Magic mint for mania

William Calezon's group purifies salvinorin A from bags of dried Salvia divinorum bought off the Internet.

For Karen Schrock, it started with a big hit off a smoking pipe filled with Salvia divinorum and a crash to the kitchen floor. From there she was off to an alien world of silhouetted figures who lived by a complex social structure. Any sense that there had ever been an Earth, a hallucinogenic drug, or a Karen Schrock disappeared. "I had no memory that this was not the real world, no sense that I was on a trip," recalls Schrock, now 26 and a science magazine editor. The September 2006 experience for her was intensely spiritual and profound. "I remember feeling at the time it was a life-changing experience because I had never had a drug trip before."

While Salvia might have flown Schrock to an alternate reality, scientists say the active ingredient, salvinorin A, holds promise for guiding drug discovery for mood disorders. Salvia's use originated with Mexican shamans who sought it out for spiritual journeys, but in recent years American youth have been buying the relative of the mint off the Internet and several states have passed legislation to control or ban its distribution.

In William Carlezon's laboratory at McLean Hospital in Belmont, Mass., half a dozen rats inside a stack of small white boxes are undergoing experiments. In the dark chambers, the rats are presented with a flash of light. If the animal pokes its nose through the appropriate hole, a sugar pellet pops out of a chute at the other end of the cage. Usually, rats readily perform the task to get their reward.

Rats that have been given salvinorin A, however, act as if they don't care. "Trials will go by without them responding," says Carlezon, who has done experiments to show that the rats haven't lost their appetites or ability to perform the task. He hypothesizes that they've lost their motivation, and the sugar pellets are no longer worth the work to get them. "The food is less rewarding to them," Carlezon says.

The effect is likely due to salvinorin A sending the animals into a short-term depressed-like state. Salvinorin A binds to Κ-opioid receptors in the brain, which are known to be involved in mood states. Carlezon has shown that activating these receptors can induce a depressed-like state in animals, and blocking the receptors acts like an antidepressant (W.A. Carlezon Jr. et al., J Pharmacol Exp Ther, 316:440-7, 2006). The idea, says McLean Hospital's Bruce Cohen, is that if people who are manic are at the opposite end of the mood spectrum from people with depression, pushing them closer to depression with salvinorin A might deliver them to a healthy medium.

That's the theory, but in practice, there are serious limitations. For one, k agonists act rapidly. For Schrock, the effect was so fast, she doesn't remember falling down after she inhaled Salvia. And though she felt like she existed in another world for an eternity, her trip lasted only five minutes. For people who have a mood disorder, Cohen says "it's entirely possible if you get something that acts rapidly on mood, it might drive people beyond their set point." As a result, "we're not convinced this will directly lead to therapeutic agents," Cohen says, "but rather to what regulates mood [so that we can] design better therapeutics."

Salvinorin A is also extraordinarily potent, says Bryan Roth, a pharmacology professor at the University of North Carolina and director of the National Institute of Mental Health's psychoactive drug-screening program. "It's the most potent naturally-occurring hallucinogen," Roth says. Inducing hallucinations in people who are manic, he notes, "would not be a good outcome."

Still, Roth says that if the hallucinogenic properties of salvinorin A can be dissociated from the benefits of the compound, it would be worth pursuing as a treatment for mood disorders, though he says he does not recommend people try it recreationally. Researchers have proposed other applications for salvinorin A, such as a pain reliever or a treatment for addiction.

The drug might also highlight neural substrates of consciousness, Roth says, and "could give us a window into what parts of the brain are active when we're perceiving reality." Or, perhaps, unreality.