Women’s Menstrual Cycle Holds Clue to Cocaine Response

Estrogen-like Compounds could Play Role in Treatment

April 23, 2001 -- Belmont, MA --  Women appear to be shielded from cocaine's brain-altering effects during the first half of their menstrual cycle when estrogen levels are high, according to a new report by McLean Hospital researchers. The findings suggest that an estrogen-like compound may be enlisted in a novel therapy to help cocaine-addicted people kick their habit—a notoriously difficult challenge for millions of Americans.

Marc Kaufman, PhD, and his colleagues delivered a dose of cocaine intravenously to 13 healthy women at two points in their menstrual cycle—in the middle of the estrogen-rich follicular phase and in the middle of the later luteal phase. Both estrogen and progesterone are high during this latter phase.

Using magnetic resonance imaging, the researchers measured blood flow to the women's brains. Blood flow was normal during the follicular phase but dropped off by 10 percent during the luteal phase. The findings appear in the May 1 Biological Psychiatry (DOI).

"Only during their luteal phase did women experience a significant degree of vasoconstriction from cocaine," said Kaufman, assistant professor of psychiatry at McLean and lead author of the study.

Though estrogen is produced during a woman's luteal phase, its protective effects appear to be mitigated by the progesterone that is also produced.

Yet even during the luteal phase, estrogen may bestow a benefit. In a previous study, the researchers found that cocaine produced a 20 percent reduction in blood flow in men, compared with the 10 percent drop that luteal phase women displayed. "If we had studied more people this might have turned out to be a significant difference," he said.

Although the researchers did not look for actual brain damage in these studies, chronic cocaine users are known to have higher rates of stroke and silent ischemic attacks than non-abusers. In addition, cocaine's squeezing off of the blood supply has been shown to produce subtler kinds of damage, such as changes in electrical activity. "Most of the brain damage that is associated with cocaine is extremely subtle--you don’t find it unless you’re really out hunting for it," says Kaufman.

He believes that by preventing such damage, estrogen could provide a much-needed adjunct to existing drug-rehabilitation therapies, many of which are plagued by high drop-out rates. "Most treatment is designed to get people to stop using drugs," Kaufman says. While engaged in such programs, people often continue to use cocaine, which leads to more brain dysfunction and, in turn, to cognitive and emotional deficits that can impair a person's ability to maintain jobs and relationships—and ultimately their therapy program.

"One thing we are learning is that relationships, jobs, and environmental factors are critically important in influencing the outcome of drug treatment," Kaufman said. "So if we can give something that helps people work better in their environment by protecting their brains and their ability to think, behave, and hold a job, that should improve outcomes as opposed to what we’re seeing now."

The prospect that estrogen—long known for its role in female sexual development—might be enlisted in the war on drugs is not a complete surprise. Researchers have known for some time that chronic cocaine abusing women generally experience fewer disruptions in cerebral blood flow and less neuronal loss in the frontal areas of their brains than men with comparable cocaine use histories. But what gave women the advantage was unclear.

Knowing that estrogen relaxes blood vessels, and therefore could counteract cocaine's constricting grip, Kaufman and his colleagues decided to compare cocaine's effect on the 13 women—who were in their 20s and 30s and were occasional cocaine users—at the two phases of their menstrual cycle.

They plan to test estrogen in men to see if it can modify the effects of cocaine and increase cerebral blood flow. He believes that the results of their experiments could apply to drugs other than cocaine.

"There are other drugs that people are using like methamphetamines and other stimulants," he said. "We don’t really know what those drugs do to the brain but some of them are vasoconstrictive like cocaine. Stimulants in general have the potential for altering blood flow in the brain."

In fact, the findings could have much wider application, possibly to a condition that sooner or later affects all people—aging. Blood flow is often impaired during the normal aging process.

"What we learn in this line of research may be applicable to improving cognitive function, reducing strokes, and reducing the asymptomatic forms of brain dysfunction that we see in cocaine abusers but that also occur in the elderly," said Kaufman.