Neuroscientists are gaining a better understanding of how LSD affects molecular brain activity


The dopamine system appears to play an important but overlooked role in the effects of LSD on consciousness, according to new research published in the journal Psychopharmacology. The findings provide new insights into the neurophysiological mechanisms responsible for the unique effects of psychedelic drugs.

“Psychedelic research is back and making up for lost time after a long period of legal restriction. These drugs produce profound effects on consciousness, giving scientists a powerful tool to try to link brain mechanisms to our subjective experience,” said study author Timothy Long (@lawn_tim), NIHR Maudsley BRC PhD student at King’s College London.

“Most research on LSD so far has suggested that it acts on a single target in the brain to produce its effects – the serotonin 5-HT2a receptor. However, it is known to have other targets, including dopamine receptors, but no research has shown that these other targets can contribute to the psychedelic state in humans (the pigs and rodents studied have difficulty explaining what they perceive!). I was really keen to explore these additional receptor systems and how they might relate to the LSD experience.

For their study, the researchers analyzed previously published data from 15 participants who underwent functional magnetic resonance imaging (fMRI) while under the influence of LSD. Lawn and his research team conducted what is called Receptor Enriched Targeted Functional Connectivity Analysis (REACT), a relatively new technique that uses molecular information about the distribution of serotonin and dopamine receptors in the brain.

Consistent with previous research, LSD appears to increase functional connectivity in areas of the brain rich in serotonin receptors. But Lawn and his colleagues found evidence that LSD also increased functional connectivity in areas of the brain that had a relatively high density of dopamine receptors. Additionally, the researchers found that the serotonergic systems were associated with the effects of LSD on visual perception, while the dopaminergic system was associated with the effects of LSD on self-perception and cognition.

“Drugs are really complicated. The brain is even more complicated. As one can imagine, this makes unraveling the effects of drugs on the brain a significant challenge,” Lawn told PsyPost.

“Most studies look at the general effects of what a drug does on different networks in the human brain. Sometimes they also block a receptor to see if that prevents the effects of the drug, which would suggest that the receptor is important in mediating them. The problems with these approaches are that network changes can represent the effects of actions on many different receptors and when you block one receptor you also block any potential downstream interaction with other receptor systems.

“By trying to bridge the gap between the receptors on which LSD acts and the network changes it causes, our study offers a new perspective that suggests that the dopamine and serotonin receptor systems may be linked to different aspects of the psychedelic experience,” Lawn explained.

The new research represents the first attempt to investigate the effects of LSD on receptor-enriched brain networks. But the study, like all research, has some caveats. The relatively small sample size, for example, means the study may not have been able to detect weak associations.

“It will be crucial to replicate these results in separate larger datasets,” Lawn said. “Furthermore, it will be very interesting to see how the enriched molecular networks derived from REACT are engaged by other psychedelic drugs with overlapping pharmacological profiles but also distinct pharmacological profiles – this is something we are very keen on. to do in the future.”

“Increased open sharing of psychedelic fMRI datasets, such as the one used in this study, will greatly expand the scope of new analysis techniques and potentially enable independent validation of results,” the researcher added. . “As the field matures, I hope this will become more common practice and advance our understanding of these drugs as well as our own brains.”

The study, “Differential Contributions of Serotonergic and Dopamine Functional Connectivity to LSD Phenomenology,” was authored by Timothy Lawn, Ottavia Dipasquale, Alexandros Vamvakas, Ioannis Tsougos, Mitul A. Mehta, and Matthew A. Howard.


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