p < 0.05 FWE after SVC). HC > NC during feedback showed greater SMA activity, and HC > NC during R2 showed increased activity in the angular gyrus. fMRI—Placebo vs LSD: Comparing Pla to LSD for HC > LC during feedback, Pla produced greater mPFC BOLD (x = 0, y = 59, z = 19). Conversely, LSD produced greater mPFC activity for LC > NC during feedback (x = -9, y = 62, z = 25). There were no significant treatment differences during the decision-making phase (R2). Extracted beta values from the mPFC ROI indicated main effects of drug (F(2,94) = 5.02, p < 0.01) and condition (F(2,94) = 3.89, p < 0.05) and a drug × condition interaction (F(4,188) significant at p < 0.005). Simple effects showed an increase from LC to HC in Pla (p < 0.001) and an increase from NC to LC in LSD (p < 0.001). fMRI—Ket + LSD vs LSD: For HC > NC during feedback, Ket + LSD produced higher BOLD than LSD in lateral OFC, inferior frontal gyrus and nucleus accumbens (p < 0.05 FWE after SVC). For LC > NC during feedback, LSD showed greater mPFC and inferior frontal gyrus activation (p < 0.05 FWE after SVC). For HC > NC during R2, Ket + LSD showed higher medial and lateral OFC activity compared to LSD. fMRI—Ket + LSD vs Placebo: No significant differences were observed between Ket + LSD and Pla in any contrast after SVC correction. Correlations with personality: A significant negative Pearson correlation was observed between Neuroticism (NEO-FFI) and the LSD-induced change in WOA (Pla–LSD) (r = -0.55, p < 0.01), indicating greater adaptation after LSD in participants with higher neuroticism. A positive correlation was found between the SRS subscale "Fulfilling Expectations" and WOA change (r = 0.45, p < 0.03), and Neuroticism and Fulfilling Expectations were negatively correlated (r = -0.455, p < 0.03). No significant correlations were found between extracted beta values and personality traits or WOA within individual treatment conditions.

Duerler and colleagues interpret their results as evidence that LSD selectively increases adaptation to others' opinions when those opinions are similar to one's own, and that this effect is linked to altered processing in the mPFC during social feedback. Behaviourally, LSD enhanced Weight of Advice in Low Conflict but not in High Conflict situations, suggesting that LSD does not produce a blanket increase in suggestibility; instead, it appears to intensify adaptation to relatively concordant group norms. Neurally, under placebo high-conflict feedback engaged mPFC, SMA, ventral striatum and precuneus—regions previously associated with conflict detection and social influence—whereas LSD shifted mPFC responsiveness toward low-conflict feedback, consistent with a change in how self-relevance or value is assigned to group opinions. The authors propose a mechanistic account in which LSD-induced modulation of self-relevance processing and a loosening of self–other boundaries increases the subjective value of opinions similar to one's own, via mPFC alterations, thereby promoting adaptation when disagreement is modest. In high-conflict situations, by contrast, LSD may reduce sensitivity to social punishment or exclusion—processes that ordinarily motivate conformity—resulting in less adaptation under strong disagreement. Pharmacologically, ketanserin fully blocked LSD-induced mPFC changes during feedback processing and abolished subjective LSD effects, implicating the 5-HT2A receptor in social feedback processing. Changes in social decision-making (the R2 phase), however, were differentially affected by ketanserin and involved OFC and other regions; the authors therefore suggest that decision-making aspects of social influence may be mediated by other neurotransmitter systems, possibly dopamine, given LSD's broader receptor affinity and prior literature linking dopamine to decision processes. Personality appeared to moderate LSD effects: higher baseline Neuroticism was associated with larger LSD-induced increases in adaptation, and lower scores on the SRS "Fulfilling Expectations" subscale predicted greater adaptation after LSD. The investigators note that stimulation of 5-HT2A receptors can attenuate negative affect and fear and enhance openness and empathy, which might disproportionately affect individuals with higher neurotic traits. These personality–effect relationships were presented as exploratory and in need of replication. Limitations acknowledged by the study team include the absence of pharmacological blockade of non-5-HT2A receptors that LSD also engages, the lack of a ketanserin-only condition to isolate ketanserin effects, and the absence of a non-social control task to determine specificity of the observed effects to social contexts. The authors conclude that their data point to a central role for 5-HT2A receptor stimulation and mPFC activity in LSD-modulated social feedback processing, and that social decision-making may involve additional neurotransmitter systems. They suggest these findings are relevant to understanding the neurobiology of social cognition and may have implications for psychedelic-assisted therapeutic approaches under investigation.