Effects of LSD on music-evoked brain activity

Music recruits widespread brain networks and can evoke powerful emotions through distinct acoustic features such as pitch, rhythm, loudness and timbre. Neuroimaging research describes a processing hierarchy in which increasingly complex acoustic properties are analysed by auditory regions and then integrated with higher-order multimodal areas to generate associations, memories and emotion. Recent work advocates naturalistic paradigms—extended listening to real music—to capture this complexity. Classic psychedelics, including LSD, perturb normal brain hierarchy by acting at serotonin 2A receptors, producing reduced functional coupling within higher-level networks and increased cross-talk between lower-level areas, and are commonly reported to amplify music-evoked emotion and imagery. Kaelen and colleagues set out to characterise how acute LSD administration alters music-evoked brain activity under naturalistic, eyes-closed listening. The primary aim was to map LSD-related changes in BOLD responses to time-varying acoustic features of real music. A secondary objective was to relate those neural changes to intensifications of ‘‘peak’’ music-evoked emotions (notably wonder and transcendence). The experiment formed part of a larger multimodal imaging project of LSD in healthy volunteers.

This was a within-subject experimental study in which participants attended two sessions separated by at least 14 days, receiving 75 µg LSD intravenously on one day and placebo saline on the other. Twenty volunteers (16 male, 4 female) were recruited and screened medically and psychiatrically; inclusion required at least one prior classic psychedelic experience. One participant withdrew during scanning and three datasets were excluded for technical reasons, leaving 16 participants (13 male, 3 female) for analysis with preserved counterbalanced order. Stimuli comprised two 7.3-minute ambient music excerpts by Robert Rich, selected and balanced for acoustic properties and emotional potency. Each participant heard both excerpts in a balanced order across sessions. LSD was infused over two minutes, subjective effects peaked around 60–90 minutes and scanning took place during peak effects at approximately 120 minutes post-dose. The scan session included three eyes-closed resting-state runs; the music-listening run (7.3 min) occurred between resting runs. Music was delivered via MR-compatible headphones at individually adjusted ‘‘loud but not unpleasant’’ volume. Acoustic analysis used the MIR toolbox to extract 23 short- and long-term features (e.g., spectral centroid, spectral flux, pulse clarity). Short-term features used 25 ms windows, long-term used 3 s windows; features were resampled to 1 s and rescaled. Principal component analysis with varimax rotation produced eight components explaining >90% variance; these component timecourses were convolved with a double-gamma haemodynamic response function (HRF), downsampled to match the 2 s TR, high-pass filtered at 0.01 Hz and truncated to avoid convolution edge artefacts. These PC timecourses served as regressors of interest in fMRI models. Imaging used a 3T GE HDx scanner with 3.4 mm isotropic functional voxels (TR/TE = 2000/35 ms) and a 1 mm isotropic anatomical scan. Pre-processing combined AFNI, FSL and ANTS steps: despiking, motion correction, brain extraction, rigid and nonlinear registration to MNI space, scrubbing using a framewise displacement (FD) threshold of 1.0 mm, 5 mm spatial smoothing and high-pass filtering. Nine nuisance regressors (six motion parameters and three anatomical signals from ventricles, draining veins and white matter) were included. Statistical analysis: individual-level general linear models (GLMs) included the eight PC regressors, their temporal derivatives and the nine nuisance regressors (27 regressors total). Contrast images for each PC were carried to group-level paired t-tests (LSD > Placebo and opposite) using mixed-effects FLAME 1+2 and cluster correction (Z > 2.3, cluster p = 0.05). To relate neural changes to subjective peak emotion, region-of-interest (ROI) masks were created by intersecting Harvard-Oxford structural parcels (10% probability threshold) with the group-level LSD>Placebo map for the timbral component; nine ROIs were defined. Spearman correlations related per-subject BOLD changes to changes in Geneva Emotional Music Scale (GEMS) scores for wonder and transcendence, with permutation testing (10,000 permutations) to correct for multiple comparisons. Psychophysiological interaction (PPI) analyses used subject-specific precuneus and right inferior frontal gyrus (IFG) timecourses, adding an interaction regressor formed from the ROI timecourse and the timbral complexity PC (PC3) to probe context-dependent connectivity.

