Discussion
The goal of this study was to investigate the effects of LSD on whole-brain EC and gauge its potential as a biomarker to decode or predict subjective effects in the future. To this end, we studied LSD-induced effects on whole-brain EC through multivariate, and machine-learning analyses and compared EC to FC. Multivariate PLSC analyses revealed stronger EC between parietal, temporal and inferior frontal regions under LSD, but weaker EC between regions in occipital cortices. When comparing FC to EC, we found notable changes in self-inhibition in around 30% of the brain regions under LSD, indicating that LSD may perturb the excitation/inhibition (E/I) balance of the brain. Moreover, our results suggest that—while EC was asymmetric (10–14% of connections)—asymmetry was largely unaffected by LSD (1.4% of connections). Lastly, our behavioural PLS and machine learning analyses showed that both FC and EC constitute promising biomarkers for future individual-level predictions of subjective effects. These analyses revealed that changes in FC and EC between several regions including angular gyrus and inferior frontal gyrus as well as connections between occipital and cerebellar regions correlated with global subjective effects of LSD and classifiers trained on either FC or EC could discriminate between LSD and placebo with high accuracy of 86% and 91%, respectively.