Psychedelic drugs increased functional connectivity between higher-order association networks and sensorimotor networks in a mega-analysis of resting-state functional magnetic resonance imaging data, suggesting a shared pattern of large-scale brain network reorganization across compounds.
In the analysis, researchers pooled 11 resting-state functional magnetic resonance imaging data sets spanning psilocybin, lysergic acid diethylamide, mescaline, N,N-dimethyltryptamine, and ayahuasca. The included data sets comprised 273 unique healthy adult participants, and the analyzed sample reflected 267 participants and more than 500 connectomes following motion-related exclusions.
Using a uniform preprocessing pipeline and Bayesian hierarchical modeling, the investigators found the most robust cross-drug effect was increased connectivity between transmodal association networks, including default mode and frontoparietal subnetworks, and unimodal sensorimotor networks, including visual and somatomotor systems.
The clearest subcortical findings involved the caudate and putamen, which showed increased coupling with cortical networks. By contrast, reductions in within-network connectivity were weaker, more selective, and often overlapped with no change, challenging broader claims that psychedelics produce widespread within-network disintegration.
Notably, thalamic connectivity changes—often emphasized in prior research—did not show consistent high-confidence effects in the Bayesian analysis, despite appearing in some average connectivity patterns.
Psilocybin and lysergic acid diethylamide showed highly similar connectivity patterns. Mescaline showed broadly similar but more variable effects. N,N-dimethyltryptamine showed the largest apparent network perturbations, although those estimates were less certain because they came from a small single-study sample. Ayahuasca showed a distinct pattern, lacking the typical increase in connectivity between association and sensorimotor networks and instead showing more widespread decreases between networks.
The Bayesian approach allowed the researchers to estimate the strength and certainty of connectivity changes across studies, rather than relying on binary statistical thresholds.
As the researchers wrote, psychedelics “most robustly increase functional integration between select pairs of transmodal and unimodal subnetworks.”
The findings are mechanistic rather than practice-changing. The study examined acute neuroimaging effects in healthy adults, not clinical outcomes in patients, and it does not establish therapeutic efficacy or support specific treatment recommendations.
Several limitations could have influenced the results. The pooled data sets varied in scanner field strength, voxel size, repetition time, dose, route of administration, and timing of imaging relative to drug administration. Study design also differed across data sets. Although most used double-blind, randomized, placebo-controlled designs, one lacked a placebo control and another used a fixed-order design. Small sample sizes for some compounds, particularly ayahuasca and N,N-dimethyltryptamine, also limited confidence in drug-specific estimates.
Still, the study offers one of the most comprehensive cross-drug views to date of how classic psychedelics may alter large-scale brain organization. Rather than showing uniform breakdown of established networks, the results suggest a more selective pattern marked by stronger communication between higher-order and sensory systems, along with specific changes in subcortical-cortical coupling.
Several researchers reported advisory roles, equity holdings, employment, or other ties to biotechnology and pharmaceutical companies; other researchers reported no competing interests.
Source: Nature Medicine