PCA of acoustic features produced eight components that together explained over 90% of variance and showed correspondence with components reported in other genres. The component labelled timbral complexity (PC3) correlated highly with similar measures from prior work. fMRI contrasts comparing LSD to placebo revealed component-specific changes. Timbral complexity produced widespread LSD-related BOLD increases in a network including bilateral auditory cortex (Heschl's gyrus, superior temporal gyrus, planum temporale), right IFG, right anterior insula, precuneus, bilateral striatum, supplementary motor area and parts of occipital cortex. Left auditory cortex effects and particularly extensive right IFG and right anterior insula activations were emphasised for this component. Other components produced distinct effects: brightness decreased under LSD in left lateral occipital cortex; fullness (related to loudness) showed increased activation in bilateral thalamus and decreased activation in occipital cortex and right middle/inferior frontal gyrus; Subband 3 produced increased occipital and decreased cerebellar activation; key clarity increased in right lateral occipital cortex and decreased in left striatum; Subband 2 increased activation in right lateral occipital cortex. A supplementary table (as reported) lists full results. Subjective music-evoked emotion, measured with the GEMS immediately after scanning, was significantly increased under LSD for wonder (t(18)=4.47, p=0.002), transcendence (t(18)=4.17, p=0.004), power (t(18)=3.82, p=0.008), tenderness (t(18)=3.78, p=0.008), nostalgia (t(18)=3.94, p=0.006), peacefulness (t(18)=4.45, p=0.003), and joyful activation (t(18)=4.86, p=0.001). Sadness and tension were not significantly different. Reported p-values were permutation-corrected. Correlation analyses focused on timbral complexity (PC3). Changes in feelings of wonder (LSD > Placebo) correlated positively with increases in timbre-evoked BOLD responses in the precuneus (Spearman r = 0.67, p = 0.034) and in the right IFG (r = 0.65, p = 0.045). A trend-level correlation was observed between transcendence and right IFG (r = 0.61, p = 0.066). Reported p-values were permutation-corrected for multiple comparisons. PPI analyses using the precuneus as seed revealed timbre-dependent connectivity changes under LSD: increased coupling between precuneus and right superior frontal gyrus (SFG) for high timbral complexity, and decreased coupling between precuneus and right IFG and right auditory cortex when timbral complexity increased. No significant timbre-specific PPI effects were found using the right IFG as seed. Head motion, assessed via framewise displacement, was greater on average under LSD (mean FD placebo = 0.091 ± 0.037; LSD = 0.174 ± 0.10), a significant difference (t(15) = -3.28, p = 0.005). However, change in FD did not correlate significantly with timbre-related BOLD changes in any of the nine ROIs; these reported correlations were uncorrected for multiple comparisons.

Kaelen and colleagues interpret the results as evidence that LSD markedly alters music-evoked brain activity and connectivity, with the most pronounced effects tied to timbral complexity. Increased BOLD responses to timbre involved auditory cortices, right IFG, right insula, precuneus, bilateral striatum and SMA—regions implicated in music perception and music-evoked emotion. The authors link these neural changes to subjective intensification of emotion: feelings of wonder were higher under LSD and their augmentation correlated with timbre-evoked activation in precuneus and right IFG. Functionally, the paper emphasises the auditory–IFG pathway as a route by which spectrotemporal (timbre) information is linked to learned representations and emotional valuation. Right IFG increases under LSD, and its correlation with enhanced emotion, are taken to indicate greater allocation of attentional resources to emotionally salient acoustic information. The precuneus, a hub associated with self-referential cognition and emotion regulation, showed reduced coupling with auditory cortex and IFG during high timbral complexity under LSD; the authors suggest this decoupling could reflect weakened top-down regulation that facilitates intensified emotional responses. Limbic structures (striatum, insula) also showed increased timbre-evoked activation; the authors note the striatum's association with reward and simple affect, and propose that complex peak emotions such as wonder may rely more on cortical networks like IFG and precuneus. On possible mechanisms, the discussion links effects to serotonin 2A receptor activation on deep layer V pyramidal cells. Over-activation of these receptors may lower firing thresholds, desynchronise high-level networks, impair top-down predictive signalling and produce a more ‘‘entropic’’ activation of mental representations. High serotonin 2A receptor density in precuneus, insula and planum temporale is proposed as one reason for the observed localisation of effects. The authors further argue for a special role of timbre—an early-developing, cross-cultural carrier of emotional information—as an ‘‘interface’’ between spectral features and emotional meaning, and suggest LSD may heighten responsiveness to this non-verbal emotional language of music. Clinical relevance is discussed: because music listening is a core element of psychedelic-assisted psychotherapy, these findings provide a neurobiological basis for music's role in facilitating peak emotional experiences that have been associated with therapeutic benefit. The authors suggest that attention to timbre in playlist design could be valuable. Key limitations acknowledged include the absence of perceptual measures for acoustic features and the use of a single, low-tempo ambient genre; these limit inferences about whether LSD alters perception of specific acoustic features or how effects generalise across musical styles. The authors note, however, that timbral complexity was not the dominant component of variance in the stimuli, supporting the validity of the component-based approach.

Under naturalistic listening conditions, LSD altered brain activity and functional connectivity evoked by distinct acoustic features of music. The most pronounced changes were tied to timbral complexity and occurred within networks implicated in music perception and emotion; increased timbre-evoked activation in precuneus and right IFG correlated with heightened feelings of wonder under LSD. These results provide a neurobiological account of how LSD modulates music processing and support the relevance of music—particularly its timbral properties—in psychedelic-assisted therapeutic settings.