Effective-connectivity of thalamocortical interactions following d-amphetamine, LSD, and MDMA administration
This re-analysis of a double-blind, placebo-controlled, crossover study (n=25) investigated the effects of LSD, MDMA and dextroamphetamine on brain measures (thalamocortical and corticothalamic interactions in resting-state fMRI data). Compared to placebo, all three substances increased the effective-connectivity from the thalamus to specific unimodal cortices while reducing their influence on the thalamus, revealing increased bottom-up and decreased top-down information flow; LSD uniquely increased effective-connectivity to both unimodal and transmodal cortices.
Authors
- Patrick Vizeli
- Stefan Borgwardt
- Felix Müller
Published
Abstract
Background
While the exploration of serotonergic psychedelics as psychiatric medicines deepens, so does the pressure to better understand how these compounds act on the brain.
Methods
We used a double-blind, placebo-controlled, crossover design and administered lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), and d-amphetamine in 25 healthy participants. By employing spectral dynamic causal modeling, we mapped substance-induced changes in effective-connectivity between the thalamus and different cortex types (unimodal vs. transmodal) derived from a previous study in resting-state functional magnetic resonance imaging (fMRI) data. Due to the distinct pharmacological modes of action of the three substances, we were able to investigate specific effects mainly driven by different neurotransmitter systems on thalamocortical and corticothalamic interactions.
Results
Compared to placebo, all three substances increased the effective-connectivity from the thalamus to specific unimodal cortices, whereas the influence of these cortices on the thalamus was reduced. These results indicate increased bottom-up and decreased top-down information flow between the thalamus and some unimodal cortices. However, for the amphetamines, we found the opposite effects when examining the effective-connectivity with transmodal cortices, covering parts of the salience network. Intriguingly, LSD increased the effective-connectivity from the thalamus to both unimodal and transmodal cortices, indicating a breach in the hierarchical organization of ongoing brain activity.
Conclusion
Results advance our knowledge concerning the action of psychedelics on the brain and refine current models aiming to explain the underlying neurobiological processes.
Research Summary of 'Effective-connectivity of thalamocortical interactions following d-amphetamine, LSD, and MDMA administration'
Introduction
The renewed clinical interest in serotonergic psychedelics is driven by promising therapeutic signals for disorders such as depression, anxiety, and addiction, yet the neurobiological mechanisms mediating these effects remain incompletely understood. One influential account, the disrupted thalamic filter model (TFM), proposes that changes in neurotransmission (for example increases in dopaminergic tone) can impair thalamic filtering and cause a ‘‘cortical flooding’’ that contributes to altered conscious states. Prior human neuroimaging studies using resting-state functional connectivity (iFC) have reported substance-induced increases in thalamocortical iFC, often localised to thalamic nuclei rich in 5-HT2A receptors, but iFC does not indicate directionality of influence. To address whether thalamocortical dysconnectivity is driven primarily by the thalamus or cortex and whether effects differ by cortical type, Avram and colleagues used spectral dynamic causal modelling (DCM) to estimate directed (effective) connectivity between the thalamus and two cortical sets: unimodal (sensorimotor and visual) and SAL-derived transmodal regions. Using a double-blind, placebo-controlled, crossover design with LSD, MDMA, d-amphetamine, and placebo in the same participants, the study tested whether these substances increase thalamus-to-cortex (bottom-up) effective connectivity for unimodal regions, and whether LSD in particular increases thalamus-to-transmodal connectivity while the amphetamines produce distinct effects, consistent with prior iFC results.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Avram, M., Müller, F., Preller, K. H., Razi, A., Rogg, H., Korda, A., Holze, F., Vizeli, P., Ley, L., Liechti, M. E., & Borgwardt, S. (2024). Effective-connectivity of thalamocortical interactions following d-amphetamine, LSD, and MDMA administration. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 9(5), 522-532. https://doi.org/10.1016/j.bpsc.2023.07.010
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Cited By (2)
Papers in Blossom that reference this study
Stoliker, D., Novelli, L., Khajehnejad, M. et al. · Biorxiv (2025)
Avram, M., Fortea, L., Wollner, L. et al. · Molecular Psychiatry (2024)
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