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Chemists identify immune system mechanism for methamphetamine binges

Chemists at The Scripps Research Institute have found evidence in laboratory studies that the immune system may be able to recognize methamphetamine and boost tolerance to the drug through an unusual vaccine-like mechanism. Their finding, if confirmed in human studies, could help explain why chronic users go on long binges with the illicit drug, also known as speed. The study could lead to new treatments for the drug's addiction, they say.

Recent studies by others have documented the drug's apparent ability to suppress the immune system, making abusers more vulnerable to diseases such as HIV. The new study is the first to suggest that the drug can engage the body's defense system to attack methamphetamine in such a way that makes users inclined to use more of the drug, the researchers say. Their study, which paints a clearer picture of the drug's effect on the immune system and its potential for abuse, was described today at the 229th national meeting of the American Chemical Society, the world's largest scientific society.

"Test animals injected with methamphetamine actually developed antibodies to the drug, which is highly unique for a molecule of its relatively small size," says study co-leader Kim Janda, Ph.D., a chemist at Scripps in La Jolla, Calif. Developing antibodies to the body's invaders, such as viruses and bacteria, is normally a good thing and forms the basis of modern vaccines, he explains. But ironically, people who abuse methamphetamine may build up antibodies to the drug itself, so they require increasing amounts to get high, resulting in binging behavior, he says.

"Without knowing it, they're essentially vaccinating themselves against the drug, and that's not a good thing as it requires more of the drug to get high," says Janda. His findings were first reported in a recent issue of the Journal of the American Chemical Society, the Society's peer-reviewed journal.

In a test tube study designed to simulate the chemica l reactions that occur with the drug when it enters the bloodstream, the researchers showed that methamphetamine reacts with glucose and proteins to form a larger-size "glycated" product. This product is then recognized by immune system components, stimulating the production of antibodies to the drug. In follow-up studies using mice, those injected with the drug developed antibodies to it.

"Antibodies are usually produced only in response to large molecule invaders such as proteins, not to small drug molecules," Janda says. "Glycation acts like a linker that allows [the methamphetamine] to be displayed to the immune system, triggering a vaccine-like reaction."

Just as a vaccine is able to remove invading pathogens by using antibodies to the pathogen, antibodies to methamphetamine attack and begin to clear the drug, Janda says. If the antibodies prevent some of the drug from reaching its place of action in the brain's pleasure center, users might require more of the drug because some of it is bound up by antibodies and "soaked up like a sponge," according to the researcher.

"If the mechanism we proposed proves true in humans, then it will help explain why addicts go on prolonged binges, requiring more frequent intake and ever-increasing amounts of the drug in order to achieve a high," says Janda, who led the study with his former student, Tobin Dickerson, Ph.D., also a chemist at Scripps.

Other drugs of abuse, including nicotine and ecstasy (which is structurally similar to methamphetamine), might share a similar mechanism of action involving immune system recognition and a consequent rise in tolerance to the drug, Janda and his associates theorize. Tolerance refers to the capacity to have a decreased response to a drug after prolonged use. Increased drug tolerance raises the likelihood that a person will become addicted.

"Right now, there's nothing really effective in getting people off methamphetamine," says Janda, who believ es that highly specific methamphetamine antibodies can be made in a laboratory and then used as a clinical treatment for addiction. In theory, antibodies to the drug could be mass produced and administered at therapeutic levels that are high enough to clear the drug from the body, he says.

"Methamphetamine has become the ‘crack' of the 21st century," Janda says. "We're just starting to unravel its mechanism of addiction." Further studies of the drug are planned, he adds.

Methamphetamine is a powerful psychostimulant that goes by a number of common names, including "speed," "ice" and "crank." It is often made in make-shift laboratories using over-the-counter drug ingredients, particularly cold and allergy medicines. Available as a powder or crystal, the drug can be injected, snorted, swallowed and smoked to provide users with a sense of euphoria. Drug effects can last for up to 12 hours. Frequent use is associated with serious health problems, including memory loss, aggression, psychotic behavior, and potential heart and brain damage.

The Skaggs Institute for Chemical Biology (at Scripps) and the National Institute on Drug Abuse provided funding for this study. In addition to Janda and Dickerson, other study co-authors include Noboru Yamamoto and Diana Ruiz, also of Scripps.

The American Chemical Society is a nonprofit organization, chartered by the U.S. Congress, with a multidisciplinary membership of more than 159,000 chemists and chemical engineers. It publishes numerous scientific journals and databases, convenes major research conferences and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.


Source:American Chemical Society

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