I. Introduction

In compliance with Section 3633 of the Children's Health Act of 2000, Public Law 106-310, as amended by section 2502 of the 21st Century Department of Justice Appropriations Authorization Act, Public Law 107-273, this report presents an update on the development of medications for the treatment of addiction to amphetamine and methamphetamine.

What are Amphetamines and Methamphetamine?

Amphetamines are part of a class of drugs called stimulants, which can profoundly alter brain and body functions. They can produce feelings of euphoria, increase alertness and arousal as well as blood pressure and heart rate, and they decrease appetite. They are Schedule II medications, which means they have a high potential for abuse and are available only through a prescription. There are only a few accepted medical indications for their use, such as the treatment of attention deficit hyperactivity disorder and narcolepsy (a sleep disorder). Methamphetamine is a form of amphetamine that is structurally and functionally similar; and once in the brain, methamphetamine and amphetamine are indistinguishable. However, methamphetamine differs from amphetamine in that, at comparable doses, much higher levels of methamphetamine get into the brain, making it a more potent stimulant than amphetamine. In addition, methamphetamine has a longer duration of action. Compared to amphetamine, methamphetamine has greater effects on the central nervous system (which leads to euphoria, motor stimulation, and anorexia) than on the sympathetic nervous system (which controls blood pressure and heart rate). This leads to a greater potential for harm to the brain. Nevertheless, both stimulants are highly addictive and have similar health liabilities. Because of their common mechanisms of action, research focusing on medications development for methamphetamine also encompasses amphetamine.

Methamphetamine is a white odorless bitter-tasting crystalline powder that dissolves easily in water or alcohol. Street names for methamphetamine include speed, meth, chalk, crystal, and glass. Methamphetamine comes in many forms and can be snorted, swallowed, injected, or smoked. In the 1980s, "ice," a smokable form of methamphetamine, came into use. Ice is a large, usually clear crystal of high purity that is smoked in a glass pipe like crack cocaine, and leaves a residue that can be re-smoked. The preferred method of methamphetamine abuse varies by geographical region and has changed over time. The routes of administration that lead to very fast uptake of the drug in brain, such as smoking and injecting, are the most dangerous since they have a greater addictive potential as well as more severe medical consequences.

Immediately after smoking or intravenously injecting amphetamine or methamphetamine, the user experiences an intense rush or "flash" that lasts a few minutes and is described as extremely pleasurable. Snorting or oral ingestion produces euphoria--a high, but not an intense rush. As with similar stimulants, amphetamines most often are used in a "binge and crash" pattern. Because rapid tolerance to the pleasurable effects of these drugs occurs, the high can disappear in minutes, even before the drug concentration in the blood falls significantly. This leads to a bingeing pattern of drug use in order to try to maintain the high.

Amphetamines affect many brain structures but predominantly those that contain the neurotransmitter (chemical messenger) dopamine, due to similarities in their chemical structures. Dopamine is involved in motivation, the experience of pleasure, motor function, and is a common mechanism of action for most drugs of abuse including amphetamine, cocaine, nicotine, marijuana and alcohol. Drugs of abuse produce a sense of euphoria by increasing dopamine neurotransmission in a variety of ways. Amphetamines are the most potent of the stimulant drugs in increasing dopamine levels, more than three times that of cocaine. This extra sense of pleasure is followed by a "crash" or depression that often leads to increased abuse of these drugs and eventually to difficulty in feeling any pleasure.

As the primary Institute within the National Institutes of Health dealing with drugs of abuse, the National Institute on Drug Abuse (NIDA) is tracking the use of amphetamine and methamphetamine and is encouraging and supporting multifaceted research on their abuse, including prevention, epidemiology, basic and clinical neurobiology, and behavioral and pharmacological treatment. The establishment of a Medications Development Program at NIDA by Congress in 1992 (Section 464P of the Public Health Service Act, 42 USC 285o-4) has greatly facilitated NIDA's efforts to develop treatments for drug addiction, including addiction to methamphetamine.

The Extent of the Problem

According to NIDA's 2004 Monitoring the Future Survey of drug use and related attitudes of America's adolescents, 15 percent of 12th graders, 11.9 percent of 10th graders, and 7.5 percent of 8th graders reported having used amphetamine at least once in their lifetime, and 6.2 percent of 12th graders, 5.3 percent of 10th graders and 2.5 percent of 8th graders have reported using methamphetamine at least once in their lifetime. These numbers, while disturbing, do not represent an increase over previous years.

Particularly concerning are findings from NIDA's Community Epidemiology Work Group (CEWG), which monitors drug abuse problems (mostly in adults) in 21 sentinel areas across the Nation, documenting increases in methamphetamine abuse in various regions across the United States and continued spread into rural communities. Long reported as a predominant drug problem in the Western United States, methamphetamine abuse has now become a substantial drug problem in other areas of the Country as well. Traditionally associated with white, male, blue-collar workers, methamphetamine is now being used by more diverse population groups that change over time and differ by geographic area.

