Category: Crystal Meth

 Young adults who use methamphetamine may be more vulnerable to age-related brain degeneration when they grow older, new animal research suggests.

"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..

The work was supported by the U.S. Army and the National Institutes of Health.

NewsPsychology (June 27, 2007) — Crystal methamphetamine use among young adults in the United States is considerably higher than previous surveys indicate, according to new research funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH). The study, published in the July issue of the journal Addiction, found 2.8 percent of young adults (ages 18-26) reported use of crystal methamphetamine in the past year during 2001-2002. This is higher than the annual prevalence of crystal methamphetamine use by young adults (ages 19-28) of 1.4 percent reported by NIDA’s 2002 Monitoring the Future Survey.

Previous national surveys indicate that methamphetamine prevalence is highest among young adults, but until now, few scientific papers have looked at the characteristics and behaviors associated with its use in this age group. Using nationally representative data, and examining the age group most prone to methamphetamine use (ages 18-26), the study found that young adult users are disproportionately white and male and live in the West, and that Native Americans were 4.2 times as likely as whites to use crystal methamphetamine. Users also tend to have lower social economic status, use other substances, such as alcohol, marijuana, and cocaine, and the male users are more likely to have had incarcerated fathers.

“Measuring drug use is always a challenge,” said NIH Director Dr. Elias A. Zerhouni. “This new information gives us a clearer picture of use among young adults, but also raises new concerns. Even occasional use of crystal methamphetamine is associated with multiple health and social risks, including a negative impact on families as well as straining emergency departments and law enforcement resources.”

“The study showed not only greater use of crystal methamphetamine, it also suggests the drug is associated with risky and antisocial behaviors, including other illicit drug use,” said NIDA Director Dr. Nora D. Volkow. “By examining these connections, we hope to identify new avenues for treatment and prevention.”

The study authors based their findings on data from the National Longitudinal Study of Adolescent Health (Add Health), which asked respondents about their use of crystal methamphetamine in the past year and past 30 days. They examined certain characteristics of crystal methamphetamine users, such as their use of other substances, sociodemographics, and novelty-seeking behavior. They also looked at what was unique about crystal methamphetamine users compared to other drug users, and the associations between past year crystal methamphetamine use and antisocial or risk behaviors, such as crime/violence and risky sexual behavior. To maintain confidentiality, Add Health administered questionnaires via laptop computer using computer-assisted self-interviewing (CASI) technology.

The study found that use of crystal methamphetamine and associations with both criminal behavior and risky sex differed between men and women. Associations with both types of behaviors tended to be stronger among women than among men. Among women, the study found crystal methamphetamine use to be significantly associated with drug sales and risky sexual behavior, such as low condom use. However, the authors emphasize that more research is needed to determine whether women who sell drugs are more likely to use crystal methamphetamine or whether use of the drug leads to criminal drug sales among women.

Crystal methamphetamine (also referred to as “ice,” “crystal,” “glass,” and “tina”) is a common form of methamphetamine, a highly addictive stimulant that affects the central nervous system. As with the powdered form, users of crystal methamphetamine are drawn to its euphoric and stimulant effects, but the drug has higher purity and more potential for abuse. Typically smoked, it produces an immediate, intense sensation and has longer acting physiological effects than powder, which also amplifies its addiction potential and adverse health consequences. Those can include: mood disturbances, cardiovascular problems, heat stroke, convulsions, and psychotic symptoms that can sometimes last for months or years after methamphetamine abuse has ceased.

“This study presents a new perspective on crystal methamphetamine users in the United States,” said Dr. Denise D. Hallfors, of the Pacific Institute for Research and Evaluation and a co-author on the study. “We hope that this new information will aid in the development of appropriate interventions and help to inform public policy.”

To date, nationally representative survey research on crystal and other methamphetamine use has been based on two Federal sources: Monitoring the Future (MTF), and the National Survey on Drug Use and Health (NSDUH). In those surveys, annual prevalence of crystal methamphetamine use was 2.1 percent among 12th graders and 1.5 percent among young adults aged 19-28 (1.8 percent for men, 1.2 percent for women). The 2004 NSDUH survey did not ask specifically about crystal methamphetamine, but reported that past year methamphetamine use was highest among young adults (18-25), compared to youths and other adults.

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The above story is reprinted (with editorial adaptations by newsPsychology staff) from materials provided by NIH/National Institute on Drug Abuse.

