Newswise — 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 chemical 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 believes 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.

The paper on this research, ORGN 432, will be presented at 3:20 p.m., Tuesday, March 15, at the Convention Center, Room 25A, during the symposium, "Proteins, Peptides, Amino Acids, and Enzymes."

Kim D. Janda, Ph.D., and Tobin J. Dickerson, Ph.D., are chemists with The Skaggs Institute for Chemical Biology at The Scripps Research Institute in La Jolla, Calif.

ORGN 432Immunological consequences of methamphetamine-based protein glycation

Methamphetamine is a potent psychostimulant that has recently seen extensive growth in its use and production in clandestine laboratories. Although numerous detrimental consequences of methamphetamine use are documented, the molecular mechanisms underlying these physiological effects remain unknown. We have discovered that methamphetamine can participate in the aberrant glycation of proteins and is detectable by various biochemical analyses. Mouse albumin can be readily modified, and injection of this protein into mice yields a significant immune response, even in the absence of adjuvants. This lecture will summarize our findings in this area, including the potential implication of this phenomenon in the context of drug addiction. Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public)

The crux of our finding is that methamphetamine can react with glucose and proteins to form what are called a "glycated" product. Additionaly, we showed that the presence of these methamphetamine-glycated proteins in the bloodstream can lead to a response from the immune system, stimulating the production of antibodies that recognize the glycated form of methamphetamine. This immune response might be one way that the body acquires resistance and may have implications for why methamphetamine addicts go on long binges. If the antibodies prevent some of the drug from reaching its place of action in the brain, addicts might require more of the drug because some of it is bound up by antibodies. What this suggests is that since methamphetamine may react with proteins and induce an immune response; perhaps the body naturally has the ability to generate antibodies that may counteract methamphetamine. If the mechanism we are proposing is correct, then addicts are in essence vaccinating themselves against the drug when they use it and thus exposing themselves to ever-increasing amounts of methamphetamine in order to achieve a high. Amphetamines in general are capable of this type of chemistry, but not all drugs of abuse. It is the molecular structure of the drug that determines if "glycation" is possible. Our initial studies into this area were with a long-lived nicotine metabolite, nornicotine, which can also participate in protein glycation. The two compounds possess similar molecular structures. Thus, our study does not necessary provide new "cautions" as methamphetamine is already known to be highly addictive and heavy use leads to tolerance, but instead, provides a previously unrecognized mechanism for why methamphetamine users develop tolerance.

How new is this work and how does it differ from that of others who may be doing similar research?

To our knowledge, no other groups are exploring the process of protein glycation in terms of drugs of abuse. Protein glycation has been previously shown to increase the immunogenicity of a glycated protein, however, not in the context of drug addiction. In our study, a drug is taken into the body, which then modifies the body's proteins. The drug user's immune system then thinks these proteins are different enough to be considered "invaders" and initiates an immune reponse to make antibodies. Although these antibodies do not bind the drug very tightly, they may serve to soak up some of the drug like a sponge, thereby decreasing the level of the drug in the user's system. In essence, this is tolerance as the drug user will then have to use an increased amount of methamphetamine to achieve the same "high" as before the immune response occurred. In terms of novelty, this type of tolerance has not been previously proposed.

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229th American Chemical Society National Meeting