The extent of methamphetamine abuse varies greatly by geographical region, but reports indicate that methamphetamine is available in all CEWG areas, and patterns in several areas appear to be in transition. In January 2005, CEWG reported that indicators of methamphetamine abuse have persisted at high levels in the Western United States including Honolulu, Seattle, San Francisco, Los Angeles, and San Diego, and have increased in several areas through 2003-2004, including Colorado, Phoenix, Atlanta, and Minneapolis/St. Paul. In Minneapolis/St. Paul, primary treatment admissions for methamphetamine as a percent of illicit drug treatment admissions increased from 10.6 to 18.7 percent from 2001 to 2004. In Atlanta, primary methamphetamine admissions represented nearly 11 percent of the illicit drug treatment admissions in the first half of 2004 compared to 6.7 and 6.9 percent in 2002 and 2003, respectively. Indicators of methamphetamine abuse have raised concern not only in metropolitan Atlanta, but also in suburban communities neighboring Atlanta and in rural Georgia. With the exception of Atlanta, methamphetamine treatment admissions in eastern CEWG areas remain low, at less than 1 percent of total substance abuse treatment admissions. However, there are increased reports of clandestine lab seizures in more rural areas of Eastern States, including Georgia, New York, and Maryland. Reports of the popularity of methamphetamine in some club contexts and within specific groups of users in eastern CEWG areas such as New York, Philadelphia, Washington DC, and Miami, underscore the potential threat of spread in areas where most indicators are still low. The clear availability of methamphetamine in these metropolitan areas warrants vigilance in monitoring indicators to track whether methamphetamine diffuses to a broader population of users or becomes popular in a wider range of contexts.

One of the contributors to the spread of methamphetamine is that it is relatively easy to manufacture. It can be synthesized with minimal equipment and the precursors are easily accessible in many areas of the United States. The widespread availability and longer duration of its effects have made methamphetamine a more desirable drug than cocaine for many drug abusers.

Health Hazards of Amphetamine/Methamphetamine Abuse

Medical and Psychiatric Complications. NIDA-supported research has yielded many insights into how all drugs of abuse, including amphetamines, affect the human body. Amphetamines 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. Chronic methamphetamine abuse can result in inflammation of the heart lining and, among users who inject the drug, damaged blood vessels and skin abscesses. Acute lead poisoning is another potential risk for methamphetamine abusers. A common method of illegal methamphetamine production uses lead acetate as a reagent, and production errors may therefore result in methamphetamine contaminated with lead. Documented cases of acute lead poisoning have been reported in intravenous methamphetamine abusers.

Hyperthermia (elevated body temperature), convulsions and coma can occur with methamphetamine overdoses and, if not treated immediately, can result in death. In fact the Drug Abuse Warning Network, maintained by the Substance Abuse and Mental Health Services Administration (SAMHSA), reported that mentions of amphetamine in drug abuse related cases in hospital emergency departments increased 125.9 percent from 1995 to 2002 (from 9,581 to 21,644) and reports of methamphetamine mentions remained stable, but high during this timeframe, at 17,696 in 2002.

Long-term amphetamine/methamphetamine abuse can result in many serious health consequences, including addiction. Research shows that addiction is a chronic, relapsing disease, characterized by compulsive drug seeking and use despite adverse consequences, which is accompanied by functional and molecular changes in the brain. In addition to being addicted to the drug, chronic abusers may experience withdrawal when use is stopped, which can include symptoms of depression, anxiety, fatigue, and an intense craving for the drug.

Chronic methamphetamine abusers also exhibit symptoms during intoxication that include violent behavior, anxiety, depression, confusion, and insomnia; and heavy users may show progressive social and occupational deterioration. Methamphetamine abusers can also display a number of psychotic features, including paranoia, auditory hallucinations and delusions. Psychotic symptoms can sometimes last for months or years after methamphetamine abuse has ceased and stress has been shown to precipitate spontaneous recurrence of methamphetamine psychosis in formerly psychotic methamphetamine abusers.

Prenatal Effects. Because these drugs are abused by women of childbearing age, fetal exposure to amphetamines could potentially cause significant problems. Unfortunately, our knowledge of the effects of prenatal exposure 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. A recent NIDA-funded study showed that prenatal exposure to methamphetamine resulted in smaller subcortical brain volumes, which was associated with poorer performance on tests of attention and memory conducted at about 7 years of age. However, most of these studies in humans are confounded by methodological problems, such as small sample sizes and maternal use of other drugs. Thus, it is important that caution is exercised in interpreting the findings thus far.

To increase our knowledge in this area, NIDA launched the first large-scale study of the developmental consequences of prenatal methamphetamine exposure in 2001, which includes seven hospitals in Iowa, Oklahoma, California, and Hawaii, states where methamphetamine abuse is prevalent. This study is evaluating developmental outcomes such as cognition, social relationships, motor skills and medical status, and comparing outcomes to well-matched controls for socioeconomic status and other variables.

HIV/AIDS. Drug abuse remains one of the primary vectors for HIV, hepatitis B, and hepatitis C transmission. The recent case of an HIV-infected methamphetamine 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 abuse increases the risk of contracting HIV not only due to the use of contaminated injection equipment, but also due to increased risky sexual behaviors as well as physiological changes that may favor HIV transmission.

