Mr. Chairman and Members of the Committee, thank you for inviting the National Institute on Drug Abuse (NIDA), a component of the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services, to participate in this important hearing. As the world's largest supporter of biomedical research on drug abuse and addiction, we have learned much about the behavioral and health effects of methamphetamine (METH). I am pleased to be here today to present an overview of what the science has taught us about METH, a stimulant drug that can have devastating medical, psychiatric, and social consequences.

NIDA has been conducting basic research on METH for more than 20 years; however, as its use has increased, NIDA's research efforts have also increased. In fact, NIDA funding of METH-related research increased almost 150% from 2000-2004, through which NIDA has been tracking its use and supporting multifaceted research aimed at better understanding how the drug affects the brain, its consequences for the brain and behavior, as well as developing effective treatments for METH addiction.

According to NIDA’s Monitoring the Future Survey, we are seeing significant decreases in METH use among eighth graders; however, the use among 10th and 12th graders appears to have stabilized (Figure 1). Of greater concern are findings from NIDA's Community Epidemiology Work Group (CEWG), which monitors drug abuse problems in sentinel areas across the Nation and is alerting us to increases in some CEWG areas and continued spread into rural communities. Moreover, according to the Treatment Episode Data Set from the Substance Abuse and Mental Health Services Administration (SAMHSA), the number of people seeking treatment for METH/amphetamine abuse has also steadily increased from 1996-2002.

Methamphetamine is a Schedule II stimulant, which means it has a high potential for abuse and is available only through a prescription. There are only a few accepted medical indications for its use, such as the treatment of narcolepsy and attention deficit hyperactivity disorder. As a powerful stimulant, methamphetamine, even in small doses, can increase wakefulness and physical activity and decrease appetite. METH comes in many forms and can be snorted, swallowed, injected, or smoked, the preferred method of use varying by geographical region and changing over time. Faster routes of administration, such as smoking and injecting, have become more common in recent years, further increasing its addiction potential as well as the severity of its consequences.

METH acts by affecting many brain structures but predominantly those that contain dopamine, due to similarities in the chemical structures of METH and dopamine. METH produces a sense of euphoria by increasing the release of dopamine. In fact, amphetamines are the most potent of the stimulant drugs in that they cause the greatest release of dopamine, more than three times that of cocaine. This extra sense of pleasure is followed by a "crash" that often leads to increased use of the drug and eventually to difficulty in feeling any pleasure.

Long-term methamphetamine abuse can result in many damaging consequences, including addiction. We know from research that addiction is a chronic, relapsing disease, characterized by compulsive drug seeking and use, which is accompanied by functional and molecular changes in the brain. In addition to being addicted to methamphetamine, chronic methamphetamine abusers exhibit symptoms that can include violent behavior, anxiety, depression, confusion, and insomnia. They also can display a number of psychotic features, including paranoia, auditory hallucinations, and delusions.

NIDA-supported research has also shown that METH can cause a variety of cardiovascular problems, including rapid heart rate, irregular heartbeat, increased blood pressure, and irreversible, stroke-producing damage to small blood vessels in the brain. Hyperthermia (elevated body temperature) and convulsions occur with METH overdoses and, if not treated immediately, can result in death.

What Does Methamphetamine Do to the Brain?

In animals, methamphetamine has been shown to damage nerve terminals in the dopamine- and serotonin-containing regions of the brain. Similarly, studies of methamphetamine abusers have demonstrated significant alterations in the activity of the dopamine system that are associated with reduced motor speed and impaired verbal learning (Figure 2). One small study also correlated changes in a marker of dopamine function with the duration of METH use and the severity of psychiatric symptoms. Moreover, recent studies of chronic METH abusers have revealed severe structural and functional deficits in areas of the brain associated with emotion, specifically depression and anxiety, as well as memory.

Although METH can produce long-lasting decreases in dopamine function, which appear to mimic the loss of dopamine seen in diseases like Parkinson's disease, autopsy studies show that the motor regions most affected in Parkinson's disease are not as severely affected in METH abusers. However, the possibility exists that moderate METH-induced effects during early life could make an individual more susceptible to Parkinsonism later in life. In contrast, METH-induced deficits in cognitive regions can be as severe as those in Parkinson's disease patients. The observed damage in Parkinson's disease is permanent due to considerable dopamine cell death. Dopamine cell death has not been documented in methamphetamine abusers, which could explain why with extended abstinence, there is some recovery from METH-induced changes in dopamine function (Figure 3).

