March 12, 1998
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Researchers See How Cocaine Affects The Brain

By William J. Cromie

Gazette Staff

It's eerie to look inside the brain of a heavy cocaine user. Blood flow is sluggish and abnormal compared to the brain of a non-user. Such an abnormality may underlie memory loss, learning problems, attention deficits, and even strokes.

With the aid of advanced types of imaging equipment, Harvard University researchers have become the first to actually see why the flow is slow. In experiments carried out at McLean Hospital in Belmont, they watched blood vessels narrow as volunteers took different amounts of the drug.

"It only takes a small amount of cocaine to constrict blood vessels in the brains of young, healthy men who are occasional users of the drug," says Marc Kaufman, assistant professor of psychiatry at the Medical School. "That has never been shown before, and we think that many episodes of such narrowing can lead to brain dysfunction or damage. "

Other experiments reveal that even thinking about cocaine can change cerebral blood flow. The brains of regular users appear noticeably different when they watch butterflies fluttering in fields and when they see others snorting the drug.

It's All in Their Heads

Kaufman and his colleagues recruited 24 men whose mean age was 29 years, and gave them injections of pure cocaine or a placebo. At a dose considered low by street standards (0.2 milligram per kilogram of body weight), three out of nine of the men showed constriction of blood vessels in their brains.

When the dose was doubled to the equivalent of snorting two lines of cocaine (0.4 mg/kg), 5 out of 8 men showed blood-flow abnormalities. Doubling the dose almost doubled the percentage of those in whom the vessel narrowing could be seen, despite the fact that the dose is still considered small by street or suburban standards.

Kaufman points out that people often take impure cocaine, or use it with other drugs such as alcohol, tobacco, or heroin. Some of them may also have abnormal arteries and veins. These are all conditions that could make the narrowing more dangerous.

One of the seven men who got a placebo instead of cocaine also showed brain-vessel constrictions. That circumstance tied in nicely with experiments done by another team at McLean Hospital's Brain Imaging Center. These experiments clearly demonstrated that expecting, or even thinking about taking cocaine affects blood flow in the brain.

In the latter experiments, six regular cocaine users were paired with six men who never used the drug. The volunteers ranged from 32 to 37 years old. With their heads in a scanner, they were entertained with soft music and videos of butterflies, or with people snorting cocaine and praising the resulting high. In the latter case, two brain areas associated with craving and cocaine use lit up on the scans of heavy users. Butterflies failed to elicit the same response.

"Knowing such details about how the brain responds will help us develop new ways to treat drug addiction," says Kaufman. "For example, we might be able to find, or design drugs to reduce vascular [blood vessel] reactivity. That might help to protect those trying to quit using cocaine. And scanning the brain for signs of craving holds promise as a tool to determine if treatments to eliminate addiction are working."

A Silent Disease

Although cocaine use has been declining for 10 years, the Substance Abuse and Mental Health Administration reports that 600,000 people in the U.S. admitted to frequent use of the drug in 1995. Nearly 2.5 million confess to occasional use, and 22 million people, age 12 and older, say they have tried cocaine at least once.

Several studies have tied heavy use of the drug to stroke and to memory and learning problems. Brain scans of such users reveal a dramatic decrease in blood flow.

Kaufman and his colleagues wanted to answer two questions: What underlies the slowed flow and how much cocaine does it take for the effect to be seen?

Their discovery that low levels of the drug cause a high incidence of vessel narrowing in healthy, occasional users was a surprise.

"These changes are silent," says Kaufman. "People don't realize they have a disease that may progress with repeated use of cocaine and may change their behavior. Those trying to quit may be less able to adhere to the requirements of treatment programs. They may also have difficulty getting through job interviews, and participating in complex social situations."

Even the brains of autopsied addicts who don't die of stroke show little physical evidence of damage. Atherosclerosis, or the blocking of vessels by accumulations of plaque, can easily be seen, but constriction due to cocaine leaves no clear traces even though it can reduce blood flow in a similar way.

"We believe transient but repeated narrowing in occasional users is one mechanism that leads to the persistent decrease in blood flow seen in heavy users of cocaine," Kaufman notes.

The body rapidly breaks down cocaine, but these breakdown products can prolong constriction. Other brain imaging studies have shown that changes can be seen up to 48 hours after the drug has been taken.

On and Off Cravings

The butterfly experiments demonstrated, to everyone's astonishment, how quickly craving for cocaine can be turned on and off. This research was led by Luis Maas, a doctoral student at the Harvard-M.I.T. Division of Health Sciences and Technology.

Maas and his colleagues advertised in local newspapers for crack cocaine users. They paired six users who answered the ads with six non-users.

The subjects, all young men in their 30s, were paid about $200 to view a 10-minute videotape with their heads in a brain-scanning machine. The video showed alternating 2.5-minute segments of flying butterflies and cocaine smoking.

The crack sequences caused increased activity in two regions of the brains of users, but not in non-users. Both regions, in the front of the brain, are known to be involved in emotional responses, including craving.

It took less than 2.5 minutes for the crack smokers' brains to respond to video cues. Then, without significant overlap, indications of craving turned off in the 2.5-minute butterfly interval.

Perry Renshaw, director of the Brain Imaging Center at McLean Hospital, noted that the findings were surprising because it was thought that craving requires much longer periods to turn on and off.

Before and after the scanning, drug users filled out questionnaires about the intensity and frequency of their desire for cocaine. Craving levels increased after seeing the tape. Brain activity during the scanning also reached higher levels in those who said they had used cocaine longer.

"Just thinking about the drug causes changes in the brain, which appear to be greater with a history of use," Kaufman notes.

"If we can identify and decrease the mechanism for craving then we can begin to think about developing new ways to treat drug addiction," Maas comments.


Copyright 1998 President and Fellows of Harvard College