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 — 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.

A pair of new vaccines designed to combat cocaine and methamphetamine dependencies not only relieve addiction but also minimize withdrawal symptoms, according to study results presented today by Baylor College of Medicine (BCM) researchers at the Annual Meeting of the College on Problems of Drug Dependence in Quebec City, Canada.

The vaccines stimulate the body to produce antibodies which then attack the drug while it is in the blood stream. This prevents the drug from reaching the brain and creating the reactions that contribute to dependency.

"These are therapeutic, not preventative, vaccines," said lead investigator Dr. Thomas Kosten, Jay H. Waggoner Professor of Psychiatry & Behavioral Sciences at the Menninger Department of Psychiatry at BCM and research director of the Veteran Affairs national Substance Use Disorders Quality Enhancement Research Initiative. "They are meant for those who are already suffering from drug addiction."

Kosten stresses that while the vaccines have been shown to help overcome drug addictions, they do not necessarily curb relapse.

"This is not a stand-alone treatment," Kosten said. "There is a reason drugs were used in the first place, and that needs to be dealt with either through counseling or behavioral therapies."

TA-CD, the cocaine vaccine, works through a series of injections over a three-month period. Study participants began to respond favorably to the vaccine after about a month. TA-CD has one more large scale human study scheduled before it is ready for the FDA approval process.

"The vaccine slowly decreases the amount of cocaine that reaches the brain," Kosten said. "It's a slow process, and patients do not go through any significant withdrawal symptoms."

Antibody production was sustained for another nine months following the vaccine treatment. Additional injections were subsequently administered every four to eight weeks, if needed at all.

The methamphetamine vaccine, still in early stages of development, has produced similar results as TA-CD. While both vaccines spur antibody production, each has a unique protein composition that help the body target the different drugs.

Both studies are being funded by the National Institute on Drug Abuse, part of the National Institutes of Health.

 A common antipsychotic drug used in emergency rooms to treat methamphetamine overdose damages nerve cells in an area of the brain known to regulate movement, a new study shows.

The findings, derived from experiments with rats, indicate that only the combination of the medication, haloperidol, and methamphetamine causes the destructive effects, not either one alone. Senior author Bryan Yamamoto, PhD, and his team at Boston University School of Medicine suspect the damage results from the exaggerated stimulation of cells by the amino acid glutamate, which proves toxic to cells producing the neurotransmitter gamma-aminobutyric acid (GABA). Their results are published in the May 30 issue of The Journal of Neuroscience.

"This work in laboratory animals raises immediate concerns that a standard treatment for methamphetamine overdose in humans might worsen drug abuse-related brain injuries," says William Carlezon, PhD, at Harvard's McLean Hospital, who was not affiliated with the study. "A crucial next step is to determine how atypical antipsychotic medications would affect methamphetamine toxicity in the same model."

The rats in the experiment were injected with either methamphetamine or a saline solution over a period of eight hours. When the rats were given haloperidol before and nearly halfway through the eight-hour period, Yamamoto and his colleagues noted more than a fivefold rise in base levels of glutamate in the substantia nigra, a part of the brain known to play a role in movement disorders such as Huntington's disease.

After examining the long-term effects of the combination, they found that glutamate concentrations in the substantia nigra were twice as high in methamphetamine-treated rats as in saline-treated ones two days after injections. Yamamoto and his colleagues were able to link this rise in glutamate to the death of GABA-containing cells in one part of the substantia nigra. This may predispose some people who have been treated for a methamphetamine overdose to seizures and the development of movement disorders, they say, although the study did not measure movement specifically.

In addition to future studies of other antipsychotic medications, says Yamamoto, "we hope to examine if the loss of cells results in abnormal involuntary movements resembling Tourette's syndrome and Huntington's disease."

The work was a supported by grants from the National Institutes of Health and a gift from Hitachi America.

A recently discovered signaling system in the brain has just been shown to be turned on by methamphetamine, an Oregon Health & Science University study found.

The signaling system could soon become a target for therapies aiming to reverse meth's adverse health effects as well as reduce the craving that drives its abuse.

Working in the recently opened Program in Chemical Biology in the OHSU School of Medicine's Department of Physiology and Pharmacology, scientists demonstrated the new target of meth, and its close relative amphetamine, is a G protein-coupled receptor known as trace amine-associated receptor 1, or TAAR1 for short.

