In 2000, a philosophy student at Case Western Reserve University smoked the legal hallucinogen Salvinorin A, the active ingredient in the Mexican plant Salvia divinorum. Concerned about the intense, nauseating experience, he approached Case Western biochemistry and psychiatry professor Bryan Roth (now at UNC) and asked how the drug worked and whether it might have lasting effects.

Intrigued by what the student told him, Roth looked at the chemical structure of Salvinorin A. It was lipid-like, and it didn’t look at all like the typical structure of a hallucinogen, he says, pointing to the chemical structure on his finger-smudged computer screen. “But the student said it was hallucinogenic, definitely. He could tell me from his own firsthand experiences,” Roth says. So Roth went online and ordered Salvinorin A. His lab had it chemically analyzed for purity, and then screened fifty possible targets. They got lucky, Roth says, when they identified a single molecular target of Salvinorin A. His group published the finding in 2002 in The Proceedings of the National Academy of Sciences.

Newly arrived at Carolina from Ohio and not quite finished filling his bookshelves, Roth is leading an effort to determine how the drug binds its target—not an easy feat when the hallucinogen does not act like a hallucinogen.

Click to read photo caption. Photo by Will Cook; ©2007 Endeavors.

Salvia divinorum, a relative of the mint plant, is often called Magic Mint. It grows naturally in Oaxaca, Mexico, and the Mazatecs used it in traditional spiritual practices. Though Salvinorin A has been reported as the most potent naturally occurring hallucinogen, the drug is sold legally in the United States. It’s available on the internet and in smoking paraphernalia shops, including ones on Franklin Street, Roth says.

While Roth has never taken the drug, he sums up the effects in two words: spatiotemporal dislocation.

He quotes a user of the drug as having been in a “confused, fast-moving state of consciousness,” with a feeling of separation from his physical body. When the user tried “returning” to his body, he ended up “back in the wrong spot in the timeline of physical existence,” Roth says. “People who take Salvinorin A are transported to an alternative reality, one not shared by you or me.”

The profound alteration in consciousness, remarkably, is mediated through one type of target: the kappa opioid receptor, which is distributed throughout the human brain and spinal cord and known to be involved in pain perception. Roth’s lab stashed fifty types of receptors in groups of human cells and stored each group of cells in a well the size of a pen tip.

Many wells and cells later, the researchers discovered that Salvinorin A stuck only to the kappa opioid receptor; it ignored the kappa receptor’s close relatives, the mu and the delta opioid receptors. This selectivity is an oddity when considering that other hallucinogens, such as LSD, target multiple types of receptors in the brain to produce their trippy effects.

Roth’s lab is starting to figure out what makes Salvinorin A so selective. They know that a few chemical bonds make Salvinorin A ignore mu and delta, but until this year the nature of those bonds was a mystery. So for a study published in 2007 in the Journal of Biological Chemistry, Roth and his colleagues made blended versions of all the opioid receptors, and mutated certain sites on the receptors. They found that a couple specific portions of the receptor rotated in a way that made Salvinorin A choose kappa over mu and delta.

Finding out how Salvinorin A binds to the receptor may help researchers understand how the receptor can be blocked for drug development, Roth says. New drugs that were more selective for a particular receptor could better treat people who have schizophrenia, Alzheimer’s disease, bipolar disorder, or other conditions that are marked by distorted perceptions. So multiple labs and drug companies are actively hunting for receptor blockers.

Selectively blocking the kappa opioid receptor is a new idea in the field of drug development for psychiatric conditions. Since the 1950s, few new drugs have arisen to treat major mental illness, Roth says. Most prescribed antipsychotic drugs come with a barrage of side effects because they aren’t selective for receptors. It’s a challenge to determine which drug-receptor interactions are important for therapy and which are producing the side effects, he says.

Roth’s lab takes up half of the eighth floor of the Burnett-Womack building. Equipment hums in the large main lab, as four people in white lab coats work side-by-side, squirting liquids into small plates with hundreds of wells. Off the main lab, two rooms—for growing cells—are warm and smell vaguely of chicken soup. Another, colder room is filled with freezers containing cell membranes.

Finding Salvinorin A’s target and determining the nature of its selectivity was more than just luck. Roth brought his lab from Case Western to Carolina last year and is picking up speed with new people and equipment. He has thirty-five employees—both at Carolina and at other universities—and equipment for imaging cells not typically found in academic labs. Roth’s lab contracts with the National Institute of Mental Health, and much of the space is dedicated to screening compounds for other labs.

He says that the operation would not be possible without Jon Evans, Sandra Hufesein, and Estela Lopez, all of whom moved here from Case Western to continue their work. Lopez updates machine software, maintains databases, and makes sure the humans and machines are in sync. Evans coordinates compound screening, and Hufesein is in charge of cell culture.

These resources are anything but robotic; man and machine work together in harmony as Roth walks through the lab. “Basically, you have to have a dedicated staff of highly trained receptor-binding technologists. Right, Stan?” Roth says loudly as he motions to the research technicians, who nod in agreement. Stan is one of five people who run the receptor binding assays. The assay begins when technicians drop chemical compounds into plates filled with human cells that express the receptor of choice. The techs then load the plates into fridge-like machines that can screen a hundred thousand drugs a day, and then the machines track the affinity of each drug for its receptor. The assay is an old technique, but Roth’s lab does it on a massive scale. The lab has available more than two hundred different human receptors, which makes up about 50 percent of the whole set of receptors in the human genome. The receptors used in the lab are targets for over half of prescribed medications. One day, Roth says, he hopes to screen all receptors—the whole “receptorome,” he calls it.

Now the real work on Salvinorin A has started. Using genetically engineered mice, Roth says they hope to identify the neurons that Salvinorin A targets. This is important, Roth says, “because it will give us some notion of how Salvinorin A alters human perception and reality.” Through biochemical studies, his team plans to identify the molecular pathways that help “encode” reality. Working with Salvinorin A-like molecules, they hope to evaluate potential uses as therapies for drug addiction, depression, chronic pain, and other conditions.