Effective-connectivity of thalamocortical interactions following d-amphetamine, LSD, and MDMA administration

While the exploration of serotonergic psychedelics as psychiatric medicines deepens, so does the pressure to better understand how these compounds act on the brain.

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.

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.

Results advance our knowledge concerning the action of psychedelics on the brain and refine current models aiming to explain the underlying neurobiological processes.