Neuroscientists gain a deeper understanding of how LSD affects molecular brain activity

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

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

“Most LSD research to date 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 a hard time explaining what they are observing!). I was eager 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) under the influence of LSD. Lawn and his research team performed a so-called Receptor-Enriched Analysis of Functional Connectivity by Targets (REACT), a relatively new technique that uses molecular information about the distribution of serotonin and dopamine receptors in the brain.

In line with previous research, LSD appeared to increase functional connectivity in brain regions rich in serotonin receptors. But Lawn and his colleagues found evidence that LSD also increased functional connectivity in brain regions with a relatively high density of dopamine receptors. In addition, the researchers found that serotonergic systems were associated with LSD’s effects on visual perception, while the dopaminergic system was associated with LSD’s effects on perceived self-image and cognition.

“Drugs are really complicated. The brain is even more complicated. As you might imagine, this makes untangling the effects of drugs on the brain a nontrivial challenge,” Lawn told PsyPost.

“Most studies look at the broad effects of what a drug does on the 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 for mediating it. The problems with these approaches are that the network changes can represent the effects of actions on many different receptors and when you block one receptor, you also block any downstream interactions with other receptor systems.

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

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

“It will be crucial to replicate these findings in separate larger data sets,” Lawn said. “In addition, it will be very interesting to see how REACT-derived molecular-enriched networks are utilized by other psychedelic drugs with overlapping but also different pharmacological profiles — this is something we’re very excited to do in the future.”

“Increasing the open sharing of psychedelic fMRI datasets, such as the one used in this study, will greatly increase the scope for applying new analysis techniques and potentially allow for independent validation of findings,” the researcher added. “As the field matures, I hope this will become a more common practice and that it will expand our understanding of these drugs and our own brains.”

The study, “Differential contributions of serotonergic and dopaminergic functional connectivity to the phenomenology of LSD,” was authored by Timothy Lawn, Ottavia Dipasquale, Alexandros Vamvakas, Ioannis Tsougos, Mitul A. Mehta, and Matthew A. Howard.

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