Sober N Clean

Using positron emission tomography (PET) to track tracer doses of methamphetamine in humans' brains, scientists at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory find that the addictive and long-lasting effects of this increasingly prevalent drug can be explained in part by its pharmacokinetics - the rate at which it enters and clears the brain, and its distribution.

This study in 19 healthy, non-drug-abusing volunteers includes a comparison with cocaine and also looked for differences by race. It will appear in the November 1, 2008, issue of Neuroimage.

"Methamphetamine is one of the most addictive and neurotoxic drugs of abuse," said Brookhaven chemist Joanna Fowler, lead author on the study. "It produces large increases in dopamine, a brain chemical associated with feelings of pleasure and reward - both by increasing dopamine's release from nerve cells and by blocking its reuptake."

Studies by Fowler and others have shown that drugs that produce greater elevations in brain dopamine tend to be more addictive. But other factors, including the speed with which a drug enters and clears the brain and its distribution within the brain, can also be important in determining its addictive and toxic potential.

In undertaking this first study of methamphetamine pharmacokinetics, the researchers also wanted to know if there were differences between Caucasians and African Americans. "Reports that the rate of methamphetamine abuse among African Americans is lower than for Caucasians led us to question whether biological or pharmacokinetic differences might explain this difference," Fowler said.

The scientists measured brain uptake, distribution, and clearance of methamphetamine by injecting 19 normal healthy men (9 Caucasian, 10 African American) with a radioactively tagged form of the drug in "trace" doses too small to have any psychoactive effects. They used PET scanning cameras to monitor the concentration and distribution of the tagged methamphetamine in the subjects' brains. On the same day, the same subjects were injected with trace doses of cocaine and scanned for comparison. The scientists also used PET to measure the number of dopamine reuptake proteins, known as dopamine transporters, available in each research subject's brain.

Like cocaine, methamphetamine entered the brain quickly, a finding consistent with both drugs' highly reinforcing effects. Methamphetamine, however, lingered in the brain significantly longer than cocaine, which cleared quickly. In fact, some brain regions, particularly white matter, still showed signs of tracer methamphetamine at the end of the 90-minute scanning session, by which time all cocaine had been cleared. The distribution of methamphetamine in the brain was remarkably different from that of cocaine. Whereas cocaine was concentrated only in the 'reward' center and cleared rapidly, methamphetamine was concentrated all over the brain, where it remained throughout the study.

"This slow clearance of methamphetamine from such widespread brain regions may help explain why the drug has such long-lasting behavioral and neurotoxic effects," Fowler said. Methamphetamine is known to produce lasting damage not only to dopamine cells but also to other brain regions, including white matter, that are not part of the dopamine network.

Surprisingly, the researchers found significant differences in cocaine pharmacokinetics between African Americans and Caucasians, with the African Americans exhibiting higher uptake of cocaine, a later rise to peak levels, and slower clearance. In contrast, the scientists found no differences in methamphetamine pharmacokinetics between these groups.

"This suggests that variables other than pharmacokinetics and bioavailability account for the lower prevalence of methamphetamine abuse in African Americans," Fowler said. "The differences observed for cocaine pharmacokinetics are surprising considering there are no differences in cocaine abuse prevalence between these two ethnic groups." These differences may merit further study, and also suggest the need to match subjects by ethnic group in future studies to avoid interference from this potentially confounding variable.

Another interesting finding was that across all research subjects, the level of dopamine transporters was directly related to the level of methamphetamine taken up by the brain. This finding suggests that transporter proteins somehow play a role in regulating the brain's uptake of this drug.

This research was funded by the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism Intramural Program, and by the Office of Biological and Environmental Research within DOE's Office of Science. Brain-imaging studies such as PET are a direct outgrowth of DOE's long-standing investment in basic research in chemistry, physics, and nuclear medicine. The ongoing neuroimaging research at Brookhaven is a prime example of how DOE's national laboratories bring together the expertise of chemists, physicists, and medical scientists to address questions of profound significance for society.
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ScienceDaily (Nov. 30, 2007) — What do suffering a traumatic brain injury and using club drugs have in common? University of Florida researchers say both may trigger a similar chemical chain reaction in the brain, leading to cell death, memory loss and potentially irreversible brain damage.