"The Program in Chemical Biology at OHSU is one of the few in the U.S. that allows biologists and chemists to work side-by-side, using their combined skills to identify drug targets and to design new drugs to treat diseases like drug addiction," said David Dawson, Ph.D., OHSU professor and chairman of physiology and pharmacology. "Chemical space — that is, the number of possible drug molecules that could exist — is incredibly large. Our aim is to mine that space in order to uncover novel therapies."

TAAR1 was originally discovered in the laboratory of David K. Grandy, Ph.D., OHSU professor of physiology and pharmacology. Grandy's lab found TAAR1 is activated by chemical relatives of meth known as phenylethylamines. The messenger RNA that codes for TAAR1 is expressed throughout the brain, including areas involved in motivation and drug craving, olfaction — the sense of smell — and temperature regulation, to name a few.

"With this kind of pharmacological profile and brain distribution, we hypothesized TAAR1 could mediate some of meth's metabolic and behavioral effects," explained Grandy, who also directed the groundbreaking research.

"In our most recent article, we provide clear evidence that methamphetamine is a full and potent agonist of TAAR1. In other words, TAAR1 has the necessary features to be considered a real target of methamphetamine and amphetamine in rodents and probably humans, too."

Grandy added that it's his hope that "these findings will eventually lead to the development of new pharmaceuticals that reduce dependence on and craving for methamphetamine."

Earlier research in the Grandy laboratory demonstrated that meth and amphetamine stimulate the production of an important second messenger known as cyclic adenosine monophosphate, or cAMP, inside cells expressing the rat TAAR1. Encouraged by this observation, Grandy's team explored the effects of these drugs on mouse TAAR1 and a human-rat TAAR1 hybrid and found all three receptors respond in similar ways.

"The results of this study unequivocally demonstrate that meth and amphetamine are able to directly activate this receptor in the laboratory, making it likely that TAAR1 is activated in chronic users of meth," the researchers state in their article, whose lead author is Edmund Reese, a graduate student working in Grandy's laboratory. Other members of the research team include James Bunzow, M.S.; Seksiri Arttamangkul, Ph.D.; and Mark Sonders, Ph.D.

Grandy and his colleagues argue that TAAR1 represents a completely new target for pharmaceutical therapy to treat meth addiction and also reduce the negative manifestations of its abuse.

"Meth addiction is such a problem and we have nothing to treat it with except group support therapy," Grandy said. "Now we have a new target, something completely different to focus on, and we think that offers a lot of hope."

Grandy is actively collaborating with Thomas Scanlan, Ph.D., director of the Program in Chemical Biology who recently relocated to Portland from the University of California, San Francisco. Scanlan's laboratory has synthesized more than 150 new compounds that are being analyzed for their ability to selectively interfere with TAAR1 and block its activity.

"So we're already on a roll," Grandy said. The goal is to "take them to the point where they can be tested in humans."

Still, there's more to be learned about how meth and amphetamine affect the entire TAAR1 signaling system that is composed of six receptor genes in humans. "When you put it all together, what you realize is that meth acts on several signaling systems and that a successful therapeutic treatment will likely require modulation of several targets simultaneously. We still have a lot to learn about how meth affects the body through this system," Grandy said. "We have our work cut out for us."

The study is published in the April edition of the Journal of Pharmacology and Experimental Therapeutics.

— Increasing rates of amphetamine and cocaine usage by young adults significantly boost their risk of stroke, with amphetamine abuse associated with the greatest risk, researchers at UT Southwestern Medical Center report.

In the study, available online in the Archives of General Psychiatry, UT Southwestern physicians examined more than 8,300 stroke patients — ranging in age from 18 to 44 — at more than 500 Texas hospitals in the years 2000 through 2003.

An analysis of risk factors and trends among stroke victims in this age group pointed to an increase in substance abuse as a major danger, particularly in the abuse of methamphetamines, which are produced in illegal drug labs or illegally imported into the country.

Amphetamines are stimulants, often prescribed for various medical uses as well as used illegally as drugs of choice or as performance enhancers. Methamphetamines (meth) produce more potent, longer lasting and more harmful effects to the central nervous system than other members of the amphetamine drug class at comparable doses, according to the National Institute of Drug Abuse.

“Using amphetamines or cocaine significantly increases an individual’s risk for a stroke,” said Dr. Arthur Westover, an instructor of psychiatry at UT Southwestern and the study’s lead author. “If we decrease the number of people who are using these substances, then we likely can decrease the number of strokes in this younger population. The implication is that it’s preventable.”