A recent neuroimaging study of METH abusers showed partial recovery of brain function in some brain regions following protracted abstinence, associated with improved performance on motor and verbal memory tests. However, function in other regions did not display recovery even after two years of abstinence, indicating that some methamphetamine-induced changes are very long-lasting. Moreover, the increase in risk of cerebrovascular accidents from the abuse of methampehtamine can lead to irreversible damage to the brain.

Developmental Exposure

In addition to its known effects in adults, NIDA is very concerned about the effects of METH on the development of children exposed to the drug prenatally. Unfortunately, our knowledge in this area is limited. The few human studies that exist have shown increased rates of premature delivery; placental abruption; fetal growth retardation; and cardiac and brain abnormalities. For example, a recent NIDA-funded study showed that prenatal exposure to methamphetamine resulted in smaller subcortical brain volumes, which were associated with poorer performance on tests of attention and memory conducted at about 7 years of age. However, most of these human studies are confounded by methodological problems, such as small sample size and maternal use of other drugs. For this reason, NIDA recently launched the first large-scale study of the developmental consequences of prenatal METH exposure, which includes seven hospitals in Iowa, Oklahoma, California, and Hawaii, states where METH use is prevalent. This study will evaluate developmental outcomes such as cognition, social relationships, motor skills and medical status.

Our knowledge about the effects of METH use later in development is also incomplete. Despite the stable low levels of METH use for 10th and 12th graders, we are concerned with any use of METH in this age group. Because the brain continues to develop well into adolescence and even early adulthood, exposure to drugs of abuse during this time may have a significant impact on brain development and later behavior. Additional research will help us understand the effects of METH use during childhood and adolescence and whether these effects persist into adulthood.

Methamphetamine and HIV

Drug abuse remains one of the primary vectors for human immunodeficiency virus (HIV) transmission. The recent case of an HIV-infected METH abuser in New York City with a particularly virulent strain of HIV is a sobering reminder of the link between drug abuse and HIV. Methamphetamine is inextricably linked with HIV, hepatitis C, and other sexually transmitted diseases. METH use increases the risk of contracting HIV not only due to the use of contaminated equipment, but also due to increased risky sexual behaviors as well as physiological changes that may favor HIV transmission.

Preliminary studies also suggest that METH may affect HIV disease progression. For example, animal studies suggest that METH use may result in a more rapid and increased brain HIV viral load. Moreover, in a study of HIV-positive individuals being treated with highly active anti-retroviral therapy (HAART), current METH users had higher plasma viral loads than those who were not currently using METH, suggesting that HIV-positive METH users on HAART therapy may be at greater risk of developing acquired immune deficiency syndrome (AIDS). These differences could be due to poor medication adherence or to interactions between METH and HIV medications. Similarly, preliminary studies suggest that interactions between METH and HIV itself may lead to more severe consequences for METH abusing, HIV-positive patients, including greater neuronal damage and neuropsychological impairment. More research is needed to better understand these interactions.

To address these issues, NIDA recently invited applications for administrative supplements to current grants to support studies on HIV in METH abusers. While there have been many studies on METH and both injection and risky sexual behavior, there is very little information on METH and HIV disease progression or on the prevalence of drug-resistant virus in METH abusers. Therefore, NIDA is planning to establish a targeted surveillance initiative to monitor the development of drug-resistant HIV in METH abusers.

What Else is NIDA Doing?

NIDA continues to support a comprehensive research portfolio on methamphetamine's mechanism of action, physical and behavioral effects, risk and protective factors, treatments, and potential predictors of treatment success. For example, recent studies have identified genetic variants that may be associated with an individual's response to various drugs of abuse. One such NIDA-funded study demonstrated that individuals with a particular variant of the dopamine transporter gene were less able to feel the effects of amphetamine, suggesting that people with this genotype may be protected from dependence because of a lack of reactivity to the drug. Understanding genetic risk and protective factors may aid in the development of targeted prevention efforts. At the other end of the spectrum, NIDA-supported research is also seeking to identify markers to predict which METH-dependent patients may be more likely to relapse to drug use following treatment. For example, a recent study noted that decreased brain activation during a decision-making task correctly predicted which patients would relapse to METH use. These findings may provide an approach for assessing susceptibility to relapse early during treatment as well as lead to new treatment approaches that are targeted towards rehabilitating these deficits, thereby increasing a patient's chance for long-term sobriety.

