Psychedelic resting-state neuroimaging: a review and perspective on balancing replication and novel analyses

Clinical research into serotonergic psychedelic drugs including psilocybin, LSD and N,N-DMT (e.g., in ‘ayahuasca’) is expanding rapidly and clinical trials across a range of psychiatric conditions have shown promising efficacy, with larger trials ongoing. Resting-state functional magnetic resonance imaging (fMRI) has emerged as a brain imaging strategy commonly used to identify associated neural mechanisms in both clinical and healthy populations. To date, 42 research articles have been published analysing resting-state fMRI data from 17 unique datasets involving the administration of a psychedelic drug. This provides a promising foundation for resolving imaging markers of the perceptual and clinical effects of psychedelics. Here we review the existing psychedelic resting-state fMRI literature through a lens that brings attention to emerging variation in core methodological decisions and promote strategies that aim to strengthen the field. We find a large degree of heterogeneity across the existing literature, with nearly all studies varying in data processing and analysis or drug evaluated. Two datasets are the foundation of more than half of the published literature, and terms such as “entropy” are often used to denote distinct metrics across studies. In light of these observations, we offer suggestions for future studies that we hope encourages coherence in the field. As a budding field of interest, psychedelic resting-state imaging will benefit from the development of novel models, hypotheses and quantification methods that may expand our understanding of the neural mechanisms mediating the intriguing acute perceptual and lasting clinical effects. Our review of the existing literature suggests that the psychedelic resting-state brain imaging field is at a crossroads at which it must also consider the critical importance of consistency and replicability to effectively converge on stable representations of the neural effects of psychedelics.