Far out: UNC scientists may have discovered why an LSD acid trips lasts so long

A tiny tab of acid on the tongue – a daylong trip full of hallucinations and psychedelic experiences.

For the first time, UNC School of Medicine researchers have discovered what the drug lysergic acid diethylamide (LSD) looks like in its active state when it’s attached to the serotonin receptor of a a human brain cell, the university announced Thursday.

When researchers first crystallized the structure of LSD, it revealed a major clue for why the psychoactive effects of the drug last so long.

Dr. Bryan L. Roth led the research published Thursday in the scientific journal “Cell.” He is the Michael Hooker Distinguished Professor of Protein Therapeutics and Translational Proteomics at the UNC School of Medicine.

“There are different levels of understanding for how drugs like LSD work,” Roth said in a university news release. “The most fundamental level is to find out how the drug binds to a receptor on a cell. The only way to do that is to solve the structure. And to do that, you need X-ray crystallography, the gold standard.”

That’s exactly what Roth’s lab did. They essentially froze LSD while it was attached to a receptor so researchers could capture images of the drug connected to the cell. Researchers discovered that when LSD latches onto the brain cell’s serotonin receptor, part of the receptor folds over the drug molecule like a lid, locking it in place.

“We think this lid is likely why the effects of LSD can last so long,” said Roth, who also works at the UNC Eshelman School of Pharmacy.

But, while lengthy, acid trips aren’t forever. Some LSD molecules pop off their receptors as the “lid” part moves around. And brain cells eventually respond to the drug molecule by pulling in its serotonin receptor, along with the drug, where the drug is then degraded or disassembled.

Postdoctoral researchers Daniel Wacker and Sheng Wang led the experiments to crystallize LSD bound to a serotonin receptor and discover why it stays there so long. Other labs have reported that LSD is washed out of brain fluid within four hours, but UNC researchers found that LSD wasn’t washed out of the brain cell’s serotonin receptors in that amount of time. Previous research didn’t extend to what was happening on or inside the brain cells that LSD attached to.

LSD and its uses

Now, because of the work by UNC researchers, scientists can begin to parse how the drug sparks such a dramatic reaction in the brain.

The medical community also has a renewed interest in LSD as a potential treatment for a number of conditions, such as cluster headaches, substance abuse and anxiety associated with life-threatening conditions. The UNC research solving the structure of LSD could help drug developers design better psychiatric drugs with fewer side effects.

LSD is illegal, but remains a popular recreational drug for its potent effects and for anecdotal evidence that it boosts creativity, relieves stress and helps people solve problems in extremely low doses. One in 10 people in the United States – tens of millions of people – reported using LSD at least once in their lives.

Before becoming a pharmacology professor and researcher, Roth was a psychiatrist specializing in schizophrenia – a disorder often characterized by a breakdown in the relationship between thought, emotion and behavior leading to faulty perception, inappropriate actions and feelings, withdrawal from reality, delusion and other symptoms.

Roth said patients would occasionally report that their first schizophrenic break happened while using LSD.

“They were never the same again,” Roth said. “Although this is rare, it has been reported. People also report flashbacks, and LSD is an extremely potent drug. So for those reasons, along with its potential as part of therapeutic treatment, LSD is scientifically interesting.”

But now the understanding of LSD will improve dramatically because of the work at UNC.

“To get crystals of a known compound bound to its receptor is incredibly difficult,” said Roth, who is also director of the National Institute of Mental Health's Psychoactive Drug Screening Program housed at UNC. “In some cases, it’s nearly impossible.”

But Roth said he and his team don’t advocate LSD use.

“It is potentially very dangerous,” he said. “But it could have potential medicinal uses, some of which were reported in the medical literature decades ago. Now that we’ve solved the structure of LSD bound to a receptor, we are learning what makes it so potent.”

The National Institute of Mental Health, a Terman Faculty Fellowship, and the Michael Hooker Distinguished Chair of Pharmacology at UNC funded the research.

Other authors include: UNC research associates David Nichols, Sheng Wang, Tao Che; UNC graduate students Katherine Lansu and Zachary Schools; Stanford graduate student Robin Betz and Stanford postdoctoral fellow A. J. Venkatakrishnan; and Brian Shoichet, professor of pharmaceutical chemistry at the University of California-San Francisco, and UCSF postdoc Anat Levit.

For more information, go to the UNC School of Medicine’s website.

This story was originally published January 26, 2017 at 6:57 PM with the headline "Far out: UNC scientists may have discovered why an LSD acid trips lasts so long."