NIDA's efforts over the years to understand the basic science underlying METH's actions are now paying off in the development of treatments for METH addiction. In early 2000, NIDA convened a group of experts to provide guidance on the establishment and research focus of NIDA's methamphetamine treatment program. In response to one of their recommendations, NIDA launched a methamphetamine medications development initiative to use animal models to identify, evaluate, and recommend potential treatments to reduce or eliminate drug-seeking behaviors and drug effects, such as reversing neurotoxicity and cognitive impairment.

To further speed medication development efforts, NIDA has also established the Methamphetamine Clinical Trials Group (MCTG) to conduct clinical (human) trials of medications for METH in geographic areas in which METH abuse is particularly high, including San Diego, Kansas City, Des Moines, Costa Mesa, San Antonio, Los Angeles, and Honolulu. For example, modafinil, a medication for the treatment of narcolepsy, which has shown preliminary efficacy in cocaine treatment and may have positive effects on executive function and impulsivity, will be tested in the MCTG for its potential in the treatment of METH addiction. Other NIDA-supported studies are also developing promising medications. For example, a preliminary study of an anti-epileptic medication, gamma-vinyl GABA (GVG), showed that half of the GVG-treated patients remained drug free for approximately six weeks despite living in their normal home environment with ready access to drugs. To treat METH overdose, NIDA is pursuing the development of monoclonal antibodies to METH, which bind to the drug in the bloodstream thereby preventing its action.

In addition to pharmacological treatments, NIDA is invested in the development and testing of behavioral treatments. Studies have now shown that a treatment program known as the Matrix Model can be used successfully for the treatment of METH addiction. The Matrix Model was initially developed in the 1980s for treating cocaine addiction. It consists of a 16-week program that includes group and individual therapy and components that address relapse and how to prevent it, behavioral changes needed to remain off drugs, communication among family members, establishment of new environments unrelated to drugs, and other relevant topics. When applied to METH abusers, the Matrix Model has been shown to result in a high proportion of METH-free urine samples at program completion and 6-month follow-up.

Another behavioral treatment, Motivational Incentives for Enhancing Drug Abuse Recovery (MIEDAR), an incentive-based method for cocaine and METH abstinence, has recently been tested through NIDA's National Drug Abuse Clinical Trials Network and also shows promise for the treatment of METH addiction. MIEDAR is currently being developed for dissemination to community treatment providers through NIDA's collaborative Blending Initiative with SAMHSA.

Because no single behavioral treatment will be effective for everyone, research into behavioral approaches for treating METH addiction is ongoing. In 2005, NIDA solicited additional research applications on the development, refinement, and testing of behavioral and combined behavioral and pharmacological (and/or complementary/alternative) treatments for METH abuse and dependence. We expect that, as with other types of addiction, combining pharmacotherapies with behavioral therapies will be the most effective way to treat METH addiction.

Because of the prevalence of drug abuse among the criminal justice population, NIDA, in collaboration with NIH's National Institute on Alcohol Abuse and Alcoholism, SAMHSA, and other federal agencies, established the Criminal Justice Drug Abuse Treatment Research Studies (CJ-DATS), a major research initiative, bringing together researchers, criminal justice professionals, and addiction treatment providers, to develop new strategies to help drug abusing offenders. As part of our efforts to combat METH addiction, CJ-DATS is collecting self-report and biological data on methamphetamine use and investigating the effectiveness of treatments in criminal justice settings for those who abuse methamphetamine. Within CJ-DATS we are also supporting two research protocols testing comprehensive treatment approaches for juvenile offenders, including those who abuse METH.

Conclusion

In closing, I would like to say that as someone who has spent almost 25 years studying the effects of psychostimulants on the brain, I am particularly concerned about the methamphetamine problem in this country both because of its powerful addictive potential and because of its high toxicity. One of NIDA's most important goals is to translate what scientists learn from research to help the public better understand drug abuse and addiction and to develop more effective strategies for their prevention and treatment. NIDA has long supported research on methamphetamine, which is now paying off in the development of effective treatments, and it is critical that these treatments become more readily available to those who need them.

Thank you for allowing me to share this information with you. I will be happy to answer any questions you may have.