A series of studies at UF over the past five years has shown using the popular club drug Ecstasy, also called MDMA, and other forms of methamphetamine lead to the same type of brain changes, cell loss and protein fluctuations in the brain that occur after a person endures a sharp blow to the head, according to recentl findings.

"Using methamphetamine is like inflicting a traumatic brain injury on yourself," said Firas Kobeissy, a postdoctoral associate in the College of Medicine department of psychiatry. "We found that a lot of brain cells are being injured by these drugs. That's alarming to society now. People don't seem to take club drugs as seriously as drugs such as heroin or cocaine."

Working with UF researchers Dr. Mark Gold, chief of the division of addiction medicine at UF's McKnight Brain Institute and one of the country's leading experts on addiction medicine, and Kevin Wang, director of the UF Center for Neuroproteomics and Biomarkers Research, Kobeissy compared what happened in the brains of rats given large doses of methamphetamine with what happened to those that had suffered a traumatic brain injury.

The group's research has already shown how traumatic brain injury affects brain cells in rats. They found similar damage in the rats exposed to methamphetamine. In the brain, club drugs set off a chain of events that injures brain cells. The drugs seem to damage certain proteins in the brain, which causes protein levels to fluctuate. When proteins are damaged, brain cells could die. In addition, as some proteins change under the influence of methamphetamine, they also begin to cause inflammation in the brain, which can be deadly, Kobeissy said.

Kobeissy and other researchers in Gold's lab are using novel protein analysis methods to understand how drug abuse alters the brain. Looking specifically at proteins in the rat cortex, UF researchers discovered that about 12 percent of the proteins in this region of the brain showed the same kinds of changes after either methamphetamine use or traumatic brain injury. There are about 30,000 proteins in the brain so such a significant parallel indicates that a similar mechanism is at work after both traumatic brain injury and methamphetamine abuse, Kobeissy said.

"Sometimes people go to the clubs and take three tablets of Ecstasy or speed," Kobeissy said. "That may be a toxic dose for them. Toxic effects can be seen for methamphetamine, Ecstasy and traumatic injury in different areas of the brain."

About 1.3 million people over the age of 12 reported using methamphetamine in the previous month, according to the 2006 National Survey on Drug Use and Health. In 2004, more than 12 million Americans reported having tried the drug, the survey's findings show.

People often think the effects of drugs of abuse wear off in the body the same way common medications do, but that may not be the case, Gold said.

"These data and the previous four years of data suggest some drugs, especially methamphetamine, cause changes that are not readily reversible," Gold said. "Future research is necessary for us to determine when or if methamphetamine-related brain changes reverse themselves."

Gold and Dennis Steindler, director of UF's McKnight Brain Institute and an expert on stem cells, are planning studies to find out if stem cells can be applied to repair drug-related brain damage.

UF researchers are also trying to uncover all the various ways drugs damage and kill brain cells. During their protein analysis, researchers discovered that oxidation was damaging some proteins, throwing the molecules chemically off balance.

"When proteins are oxidized they are not functional," Kobeissy said. "When proteins are not working, the cell cannot function."

Neurologist Dr. Jean Lud Cadet, chief of the molecular neuropsychiatry branch of the National Institute on Drug Abuse, said analyzing proteins is important to understanding how drugs such as methamphetamine affect the brain.

"I think saying the results of methamphetamine abuse are comparable to the results of a traumatic brain injury is a new idea," Cadet said. "I agree with (the findings). Our own work shows that methamphetamine is pretty toxic to the brains of animals. In humans, imaging studies of patients who use methamphetamine chronically show abnormalities in the brain.

"Abuse of methamphetamine is very dangerous."

This research was presented at a Society for Neuroscience conference held recently in San Diego.

Adapted from materials provided by University of Florida.