Cortical structural differences following repeated ayahuasca use hold molecular signatures
Using 7 T MRI and morphometric similarity networks in 24 Santo Daime members and matched controls, repeated ayahuasca use was associated with sensorimotor structural differentiation and transmodal de-differentiation across the cortex. These macroscale cortical remodellings spatially correlated with dysregulation of 5‑HT2A and other psychedelic-target genes, and with altered expression of transcription factors and immediate early genes implicated in psychedelic-induced neuroplasticity, suggesting molecular mechanisms scale up to whole-brain organisation.
Authors
- Johannes Ramaekers
- Nathalie Mason
- Jan Reckweg
Published
Abstract
Introduction
Serotonergic psychedelics such as ayahuasca are reported to promote both structural and functional neural plasticity via partial 5-HT2A agonism. However, little is known about how these molecular mechanisms may extend to repeated psychedelic administration in humans, let alone neuroanatomy. While early evidence suggests localised changes to cortical thickness in long-term ayahuasca users, it is unknown how such findings may be reflected by large-scale anatomical brain networks comprising cytoarchitecturally complex regions.
Methods
Here, we examined the relationship between cortical gene expression markers of psychedelic action and brain morphometric change following repeated ayahuasca usage, using high-field 7 Tesla neuroimaging data derived from 24 members of an ayahuasca-using church (Santo Daime) and case-matched controls.
Results
Using a morphometric similarity network (MSN) analysis, repeated ayahuasca use was associated with a spatially distributed cortical patterning of both structural differentiation in sensorimotor areas and de-differentiation in transmodal areas. Cortical MSN remodelling was found to be spatially correlated with dysregulation of 5-HT2A gene expression as well as a broader set of genes encoding target receptors pertinent to ayahuasca’s effects. Furthermore, these associations were similarly interrelated with altered gene expression of specific transcriptional factors and immediate early genes previously identified in preclinical assays as relevant to psychedelic-induced neuroplasticity.
Conclusion
Taken together, these findings provide preliminary evidence that the molecular mechanisms of psychedelic action may scale up to a macroscale level of brain organisation in vivo. Closer attention to the role of cortical transcriptomics in structural-functional coupling may help account for the behavioural differences observed in experienced psychedelic users.
Research Summary of 'Cortical structural differences following repeated ayahuasca use hold molecular signatures'
Introduction
Classical serotonergic psychedelics including psilocybin, LSD and DMT are thought to promote both acute subjective effects and longer-term neuroplastic adaptations via partial agonism at the 5-HT2A receptor. Preclinical work has shown 5-HT2A agonists can trigger immediate early genes (IEGs), and later synaptogenesis, dendritogenesis and other markers of structural plasticity; human neuroimaging studies have likewise reported persistent changes to large-scale functional networks after single doses. Less is known, however, about how repeated psychedelic exposure affects brain anatomy at a macroscale level, or how any structural differences map onto molecular signatures associated with psychedelic pharmacology. Mallaroni and colleagues set out to examine whether sustained ayahuasca use is associated with altered whole-cortex anatomical organisation and whether such alterations spatially co-locate with cortical gene expression relevant to ayahuasca's pharmacology and plasticity-related pathways. Using high-field 7T MRI from 24 long-term Santo Daime members and 24 matched controls, the study employed morphometric similarity network (MSN) analysis to characterise cortical structural network topography and related regional MSN differences to transcriptional maps from the Allen Human Brain Atlas, testing hypotheses about group differences in MSNs, their clustering within functionally relevant networks, and co-localisation with 5-HT2A expression and other candidate genes.
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Study Details
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- APA Citation
Mallaroni, P., Mason, N. L., Kloft, L., Reckweg, J. T., van Oorsouw, K., & Ramaekers, J. G. (2023). Cortical structural differences following repeated ayahuasca use hold molecular signatures. Frontiers in Neuroscience, 17. https://doi.org/10.3389/fnins.2023.1217079
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