Stanford University School of Medicine investigators have succeeded in distinguishing the molecular pathway responsible for an illicit drug’s abuse potential from the one behind its propensity to make people feel sociable.

The discovery, described in a study published Dec. 11 in Science Translational Medicine, could lead to novel treatments for psychiatric disorders marked by social awkwardness and withdrawal.

The findings were made in mouse experiments.

Methylenedioxy-methamphetamine — better known by its acronym, MDMA, or its street name, ecstasy — is a mind-altering drug used by 3 million Americans annually. MDMA is especially popular as a party drug because it gives people who take it a sense of well-being and makes them extremely sociable — even instilling feelings of unguarded empathy for strangers. That makes MDMA a natural fit for raves, dance parties featuring lots of densely packed, sweaty bodies and unfamiliar faces.

It may also may make MDMA a good medicine for psychiatry. It’s now in late-stage, multicenter clinical trials as an adjunct to psychotherapy for post-traumatic stress disorder. The goal is to harness MDMA’s prosocial effects to strengthen the bond between patient and therapist. Thus, people who have experienced trauma may be able to feel comfortable reliving it through guided therapy.

Some 25 million people in the United States who suffer from PTSD could benefit from a drug capable of establishing, with a single dose in a therapist’s office, a trust level that typically takes months or years to achieve, said Boris Heifets, MD, PhD, assistant professor of anesthesiology, perioperative and pain medicine, the study’s lead author.

But MDMA can be addictive. Taken in the wrong settings or in repeated or oversized doses, it can have life-threatening consequences.

“We’ve figured out how MDMA promotes social interaction and showed that’s distinct from how it generates abuse potential among its users,” said the study’s senior author, Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences.

Stimulation of reward circuitry

MDMA’s abuse potential stems from its capacity to stimulate the brain’s reward circuitry, Malenka said. “The brain’s reward circuitry tells us something is good for our survival and propagation. It evolved to tell us food is good when we’re hungry, water is good when we’re thirsty, and warmth is good when we’re cold. For most of us, hanging out with friends is fun, because over the course of our evolution it’s promoted our survival.”

A crucial connection in the reward circuitry is between nerve cells, or neurons, projecting from one midbrain structure, the ventral tegmental area, to another, the nucleus accumbens. When those neurons release a chemical called dopamine, the nucleus accumbens forwards signals throughout the brain that induce a sense of reward.

“Drugs of abuse trick our brains by causing an unnatural dopamine surge in the nucleus accumbens,” Malenka said. “This massive increase is much higher and more rapid than the one you get from eating ice cream or having sex.”

Like all addictive drugs, MDMA triggers dopamine release in the nucleus accumbens. That explains its abuse potential but leaves open the question of why the prosocial effect dwarfs that of most other abused drugs.