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

A core feature of the human self is the attribution of personal relevance to sensory input, which allows individuals to experience their environment as meaningful. Abnormalities in attributing personal relevance are central to several psychiatric disorders, but the neurochemical and anatomical substrates that enable meaningful experiences are not well understood. Lysergic acid diethylamide (LSD) is known to alter the subjective meaning of percepts, and the serotonin 2A receptor (5-HT2A R) has been implicated in psychedelic effects, yet the receptor-specific contributions to altered personal relevance attribution in humans remained unclear. Preller and colleagues set out to investigate the neuropharmacology of personal relevance processing by combining functional MRI with pharmacological manipulation: administration of LSD with and without pretreatment with the 5-HT2A R antagonist ketanserin. The study tested whether 5-HT2A R activation mediates LSD-induced changes in subjective experience and in the neural processing of stimuli that vary in personal meaningfulness, using a music paradigm to probe self-referential attribution of meaning.

The study used a within-subjects, repeated-measures design in which each participant completed three treatment sessions: placebo after placebo pretreatment (Pla), LSD after placebo pretreatment (LSD), and LSD after pretreatment with ketanserin (Ket + LSD). The extracted text indicates 22 participants for behavioural measures (n = 22 reported in figure captions). Full procedural details and participant characteristics are referenced to supplemental material, which is not included in the extracted text. During each session participants completed behavioural questionnaires and an fMRI music paradigm. Subjective measures included the Altered States of Consciousness questionnaire (5D-ASC) administered retrospectively and the Positive and Negative Affect Schedule (PANAS) assessed across timepoints. The music paradigm presented three categories of musical excerpts: personally meaningful, neutral, and personally meaningless (no personal relevance); after each trial participants rated the meaningfulness of the excerpt. The investigators used these ratings both as categorical task conditions and as parametric modulators in imaging analyses. Neuroimaging analyses contrasted BOLD (blood-oxygenation-level-dependent) signal between music conditions and treatment conditions, for example meaningless > meaningful and meaningless > neutral contrasts. Statistical analyses reported include repeated-measures ANOVAs for questionnaire and rating data (treatment and music condition factors) and whole-brain fMRI contrasts; some analyses incorporated participants’ trial-by-trial meaningfulness ratings (parametric modulation). The extraction does not provide complete MRI acquisition or preprocessing parameters nor full details of randomisation, blinding, or dosing regimen; these are referred to Supplemental Experimental Procedures.

Subjective effects: Repeated-measures ANOVA on 5D-ASC scores showed significant main effects of treatment (F(1.00, 21.08) = 65.39, p < 0.001) and scale, and a significant treatment-by-scale interaction. Bonferroni-corrected comparisons indicated higher scores on 9 of 11 5D-ASC scales in the LSD condition relative to Pla and Ket + LSD (all p < 0.05); spiritual experience and anxiety scales did not differ across conditions. Scores in the Pla and Ket + LSD conditions did not differ on any 5D-ASC scale (all p > 0.90). PANAS analyses revealed a main effect of scale (positive > negative affect), a main effect of treatment (F(1.52, 32.01) = 6.13, p < 0.01), and significant interactions including treatment-by-time. After drug administration positive affect was greater in the LSD condition than in Pla and Ket + LSD (all p < 0.05), and negative affect was greater in LSD than Pla (p < 0.05). In summary, the LSD-induced subjective effects on 5D-ASC and PANAS were effectively abolished by ketanserin pretreatment, implicating 5-HT2A R mediation of the measured psychedelic effects. Behavioural meaningfulness ratings: Pre-task ratings confirmed that the selected music categories differed as intended. During the music paradigm a repeated-measures ANOVA of trial ratings found significant main effects of treatment (F(2, 42) = 12.35, p < 0.001) and music condition (F(2, 42) = 179.39, p < 0.001), and a treatment-by-music interaction (F(2.28, 47.78) = 5.26, p < 0.01). Pairwise tests showed that music was rated more meaningful in the LSD condition than in Pla or Ket + LSD (all p < 0.005). Notably, LSD increased meaningfulness ratings for previously meaningless and neutral excerpts relative to Pla and Ket + LSD (all p < 0.05), and ketanserin normalised these increases. fMRI findings: Comparing LSD to Pla for the meaningless > meaningful contrast revealed greater BOLD signal in the left supplementary motor area (SMA). For meaningless > neutral, LSD produced greater BOLD in bilateral ventrolateral prefrontal cortex (vlPFC) and left dorsomedial prefrontal cortex (dmPFC) relative to Pla. Direct contrasts for other combinations showed no significant clusters. Comparing LSD to Ket + LSD, the meaningless > meaningful contrast showed greater BOLD in the left dorsal anterior cingulate cortex (dACC) after LSD without ketanserin; the meaningless > neutral contrast revealed greater BOLD in left dACC, left middle frontal gyrus and left superior frontal gyrus for LSD versus Ket + LSD. Comparing Pla to Ket + LSD for meaningful > meaningless revealed greater posterior cingulate cortex (PCC) BOLD after Ket + LSD. Parametric modulation analyses that used participants’ meaningfulness ratings were reported but specific cluster statistics are not provided in the extracted text. Overall, listening to meaningless music under LSD increased activation in lateral frontal areas and cortical midline structures (SMA, dACC, dmPFC), whereas PCC activity was relatively greater for meaningful music in the Ket + LSD condition compared to Pla.

Preller and colleagues interpret their findings as demonstrating a central role for 5-HT2A receptor activation in mediating the subjective and neural effects of LSD, particularly the increased attribution of personal relevance to stimuli that are otherwise meaningless. The authors highlight that ketanserin fully blocked LSD-induced changes on the 5D-ASC and PANAS, supporting the conclusion that 5-HT2A R stimulation is the key mechanism for the measured psychedelic effects in humans. This human finding aligns with animal literature showing that 5-HT2 R antagonists block LSD-induced behaviours and with prior work showing ketanserin reduces effects of related psychedelics. In terms of meaning processing, LSD increased behavioural ratings of meaning for neutral and meaningless music excerpts and produced increased activation in cortical midline regions (SMA, dmPFC, dACC) and lateral prefrontal areas (vlPFC) when participants listened to meaningless stimuli. The investigators note that these regions have been implicated in self-referential cognition, appraisal of external stimuli, autobiographical salience, and the transformation of sensory input into self-related processing. Ketanserin pretreatment blocked both the behavioural increase in attributed meaning and the accompanying increase in activity of self-related brain regions, supporting a 5-HT2A R-dependent mechanism. The authors also report an unexpected increase in PCC activation for meaningful versus meaningless music in the Ket + LSD condition relative to Pla and consider a potential dopaminergic contribution: because LSD also binds dopamine receptors and 5-HT2A R was blocked in the Ket + LSD condition, residual dopamine receptor stimulation by LSD could modulate processing of personally relevant stimuli. They acknowledge this interpretation is speculative and note supporting literature linking dopaminergic function to salience attribution. Key limitations the authors acknowledge include the inability to assess LSD and ketanserin effects independently due to the study design (a full factorial design would be preferable), the possibility of ceiling effects in meaningfulness ratings (limiting sensitivity to detect increases under Ket + LSD), and that other receptors besides 5-HT2A may contribute to LSD’s effects. They also discuss that the absence of increased spiritual experience in their sample may reflect dose, personality, or the clinical MR setting. Finally, the authors suggest further work to disentangle contributions of other receptor systems, to test independent drug effects, and to examine additional factors that could influence altered meaning processing.