Preliminary studies also suggest that methamphetamine use may affect HIV disease progression. For example, animal studies suggest that methamphetamine abuse 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 methamphetamine abusers had higher plasma viral loads than those who did not, suggesting that HIV-positive methamphetamine abusers on HAART therapy may be at greater risk of developing AIDS. These differences could be due to poor medication adherence or to interactions between methamphetamine and HIV medications. Similarly, preliminary studies suggest that interactions between methamphetamine and HIV itself may lead to more severe consequences for methamphetamine abusing, HIV-positive patients, including greater neuronal injury and neuropsychological impairment. More research is needed to better understand these interactions.

Effects of Amphetamine/Methamphetamine Abuse on the Brain

Basic Research Findings. NIDA has been conducting basic research on amphetamines for more than 20 years. As the abuse of methamphetamine has increased, NIDA's research efforts in this area have also increased. Basic animal (preclinical) research studies are critically important to the understanding of drug effects, and have provided important information that is now facilitating the development of effective medications for treating problems associated with drug abuse.

Scientific studies examining the consequences of amphetamine exposure in animals have demonstrated its toxic effects on the brain. In animals, high doses of amphetamines cause damage to nerve endings of brain cells that produce the neurotransmitters dopamine and serotonin. In rats, one high dose is enough to cause damage, and prolonged exposure seems to make it worse. Researchers have reported that as much as 50 percent of the dopamine-producing cells in the brain can be affected after prolonged exposure to methamphetamine. Researchers have also found that serotonin-containing nerve cells may be damaged even more extensively. However, some of methamphetamine's effects on the dopamine and serotonin systems have also been shown to be reversible suggesting that these cells may be capable of some degree of recovery.

Clinical Research Findings. Brain imaging technologies allow researchers to look into the brains of living drug abusers. This provides important information on how drugs of abuse change the structure and functioning of specific brain regions. However, the limitations of brain imaging in humans make it difficult to determine conclusively that brain cells are damaged or destroyed. Nevertheless, using sensitive neuropsychological and cognitive testing, it is possible to gain insight into how brain changes may be affecting behavior and function, and also determine whether these changes can be reversed.

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. Moreover, recent studies in chronic methamphetamine abusers have revealed severe structural alterations and functional deficits in areas of the brain associated with emotion as well as memory. These findings may help account for many of the emotional and cognitive problems observed in chronic methamphetamine abusers.

Fortunately, some of the effects of chronic methamphetamine abuse appear to be, at least partially, reversible. A recent neuroimaging study showed recovery in some brain regions following protracted abstinence (2 years, but not 6 months). This was associated with improved performance on motor and verbal memory tests. The results of this study may be highly significant for the development of treatments to reverse the harmful effects of methamphetamine abuse on the brain. However, function in other brain regions did not display recovery even after 2 years of abstinence, indicating that some methamphetamine-induced changes are very long lasting if not permanent. Moreover, the increased risk of cerebrovascular accidents from the abuse of methamphetamine can lead to irreversible damage to the brain.

Current Treatments

At this time, the most effective treatments for methamphetamine addiction are behavioral interventions. These approaches are designed to help modify the patient's expectancies and behaviors related to drug use, and to increase skills in coping with various life stressors.

Emergency room physicians who treat individuals exhibiting methamphetamine intoxication and overdose have also established some useful protocols. For example, acute methamphetamine intoxication can often be handled by observation in a safe, quiet environment. In cases of extreme excitement or panic, treatment with anti-anxiety agents such as benzodiazepines has been helpful, and in cases of methamphetamine-induced psychoses, short-term use of antipsychotic medications has been reported to successfully manage this syndrome. Antidepressant medications may also be helpful in combating the depressive symptoms frequently seen in methamphetamine withdrawal, although most antidepressants are not effective for several weeks, diminishing their utility for treating an acute depressive response. Also, to combat hyperthermia and convulsions, which can be fatal complications of methamphetamine overdose, patients are cooled off in ice baths and anticonvulsant drugs may be administered.

There are, however, no specific medications that counteract the effects of methamphetamine or that prolong abstinence from and reduce the abuse of methamphetamine by an individual addicted to the drug. Thus, there remains a significant unmet need in addressing an urgent National priority.

Efforts by NIDA to date to enlist the private sector in its program to identify, develop, and commercialize effective medications for the treatment of methamphetamine addiction have been only partially successful. The pharmaceutical industry continues to be reluctant to become involved in the development of anti-addiction medications. This is due largely to the existence of a number of disincentives, which are primarily financial in nature. The costs of bringing a new medication to market are in the range of $500 million to $1 billion and require at least a 10-year commitment. Such a commitment by private industry is unlikely to provide a profitable return on the investment for developing and bringing to market an anti-addiction medication. In order to stimulate private sector involvement in development of anti-addiction medications, strong market incentives are needed. This has been underscored by both the Institute of Medicine in its 1995 report "Development of Medications for the Treatment of Opiate and Cocaine Addictions: Issues for the Government and Private Sector" and by a 1997 NIH Consensus Development Conference on the Effective Medical Treatment of Heroin Addiction.