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News Volume 13, Number 3 (July, 1998)

By Steven Stocker, NIDA NOTES Contributing Writer

In 1977, a 43-year-old man came to an emergency room in New York City after having injected cocaine into a muscle in his left arm. Between 1 and 2 hours after the injection, he had begun having trouble speaking and was weak in his right arm and leg. After performing a brain scan, doctors at the hospital determined that the man had had a stroke on the left side of the brain. Although the man also abused other drugs, the fact that the stroke had occurred shortly after he had injected cocaine suggested that cocaine had contributed to the stroke. This case was one of the earliest verified reports of a stroke associated with cocaine use. In their report, the doctors concluded, "If, in fact, cocaine played a causal role [in the stroke], we anticipate that more strokes will be seen among the many abusers of this agent in American cities."

Their prediction turned out to be correct. In subsequent years, cocaine-related strokes became more frequent, particularly in the mid-1980s after the advent of crack cocaine. These strokes involved sudden dramatic reductions in blood flow to areas of the brain, resulting in neurological symptoms, such as paralysis, loss of speech, and dementia.

In the late 1980s, researchers began noticing another type of blood flow disturbance associated with cocaine use. This second type involved less dramatic but more persistent reductions in cerebral blood flow that could lead to difficulties concentrating, slowed thought processes, and memory deficits.

Until recently, scientists could only theorize about how cocaine was causing these cerebral blood flow disturbances. Now NIDA-supported scientists have learned more about how cocaine causes strokes and produces the persistent blood flow deficits. Other NIDA-funded researchers have observed that the brain damage caused by these deficits interferes with drug treatment, and they are studying how to modify treatment to accommodate patients with this type of brain damage.

Short-term Reductions in Blood Flow

Using magnetic resonance angiography (MRA), an imaging technique that shows blood flow in large- and medium-sized arteries in the brain, NIDA-funded researchers Dr. Marc Kaufman and Dr. Jonathan Levin and their colleagues at McLean Hospital in Belmont, Massachusetts, have demonstrated that cocaine use temporarily narrows arteries in the brain, thereby reducing the blood supply to various brain regions. Researchers had suspected this for many years because they knew that cocaine could cause vasoconstriction, or narrowing of blood vessels, in the heart and other regions of the body. This study conclusively demonstrated this effect in the human brain.

The researchers administered either cocaine or a placebo solution to 24 men, ages 24 to 34. The volunteers had used cocaine occasionally but were not dependent on the drug. The cocaine doses administered were relatively low, resulting in cocaine blood levels that were at the low end of the range typically experienced during cocaine abuse.

Images of the brain were obtained before and 20 minutes after the cocaine was administered. By comparing before and after images, the researchers could see where blood vessels were narrowed. Among the 7 men who received the placebo, only 1 showed blood vessel narrowing, but among the 9 men who received the lowest dose of cocaine, 3 had vasoconstriction in several brain arteries. Among the 8 men who received a higher dose, 5 showed this effect. The vasoconstrictions ranged from small reductions in blood vessel diameter to more significant obstructions of blood flow.

The more often the men had used cocaine in the past, the more likely the drug was to narrow blood vessels, which suggests that cocaine has a cumulative effect on brain arteries. "This cumulative effect may start with as few as 5 to 10 exposures to cocaine," says Dr. Kaufman. "As a result, people who use cocaine many times probably have a high incidence of vasoconstriction in their brains."

One possible outcome of cocaine's cumulative effect may be a stroke. As a result of many cocaine exposures, brain arteries may be more reactive to the chemical stimuli that normally cause them to constrict, Dr. Kaufman says. This constriction could substantially reduce the blood supply to a region for several minutes, thereby damaging nerve cells and possibly causing stroke-like symptoms. A more likely outcome of the cumulative effect would be persistent blood flow reductions to large areas of the brain. These reductions are less substantial than those that occur in a stroke and may not kill nerve cells, but they could cause thinking and memory deficits, says Dr. Kaufman.

Long-term Reductions in Blood Flow

Scientists began to observe that cocaine could cause persistent blood flow deficits in the brain in the mid-1980s. NIDA-funded scientist Dr. Nora Volkow and her colleagues at the Brookhaven National Laboratory in Upton, New York, and at the University of Texas Health Science Center in Houston used another imaging technique called positron emission tomography (PET), which can show the flow of blood in the brain tissue rather than in the brain arteries, as MRA does. When the researchers compared PET scans of young adult cocaine-abusing men with scans of normal volunteers, they found that most of the abusers had less blood flow in some areas of the brain. When the researchers performed PET scans again 10 days later, the blood flow deficits were still there, even though the abusers had stopped using cocaine. Many of the volunteers had difficulties concentrating and performing simple calculations, which the researchers concluded were associated with the blood flow deficits.

Subsequently, other scientists verified that cocaine abusers had blood flow deficits in the brain and that these deficits persisted long after the individuals stopped abusing cocaine. Using a technique similar to PET called single photon emission computed tomography (SPECT), Dr. Tony Strickland of Charles R. Drew University of Medicine and Science in Los Angeles and the University of California, Los Angeles, School of Medicine and his colleagues took brain images of cocaine abusers who had abstained from cocaine for at least 6 months before evaluation. Even after this long period of abstinence, the images showed that the abusers still had blood flow deficits compared to control subjects, suggesting that the deficits may be long-term or perhaps even permanent.