The study focused on two kinds of strokes: hemorrhagic and ischemic. Most strokes — which involve a sudden interruption in the blood supply of the brain — are ischemic, caused by an abrupt blockage of arteries leading to the brain. Hemorrhagic strokes, on the other hand, result from bleeding into brain tissue when a blood vessel bursts.

An evaluation of patient study data from 2003, the first year that U.S. hospitals were required to make a distinction between the two types of strokes in their diagnoses of stroke victims, showed that young people who abuse amphetamines are five times more likely to have a hemorrhagic stroke than non-abusers. If cocaine is abused, the person’s likelihood of having either a hemorrhagic or an ischemic stroke more than doubles.

In addition, the 2003 data showed that more than 14 percent of hemorrhagic strokes and 14 percent of ischemic strokes were caused by abuse of drugs, including amphetamines, cocaine, cannabis (marijuana) and tobacco.

“Basically, speed kills,” said Dr. Robert Haley, the study’s senior author and chief of epidemiology at UT Southwestern. “And meth seems to be increasing as the preferred drug of abuse among the youngest population – people who don’t always know its dangers, often thinking it’s fairly safe.

“This is the first study large enough to confirm the link that meth kills by causing strokes. We hope that our findings will lead to getting the word out to young people who are tempted to use meth, explaining that the drug is extremely dangerous and can kill them.”

Also involved in the study was Dr. Susan McBride from the Dallas-Fort Worth Hospital Council in Irving. The study was supported in part by a grant from the National Institute of Mental Health.

Methamphetamine use may be associated with increased risks of major neck artery tears and stroke, according to an article published in the December 26, 2006, issue of Neurology, the scientific journal of the American Academy of Neurology.

"It appears methamphetamine use is toxic to large blood vessels," said the study's senior author Wengui Yu, MD, PhD, with the University of California, Irvine Medical Center and a member of the American Academy of Neurology.

The article reviewed the cases of two women, ages 36 and 29, who had sudden onset of speech difficulty and weakness following recent use of methamphetamine.

Brain scans showed both women had severe strokes from carotid artery dissection, which is a tear in the inner lining of one of the major arteries in the neck. On the National Institutes of Health Stroke Scale, the 36-year-old woman received a score of 21 and was treated with tissue plasminogen activator. The 29-year-old woman, who required a stent to treat the blockage in her common carotid artery, received a score of 17. Stroke Scale scores over 16 predict a high probability of death or severe disability.

"While methamphetamine use has been associated with aortic dissection, a tear in the wall of the aorta, the largest artery of the body, this is the first time there's been a possible link between methamphetamine use and carotid artery dissection, a tear in the neck artery," said Yu.

"Since cocaine has similar effects and has also been linked to aortic and carotid artery dissection, it's therefore likely that the tears in the arteries may be due to a drug class effect rather than a specific drug, like methamphetamine," he said.

Besides methamphetamine use, the women did not have any other significant risk factors for stroke. Both recovered with mild to moderate disabilities after acute stroke therapy.

Babies can be exposed to methamphetamine or "crystal meth" while in the womb, reveals an analysis of hair samples, published ahead of print in the Fetal and Neonatal Edition of Archives of Disease in Childhood.

Unlike hair, the most commonly used detection methods (blood and urine), cannot register long term use, nor can they always distinguish among different drugs, say the authors. Bleaching or straightening the hair will not erase the chemical evidence it holds.

Crystal meth boosts alertness and promotes a sense of wellbeing, euphoria, and exhilaration. It also curbs appetite and enhances sexual arousal. But long term abuse damages nerves in the brain and can lead to psychotic behaviour and aggression.

The drug is very easy to manufacture in home laboratories, and global use has soared, particularly among young women, say the authors. An estimated half a million Americans alone are thought to use it every week, including 5% of pregnant women.

The authors carried out hair sample analysis on more than 8,000 people, totalling more than 34,000 test results between 1997 and 2005.

In all, 396 samples tested positive for crystal meth, accounting for 8% of the total during this period. This number included 11 mother and baby pairs.

All but 14 of the samples testing positive for crystal meth had been sent for analysis in 2005. The first positive cases dated from 2003.

Wide ranging levels of the drug were found in both the mothers' and the newborns' hair samples. But the levels matched, indicating that the drug is able to cross the placenta directly to the developing fetus, say the authors.

