By David N. Leff

What cholesterol does to the heart — i.e., starve it of oxygen — cocaine seems to do to the brain.

Human volunteers who shot up high and low doses of pure cocaine in a double-blind, control-matched trial experienced transient narrowing of the cerebral arteries that nourish the brain.

The effect apparently wore off in minutes, but neuropharmacologist Marc Kaufman, who conducted the trial, pointed out, "It's not clear whether the drug, or one of its breakdown metabolites — some of which themselves can constrict blood vessels — is causing the effect.

"That's an important point," he added, "because cocaine is metabolized very quickly in the blood, but some of the metabolites can persist for long periods of time, and might prolong the incidence of this phenomenon."

Kaufman is a faculty member at Harvard Medical School, in Boston, and is a research pharmacologist in the brain imaging center of Harvard-affiliated McLean (Psychiatric) Hospital. He is first author of a paper in this week's Journal of the American Medical Association (JAMA), dated Feb. 4, 1998. Its title: "Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography."

Currently, neurologists visualize the brain's blood supply by means of cerebral angiography. This usually involves threading a slender catheter through a remote artery all the way up to the cranial blood vessels, and pumping in a contrast medium opaque to X-ray imaging.

"The wonderful thing about magnetic resonance angiography," Kaufman told BioWorld Today, "is that you can do repeated measurements on individuals over a period of time, because the MR machine doesn't use ionizing radiation, such as X-rays."

Researchers Recruited Cocaine Users For Study

For the trial reported in JAMA, McLean advertised in area newspapers for volunteers to take part in a brain-imaging study related to cocaine. They recruited 24 healthy men aged 24 to 34 who had used cocaine in the course of their lives. These two dozen subjects reported lifetime exposure to the drug on eight to more than 40 occasions.

Nine of the 24 received a low dose of cocaine, 0.2 milligrams per kilogram of body weight; eight others got twice as much. Seven controls received a placebo.

Each of the participants had his brain scanned by magnetic resonance imaging twice — just before being given their cocaine fix, and 20 minutes after.

Five of the eight high-dose recipients showed constricted blood vessels in their brains. Only three of the nine low-ball contingent experienced such changes, as did — curiously — one of the seven placebo controls.

A separate study, now in press, finds, Kaufman said, "that cocaine reduces the volume of blood in the brain, which we interpret as meaning that the pipes are smaller, the vessels are constricted. We weren't able to determine the degree of narrowing that the cocaine is inducing, but we are able to determine that the phenomenon occurs, and that is important in and of itself. "

He pointed out that "the reason MR cerebral angiography is so good at detecting this vessel constriction is that as vessels narrow, the blood flow through the opening is agitated, so you get turbulence. The blood is encoded in the scanner, and as it moves turbulently after each constriction, parts of the column of blood slow down. Thus, as it flows more slowly and becomes out of phase with the rest of the blood before the constrictions, the signal intensity goes down."

As for this phenomenon's effect on the drug user, Kaufman observed that "a very small proportion of people who take cocaine, and go to the hospital with a cocaine-related complication, report something related to either neurologic dysfunction or a stroke-like event. So if you are constricting a blood vessel at the same time that your blood pressure and heart rate go up, and you have a weakened artery, that may explain the increased incidence of stroke in such cocaine users."

But he went on "to stress that stroke and neurologic complications associated with acute cocaine — 24 to 48 hours after someone has taken a fix — is a very rare event; it occurs on the order of less than 3 percent of the time.

"In individuals with a history of long-term, heavy cocaine use," Kaufman continued, "another technology that images just the intensity of blood flow throughout all areas of brain tissue, without looking at the vessels, lets us see areas where blood flow is abnormally low. In a control subject, the image is usually coded in kind of a yellow-red scale, very nice intensity of color throughout the brain's cortex. But in a heavy-duty user, you have areas where it looks as if there are holes. They probably aren't complete blockages or reductions in blood flow, which would be characteristic of a stroke.

"The important thing about those effects," Kaufman pointed out, "is that the people who have them really won't know it; won't feel impaired; won't feel like they're having a stroke." And he went on, "There's a very high association of cognitive abnormalities — such as loss of memory, learning, attention — with those blood-flow abnormalities.

"The question that we wanted to address in our initial study is: What amount of cocaine could cause vessel narrowing, which repeated many times in the course of chronic cocaine use could induce such a double phenomenon: abnormal blood flow and cognitive defects? So we're trying to look at the beginning of the process, what we consider a continuous or cumulative disease course with increased, prolonged cocaine use."

A Milligram Of Prevention . . .

Alan Leshner, director of the National Institute On Drug Abuse, which funded the McLean project, commented: "This study suggests the mechanism by which cocaine has some of its most devastating effects. It also suggests a target for developing better treatments to protect against or reverse some of cocaine's actions."

Anent this therapeutic potential, Kaufman envisions "having people focus on trying to prevent the vessel narrowing. Anything that can reduce or modify vessel constriction would be something we'd be interested in looking at.

"And at the same time that we're trying to get cocaine users to reduce their drug consumption, or stop altogether, it would be very useful to try and protect them until they do.

"The obvious reason," he concluded, "is that if these users are compromised in their cognitive function, they may be far less able to adhere to treatment programs designed to reduce or stop their drugs." *