Psychedelics belong to a group of compounds called psychoplastogens, which can promote neuronal growth and restore atrophied connections in the brain. This ability makes the molecules promising as potential treatments for neuropsychiatric diseases such as chronic depression and addiction. In a new study, scientists have untangled the mechanism of how these compounds trigger the rewiring of the brain, providing a better understanding of why these compounds differ from other neurochemicals that share the same binding targets (Science 2023, DOI: 10.1126/science.adf0435).
Classic psychedelics such as psilocybin and LSD bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor, an important G-protein-coupled receptor (GPCR) that’s involved in cellular signaling. But so does serotonin, the ubiquitous, mood-dictating neurotransmitter. The lingering mystery is why serotonin doesn’t stimulate the same neuroplasticity effects that psychedelic compounds do.
The new study has found the answer. “The location of the 5-HT2A receptor is critical for determining the kinds of signaling pathways that a ligand can induce,” says David E. Olson, a chemist at the University of California, Davis, who led the research.
For a GPCR, the 5-HT2A receptor is weird. Most GPCR proteins reside on the cellular surface to relay signals between the cell and its environment. But in neurons, the majority of 5-HT2A receptors populate the inside of the cell.
Olson’s team discovered that psychoplastogens need to reach the receptors within neurons to spark intracellular signaling. Merely hitting the receptors on the outside won’t count.
“The fact that psychedelics may interact with intracellular receptors—that’s really interesting,” says Bryan Roth, a pharmacologist at the University of North Carolina School of Medicine who wasn’t involved in the research. In a follow-up email, he calls the study “a major advance.”
Serotonin—unlike N,N-dimethyltryptamine (DMT),which is found in ayahuasca brew, for example—is a polar molecule, so it can’t easily cross the lipid bilayer of the cell membrane to get inside. On the other hand, greasy compounds can access the intracellular space, Olson says.
However, if serotonin is able to enter the cell, it too can kick-start the same signaling events that would lead to neuronal growth. After Olson and his group forced neurons to take up serotonin, the researchers observed them sprouting more branches and more protrusions as a result. The researchers also genetically engineered mice to express a serotonin transporter and saw antidepressant-like behavior, unlike control mice that did not produce the same protein.
The paper is a landmark study, because it opens up new questions about this particular plasticity mechanism, says Javier González-Maeso, a GPCR biophysicist at Virginia Commonwealth University who didn’t participate in the research. “What are the pathways activated by the serotonin 2A receptor located intracellularly? What are the pathways responsible for these medical effects?” he asks.
The research may help inform the design of new psychedelic drugs. Olson is the cofounder of Delix Therapeutics, a start-up with the goal of creating designer psychoplastogens that are safer and more accessible than traditional psychedelics. Compounds that can target the 5-HT2A receptor within neurons are a good place to start, he says.