June 26, 2007 Scientists have found that chronic abuse of the highly addictive drug methamphetamine may be an unrecognized risk factor in the development of a number of potentially serious cardiovascular disorders frequently reported by methamphetamine abusers.
In recent years, the spread of methamphetamine abuse across the United States has been as rapid as it has been alarming. Until about six years ago, methamphetamine use was seen mostly in the western and rural United States. Today, methamphetamine abuse has expanded rapidly throughout the rest of the country and across different ethnic groups. According to the 2005 National Survey on Drug Use and Health (NSDUH), an estimated 10.4 million Americans ages 12 or older have used methamphetamine at least once in their lifetimes for non-medical reasons.
The study showed that long-term methamphetamine use changes endogenous proteins in drug users, causing aberrant immune responses. As a result, increased levels of proinflammatory cytokines-proteins involved in immune response-may be a previously unrecognized molecular mechanism for the development of cardiovascular disorders such as vasculitus, an inflammation of the blood vessels.
"Our previous studies showed that methamphetamine can glycate or add sugars to proteins," said Scripps Research Professor Kim Janda, who conducted this study in collaboration with Scripps Research Assistant Professor Tobin Dickerson and other colleagues. "In this study, we found that the immune system responds dramatically to this methamphetamine-induced glycation, which may lead to vascular inflammation and deterioration if left untreated. These problems are the direct result of long-term methamphetamine abuse."
Previous studies may have missed the impact of chronic methamphetamine use on the vascular periphery, Janda said, because they focused on the response of the microglia-the immune cells of the central nervous system-and the appearance of methamphetamine-related neurotoxicity in the central nervous system.
The study found that there was a direct relationship between methamphetamine intake and the level of circulating antibodies in animal models. This immune response, coupled with antibodies binding to methamphetamine, might make the drug less biologically available leading to an increased need for higher and higher doses, a problem found among chronic methamphetamine users.
The resulting glycated proteins-called advanced glycation endproducts (AGEs)-are associated with a number of diseases including diabetes and Alzheimer's disease. Long-lived AGEs can easily modify protein function, initiate adverse cellular reactions, and form damaging deposits on arterial walls. Methamphetamine-AGE proteins not only increased antibody production, the study said, but were strong enough to overcome the drug's natural immunosuppressive qualities. In addition, a wide range of cytokines directly linked to AGE exposure were increased in rats that self-administered methamphetamine.
The study also showed that even limited daily access to the drug was enough to produce an over-expression of vascular endothelial growth factor (VEGF), a potent signaling cytokine involved in angiogenesis and vasodilation. "Our data suggest that even methamphetamine use at lower doses may be enough to increase VEGF to potentially detrimental levels," Janda said.
The study is being published the week of June 25 in an advanced online edition of the Proceedings of the National Academy of Sciences.
In addition to Janda and Dickerson, both of Scripps Research's Skaggs Institute for Chemical Biology and Worm Institute for Research and Medicine, authors of the study, Self-Vaccination by Methamphetamine Glycation Products Chemically Links Chronic Drug Abuse and Cardiovascular Disease, include Scripps Research investigators Jennifer Treweek, George F. Koob, and Sunmee Wee.
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