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Protein structure reveals how LSD affects the brain

An artistic representation of LSD (in blue) fitting into a serotonin receptor (the white ribbon).Bryan Roth

Lysergic acid diethylamide, or LSD, can alter perception (awareness of surrounding objects and conditions), thoughts, and feelings. It can also cause hallucinations—sensations and images that seem real even though they’re not. These “trips” can last many hours, long after LSD has been cleared from the bloodstream.

LSD was first synthesized in 1938, and its hallucinogenic effects discovered soon afterward. However, how the compound causes its effects in the brain hasn’t been well understood. LSD is a member of a class of drugs called ergolines, which are used to treat many conditions, including migraine headaches and Parkinson’s disease. Understanding how the compound exerts its unique effects could provide insights to guide the development of future therapeutics.

LSD interacts with proteins on the surface of brain cells called serotonin receptors. Serotonin is a chemical messenger that helps brain cells communicate. LSD appears to act through a particular receptor called 5-HT_2AR. To gain insights into LSD’s effects, a research team led by Dr. Bryan Roth at the University of North Carolina crystallized a related receptor, 5-HT_2BR, attached to LSD. The scientists used x-ray crystallography to visualize the structure. Their study was supported by NIH’s National Institute of Mental Health (NIMH). Results were published on January 26, 2017, in Cell.

Serotonin receptors activate 2 major signaling pathways within cells: through G-proteins and through β-arrestins. The researchers found that LSD binds its receptor in a way that causes it to act mostly through the β-arrestin pathway instead of the G-protein pathway. Related ergoline compounds, the scientists found, differ in the way they structurally interact with the receptor. Further laboratory experiments and computer analyses revealed that these distinct but similar compounds can shape the structure of the receptor to trigger different effects.

The team also found that the serotonin receptor closes a “lid” over the LSD molecule, preventing it from quickly detaching. This likely explains the drug’s long-lasting effects. A mutant form of the receptor with a weaker lid had reduced β-arrestin pathway activity, while leaving G-protein pathway activity unaffected.

“This study sheds light on the mechanism of psychoactive drug action, including how certain drugs activate one signaling pathway inside cells while avoiding another,” explains Dr. Laurie Nadler, chief of NIMH’s Neuropharmacology Program. “Taken together with other recent studies of drug-receptor complexes, this work provides proof-of-concept for the design of drugs with desired signaling properties and fewer undesired side-effects.”

Roth and other colleagues recently showed the potential of such structure-based design. Based on similar discoveries about an opioid receptor, they created a molecule that effectively alleviates pain in mice, but with fewer side effects than morphine.