"The emergence of behavioral deficits in animals months after methamphetamine discontinuation may be relevant to human methamphetamine abusers," says Nora Volkow, MD, director of the National Institute for Drug Abuse. "It suggests that even though their current use may not result in deficits, as they age these deficits will become manifest." Volkow did not participate in the study.

The new work examines the idea that methamphetamine puts young users at risk of developing deficits later in life that are symptomatic of Parkinson's disease in individuals with depletion of glial derived neurotrophic factor (GDNF), a protein that protects and repairs dopamine in areas of the brain related to movement control. Loss of nerve cells that produce dopamine is a major factor in the disease.

In their work, published August 15 in The Journal of Neuroscience , Jacqueline McGinty, PhD, at the Medical University of South Carolina, and her colleagues examined the role of GDNF in mice. At 2.5 months of age, the equivalent of adolescence in humans, mice with a partial GDNF gene deletion were compared to mice without the gene deletion; both were given either methamphetamine or saline injections four times over an eight-hour period. McGinty's team discovered that the effects of this methamphetamine binge were exacerbated in the mice with the GDNF deletion. In addition, at 12 months, the GDNF-depleted mice moved significantly less than genetically normal mice treated with methamphetamine.

"Methamphetamine intoxication in any young adult may have deleterious consequences later in life, although they may not be apparent until many decades after the exposure," says McGinty. "These studies speak directly to the possibility of long-term public health consequences resulting from the current epidemic of methamphetamine abuse among young adults."

Future studies might involve identifying the reasons for increased vulnerability to methamphetamine in GDNF-depleted mice in order to help minimize the harm methamphetamine causes to the brain..

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At least one-third of patients cannot tolerate high-dose niacin, according to Shah. The most common side effect is flushing and itching that drives some people nuts. He said methods exist to minimize the problem, but they do not work for everyone.

Meanwhile, new medications have proved disappointing. Trials of one drug, torcetrapib, ended abruptly because the drug increased mortality risk and raised blood pressure. The class of diabetes drugs called thiazolidinediones (which include Avandia and Actos) increase HDL, but also seem to raise the risk of cardiovascular problems.

The once highly touted weight-loss drug rimonabant, which blocks the brain receptors activated by marijuana, does raise HDL; however, the U.S. Food and Drug Administration recently refused to approve it because it also seems to elevate risk for psychiatric problems like depression.

I'm much more excited about the prospect of what's coming in this area in the next three to five years, said Shah, who is studying approaches to boosting HDL that use different mechanisms from those that have been associated with problems. Clinical trials of a gene therapy based on his research are currently under way.

Despite the recent negative HDL trials, this field is extremely exciting and the pace of discovery is unbelievably fast, Shishehbor said. At least one other drug with a novel mechanism of action is also in trials ” and at least three other approaches have led to new drugs in the pipeline.

People with blood levels of HDL lower than 35 mg/dL have eight times the risk of heart disease compared to those with 65mg/dL or more. Some 16 percent to 18 percent of men have low levels, compared with 3 percent to 6 percent of women.

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