In addition to taking brain images with SPECT, Dr. Strickland's group also administered neuropsychological tests to the cocaine abusers. These tests detected many abnormalities that seemed to be associated with reduced activity in the parts of the brain affected by the reduced blood flow. These abnormalities included deficits in attention, memory, concept formation, and mental flexibility. The tests also showed that long-term cocaine abusers had trouble inhibiting inappropriate behaviors, a condition psychologists call disinhibition.

Dr. Levin, who worked on the MRA study with Dr. Kaufman, thinks that chronic cocaine abuse may lead to strokes and long-term blood flow deficits by accelerating atherosclerosis in brain arteries. Atherosclerosis is a thickening on the inside of blood vessels that some researchers believe makes the vessels more likely to go into vasospasm, which is a vasoconstriction that lasts for minutes rather than seconds. "Let's say a blood vessel in a person's brain has atherosclerosis as a result of some injury to the blood vessel. If the person takes a compound such as cocaine that causes vasoconstriction, the part of the blood vessel that is likely to go into spasm is the part with the atherosclerosis," explains Dr. Levin. This vasospasm may then damage the inner lining of the blood vessel, which would further promote the development of atherosclerosis. If the person continues to take cocaine, more vasospasms would occur and hence more atherosclerosis. "It becomes a vicious cycle," he says.

This would explain how cocaine could cause strokes. Eventually, the vasospasms induced by cocaine last so long that nerve cells die from a lack of blood. The explanation for the persistent blood flow deficits might be that the atherosclerosis is slowly clogging the inside of the blood vessels, thereby reducing blood flow. One piece of evidence in favor of this theory is that aspirin has been shown to reverse temporarily the cerebral blood flow deficits caused by cocaine. Aspirin inhibits the formation of blood clots that are part of the atherosclerotic process.

Using a technology called transcranial Doppler sonography (TCD), Dr. Ronald Herning, Dr. Jean Lud Cadet, and colleagues in NIDA's Division of Intramural Research in Baltimore have found evidence that cocaine abusers do indeed have significant atherosclerosis in their brain arteries. In TCD, very high frequency sound waves are bounced off the blood flowing in large arteries in the brain, and the characteristics of the reflected sound waves can be used to estimate the constriction of the arteries. "Our data suggest that cocaine abusers in their thirties have arteries that are as constricted as those of normal subjects in their sixties," says Dr. Herning.

Mental Deficits

Drug treatment providers should be aware that mental deficits that develop in cocaine abusers as a result of reduced blood flow may hamper the ability of these patients to benefit from treatment, says Dr. Strickland. Some patients have trouble paying attention or remembering conversations; others disrupt the therapy by being disinhibited. They constantly interrupt the therapist, they begin tasks without waiting for all the instructions, and they may become aggressive.

Dr. Strickland recommends giving new drug abuse patients neuropsychological screening tests to identify their deficits. Once these deficits are identified, the therapist can modify the drug treatment to accommodate the deficits, he suggests. For example, if the patient has trouble paying attention and remembering, the therapist could present information in small segments and repeat each segment until the patient learns it.

A major component of therapy is simply informing these patients that their long-term drug abuse has changed the way their brains function, Dr. Strickland says. "Some of these patients know that something is wrong but don't know what it is," he says. "They are relieved to learn that they're not Ôcrazy' and that the source of their problems is that drugs have altered the way their brains process information. They also are relieved to learn that they can take steps to enhance their performance."

"Compared to patients who have brain injury from motorcycle accidents, gunshot wounds, or other causes, drug abuse patients have considerably less impairment," notes Dr. Strickland. "We're successful in helping traumatic brain injury patients, and so the chances of helping patients with drug-induced brain injury are comparatively good."

In addition to modifying drug abuse treatment to accommodate the mental deficits of cocaine abusers, NIDA scientists are also investigating the possibility of treating their blood flow and mental deficits with medications. TCD will be particularly useful for monitoring the blood flow effects of medications, says Dr. Herning. "TCD is a quick, easy, relatively inexpensive measure that can be used repeatedly, so you can give your subjects medications and monitor them weekly, which you cannot do with PET or SPECT."

Sources

Brust, J.C.M.; and Richter, R.W. Stroke associated with cocaine abuse? New York State Journal of Medicine 77:1473-1475, 1977.

Herning, R.I.; King, D.E.; Better, W.; and Cadet, J.L. Cocaine dependence: A clinical syndrome requiring neuroprotection. Annals of the New York Academy of Sciences 825:323-327, 1997.

Kaufman, M.J., et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. The Journal of the American Medical Association 279(5):376-380, 1998.

Kosten, T.R.; Malison, R.; and Wallace, E. Neuropsychological abnormalities in cocaine abusers: Possible correlates in SPECT neuroimaging. In: Majewska, M.D., ed. Neurotoxicity and Neuropathology Associated with Cocaine Abuse. NIDA Research Monograph Series, Number 163. NIH Publication No. 96-4019. Pittsburgh, PA: Supt. of Docs., U.S. Govt. Print. Off., 1996, pp. 175-192.

Strickland, T.L., et al. Cerebral perfusion and neuropsychological consequences of chronic cocaine use. Journal of Neuropsychiatry 5(4):419-427, 1993.

Strickland, T.L.; Stein, R.A.; Khalsa-Denison, M.E.; and Andre, K. Neuropsychological effects of chronic cocaine use following sustained abstinence. Archives of Clinical Neuropsychology 11(5):456-457, 1996.

Volkow, N.D.; Mullani, N.; Gould, K.L.; Adler, S.; and Krajewski, K. Cerebral blood flow in chronic cocaine users: A study with positron emission tomography. British Journal of Psychiatry 152:641-648, 1988.

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