Only one newborn had no evidence of the drug in its hair. Fetal hair starts to grow at about 20 weeks.

The authors say that the precise effects of crystal meth on a fetus are not fully known, but the evidence to date points to restricted fetal growth and developmental problems.

Crystal meth users were also significantly more likely to use other drugs, the results showed. Most (85%) of the 396 samples positive for crystal meth also tested positive for at least one other illegal drug, predominantly cocaine. .

Drug abuse increases complications of pregnancy and triples the likelihood of serious medical problems among the babies born, say the authors.

Oregon Health & Science University research showing stress triggers a relapse of methamphetamine abuse in mice could be a step toward developing a drug to curb this frustrating obstacle to recovery.

Results of the study, headed by Gregory Mark, Ph.D., associate professor of behavioral neuroscience in the OHSU School of Medicine, not only validate earlier studies on the effects of stress on drug relapse in humans, they also show a compound researchers used in the study to mimic metabolic changes that occur during periods of stress creates a useful model for studying this effect in the laboratory.

"One of the big problems we have in treating addiction is relapse. The incidence of relapse is really high," said Mark, an investigator with the Methamphetamine Abuse Research Center (MARC) at OHSU and the Portland Veterans Affairs Medical Center. "What we want to do is see if we can inhibit this response to stress."

The results are being presented today during a poster session at Neuroscience 2006, the Society for Neuroscience's 36th annual meeting in Atlanta. The session is at 5 a.m. (Pacific time) at the Georgia World Congress Center, Halls B3-B5.

Mark and study co-authors Deborah Finn, Ph.D., OHSU associate professor of behavioral neuroscience and VAMC research pharmacologist, and Larry Huang, OHSU research technician of behavioral neuroscience, trained mice to optionally administer small doses of meth to themselves by pressing a lever during daily four-hour sessions over three weeks.

"We structured the drug availability for the mice to be relative to the model that we commonly see meth addicts following," Mark said. "This is an animal model for drug-seeking behavior. We found that getting the drug was rewarding to them."

The drug was then taken away and replaced with harmless saline solution. This caused the lever-pressing rate by the mice to immediately increase.

"We think this is a frustration response," said Mark, who likened the effect to when a person puts money in a soda machine and presses the button, but gets nothing in return. "Analogous to the human world would be 'Come on, it's got to work!'" The mice even pressed a nearby inactive lever they rarely touched before in an attempt to get the drug. But demand for the drug eventually waned. "Over a few days, (the mice) generally give up," Mark explained. When the saline doses dropped to less than one per hour for three consecutive days, the mice received either more saline or a dose of 2-deoxyglucose, or 2-DG, a drug that lowers glucose levels in the blood, creating a condition similar to hypoglycemia in humans.

"People feel stress when they're hypoglycemic," Mark explained.

Five minutes later, the mice were placed in chambers where they previously received meth. The mice that received 2-DG attempted to self-administer meth at a rate five times higher than the mice given saline, making "2-DG an effective stimulus for reinstating drug-seeking behavior."

And as a metabolic stressor, 2-DG is innocuous enough to be used in research on both animals and humans, Mark added. "You don't want to stress a human by putting him in front of a lion."

Mark believes meth causes nerve cells that survive the drug's neurotoxic effect to be rewired or go through long-term "neuroadaptation." As a result, users respond to stress differently than nonusers, who are generally better able to cope with fatigue, motivation to achieve, peer pressure and other stressful situations.

"The drug changes the brain and those changes last a long time," he said. "This rewiring is something we need to pay attention to, to stop the cycle of taking the drug, getting off the drug and getting back to taking the drug."

One method may be a pharmaceutical therapy targeting brain regions that process stress responses, Mark suggests. These regions include the nucleus accumbens, prefrontal cortex, neostriatum and amygdala. Mark's lab also is studying the effects the neurotransmitters dopamine and acetylcholine have on stress response.

"We want to find those areas of the brain that are sensitive to the (2-DG) stressor and that area should be linked to other areas of the brain that cause the animal to push that lever again, to relapse," Mark said. "We think if we can find the candidate regions, and we can find the neurotransmitters that cause relapse, we can develop a drug that blocks one or more neurotransmitters in one or more of those brain areas. Maybe we could offer some kind of neuropharmaceutical hope."

The study was funded by the National Institutes of Health.