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New research provides unique insights into how different drugs, including psychedelic substances, engage with the brain’s neurotransmitter landscape to produce their effects on brain activity. The findings, published in Science Advances, indicate that psychoactive drugs interact with the brain’s neurotransmitter system in complex and unexpected ways, leading to large-scale hierarchical effects on brain function.
The study was motivated by the desire to better understand the relationship between neurotransmitters (chemicals in the brain that transmit signals between neurons) and the brain’s functional connectivity, which refers to how different brain regions communicate with each other. By mapping the relationship between neurotransmitters and drug effects on brain function, scientists can identify specific neurotransmitter targets for potential therapeutic interventions.
“Pharmacology is extremely important in modern medicine, including for psychiatric disorders,” said study author Andrea Luppi, a Molson Neuro-Engineering Fellow at the Montreal Neurological Institute of McGill University.
“And we know that drugs that act on the brain, typically do so by engaging the brain’s many neurotransmitter systems, by acting on various receptors. So to have a better understanding of how different drugs work, and possibly aid the development of new ones, it’s important to have as detailed picture as possible of how each drug acts on each receptor.”
To conduct the study, the researchers analyzed two main datasets. The first dataset consisted of in vivo maps of regional expression from 19 different neurotransmitter receptors and transporters, obtained through positron emission tomography (PET) scanning of over 1,200 individuals. These maps provided detailed information about the distribution of neuromodulators in the brain.
The second dataset included resting-state functional magnetic resonance imaging (rs-fMRI) data collected from 224 individuals under the effects of different psychoactive drugs. These drugs included general anesthetics (propofol and sevoflurane), cognitive enhancers (modafinil and methylphenidate), ketamine (acting as both a psychedelic and a dissociative anesthetic), and serotonergic psychedelics (LSD, psilocybin, DMT, ayahuasca, and MDMA).
Luppi and his colleagues discovered some interesting discrepancies between the drugs’ effects on various neurotransmitter receptors and transporters and their known primary targets in the brain. Neurotransmitter transporters are responsible for reabsorbing neurotransmitters after they have been released. On the other hand, neurotransmitter receptors are the specific sites where neurotransmitters bind to transmit their signals.
For example, ketamine is known to antagonize NMDA receptors, which are important for learning and memory processes. However, the study revealed only a weak alignment between ketamine and NMDA receptors. This suggests that ketamine’s effects on the brain may involve additional mechanisms beyond its direct interaction with NMDA receptors.
Similarly, MDMA is known to primarily target the serotonin 2A receptor, which plays a role in mood regulation. Surprisingly, the study found a weak alignment between MDMA and the serotonin 2A receptor. However, MDMA showed a strong alignment with serotonin and dopamine transporters, which it blocks. This indicates that MDMA’s effects on the brain may be mediated more through its impact on neurotransmitter transporters rather than direct activation of the serotonin 2A receptor.
These findings suggest that drugs can have broader interactions with multiple molecular targets in the brain. The pharmacological effects of drugs may involve not only their primary targets but also indirect modulation of other neurotransmitter systems.
“We are used to thinking that a drug will act through only one or a few receptors in the brain,” Luppi told PsyPost. “What we found is that most drugs that act on the brain seem to exert their effects through many different receptors. This is because the brain is a very complex system.”
This finding is particularly surprising, Luppi added, “because often you can stop the action of a drug by blocking a single receptor.” For example, ketanserin is known to block the effects of LSD by acting as a selective antagonist at the 5-HT2A receptors. As an antagonist, ketanserin binds to these receptors without activating them, thereby preventing LSD from binding to and stimulating the receptors.
When examining the patterns of connections between drug effects on brain activity and the distribution of neurotransmitter receptors, the researchers found a distinction between traditional anesthetics and other psychoactive substances. “Anesthetics and psychedelics/cognitive enhancers are largely opposite in terms of their association with neurotransmitters in the cortex, although not without exceptions,” they wrote.
Regarding the study’s limitations, Luppi said that “this work only considered acute effects from a single drug dose, not the effects from prolonged use, which will need to be studied in future work. Also, the studies included here are from small samples, almost all in healthy individuals, so replication with bigger groups of people will be required.”
“This work is based on correlation, and dedicated causal intervention studies are also required to complement the insights that we provided,” he added.
The study, “In vivo mapping of pharmacologically induced functional reorganization onto the human brain’s neurotransmitter landscape“, was authored by Andrea I. Luppi, Justine Y. Hansen, Ram Adapa, Robin L. Carhart-Harris, Leor Roseman, Christopher Timmermann, Daniel Golkowski, Andreas Ranft, Rüdiger Ilg, Denis Jordan, Vincent Bonhomme, Audrey Vanhaudenhuyse, Athena Demertzi, Oceane Jaquet, Mohamed Ali Bahri, Naji L. N. Alnagger, Paolo Cardone, Alexander R. D. Peattie, Anne E. Manktelow, Draulio B. de Araujo, Stefano L. Sensi, Adrian M. Owen, Lorina Naci, David K. Menon, Bratislav Misic, Emmanuel A. Stamatakis.
