Psychedelics and anesthetics cause unexpected chemical reactions in the brain

The brain is the most complex part of the human body. To keep our heads running smoothly,  more than 100 types of neurotransmitters must shuttle messages across multiple regions of white and gray matter. It’s difficult for researchers to track the immense number of connections that these chemical messengers make—Google recently created one of the most detailed maps of neuronal connectivity patterns, but even the tech giant could only focus on a small section of the brain. 

While it may take decades until someone fully maps out the human brain, there are ways to trace different aspects of connectivity. A new study published today in Science Advances used mind-altering drugs, such as ketamine and the surgical anesthetic propofol, to follow which neurotransmitter systems those pharmaceuticals activate. The findings help identify associations between these drugs and unexpected neurotransmitters. They could also help identify new treatment options for certain conditions and diseases, as the authors found that brain regions commonly altered by different drugs were often similarly affected by various neurological disorders.

Pharmacological agents such as mind-altering drugs have powerful uses in medicine, says Andrea Luppi, a postdoctoral researcher of network neuroscience at the Alan Turing Institute in the United Kingdom. “Anesthetics are extremely useful for surgery. Modafinil and methylphenidate are used to treat certain conditions,” Luppi says. “So it’s important to know how they act on the brain to exert their effects.”

But these types of chemicals can be tricky to understand, because they activate more than one neurotransmitter receptor. Knowing how they work in the brain can improve how they are used in clinical practice in the future. But it’s not enough to predict a drug’s mechanism based purely  on its clinical effects. There is also a chance these drugs could influence other neurotransmitters beyond their main targets. 

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To address these questions, Luppi and his coauthors analyzed two sets of neuroimaging data from past studies to map out the ways the human brain changes when taking 10 mind-altering drugs. These drugs fell under three categories: psychedelics (psilocybin, DMT, LSD, MDMA, ayahuasca, and ketamine), anesthetics (propofol and sevoflurane), and cognitive enhancers (modafinil and methylphenidate). The first data set, based on the PET scans of 1,200 people, helped the team sketch out 19 types of molecules in the brain: all neurotransmitter receptors and transporters.  

The second dataset used the fMRI scans of 224 people who had acute exposure to one of the 10 drugs. According to the authors, this is the largest fMRI study to date that has plotted a detailed map of the neurotransmitter landscape when under the influence.

Brain mapping showed that mind-altering drugs work with multiple neurotransmitter systems. The mapping showed expected relationships, such as the link between MDMA and its well-known target, the serotonin 2A receptor. However, the team noticed some mind-altering drugs, like anesthetics and psychedelics, can affect other neurotransmitters beyonds their main molecular targets. For example, anesthetics at the lowest dose primarily target molecules in the brain called GABAA receptors. But the molecules that the drugs bind to changes as doses increase, the authors found, activating a more diverse group of neurotransmitters. 

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“We are used to thinking that many drugs have a single or few molecular targets. What we see suggests that even when a drug exerts its effect through a specific receptor, it can have downstream consequences on many neurotransmitter systems. This reinforces the idea that the brain is a complex system,” Luppi says. 

According to the study authors, their mapping provides new opportunities to explore how each of these mind-altering drugs affects the neurotransmitter landscape. It could also help vet certain drugs for neuropsychiatric treatments. The changes in activity caused by mind-altering drugs are similar to the changes seen in the brains of patients with conditions such as autism, depression, and schizophrenia, the authors say. Administering mind-altering drugs that rewire the connections in functionally impaired brain areas could be another treatment option for people who live with these conditions. 

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