Justification
(Numbers in the Congressional Justification do not include AIDS Funding, which would make the IC FY 2001 total $725,467,000)
| Authorizing Legislation: | Section 301 and Title IV of the Public Health Service Act, as amended. Reauthorizing legislation will be submitted. | ||||||
| Budget Authority: | |||||||
| FY 1999 Actual | FY 2000 Estimate | FY 2001 Estimate | Increase or Decrease | ||||
| FTE | BA | FTE | BA | FTE | BA | FTE | BA |
| 359 | $428,490,000 | 372 | $469,149,000 | 372 | $496,294,000 | --- | +$27,145,000 |
This document provides justification for FY 2001 Non-AIDS activities of the National Institute on Drug Abuse (NIDA). Justification of NIH-wide FY 2001 AIDS activities can be found in the NIH section entitled, "Office of AIDS Research (OAR)."
Introduction
The National Institute on Drug Abuse (NIDA) has just celebrated its 25th anniversary. Those reflecting on this commemoration concur that the Institute has provided the Nation an extremely strong knowledge base from which to develop ever better strategies to reduce drug abuse and addiction and to prepare for the public health challenges that tomorrow will undoubtedly bring. Moreover, the dramatic scientific advances realized since NIDA's inception continue to come at an extraordinary pace. Modern technologies, such as enhanced molecular genetic techniques and real-time brain imaging, are rapidly leading researchers to exciting new opportunities for understanding, treating, and preventing drug addiction. Building on a foundation of significant scientific accomplishment, NIDA is poised to take advantage of the myriad of scientific opportunities now presenting themselves and to offer new hope for a problem that directly or indirectly affects every citizen of the United States.
The latest estimate indicates that the economic burden for illegal drug use well exceeds $110 billion. Those costs are incurred through virtually every sector of American society. Consequently, research aimed at reducing the extent and health consequences of drug abuse and addiction is critically important. As the supporter of over 85% of the world's research on the health aspects of drug abuse and addiction, it is imperative that NIDA continue to assert its leadership role to seize new research opportunities. Toward this end, NIDA supports a comprehensive portfolio of research into all aspects of drug abuse and addiction. This broad approach has led to many significant findings and opportunities over the past year.
For example, NIDA has declared as one of its primary goals for the next decade improving the quality of drug addiction treatment throughout the nation, using science as the vehicle. The extent of recent advances in treatment research has enabled the Institute to accelerate the launch of its much-anticipated and needed National Drug Abuse Treatment Clinical Trials Network (CTN). The CTN, part of a broader NIDA Treatment Research Initiative, is serving not only as an infrastructure for testing science-based treatments in diverse patient populations and treatment settings, but also as a mechanism for promoting the rapid translation of new treatment components into actual community clinical settings throughout the nation. NIDA awarded the first five regional sites in FY 1999. NIDA hopes to expand this network so more patients in need of drug addiction treatment can participate in these trials. By teaming researchers with community treatment practitioners to test science-based treatments in real life settings, NIDA is taking a dramatic leap toward improving national drug abuse treatment.
The CTN will also enhance other research areas of NIDA's portfolio. For example, the diverse extent and breadth of the patient/subject pools that will be studied and benefit from this Network will provide an exceptional opportunity to expand NIDA's efforts directed toward reducing health disparities among various ethnic and racial groups.
As a second example, participants in the Network will provide opportunities to better understand the genetic and environmental factors that contribute to an individual's vulnerability to drug use. In fact, through NIDA's "Vulnerability to Addiction" initiative we are making great progress toward understanding the factors that contribute to addiction. For instance, evidence from adoption and twin studies, from genetic inbred strains of rodents, and from induced mutations in mice, suggest that one's vulnerability to becoming addicted to drugs has a moderate to significant heritable component. Although the gene variants underlying increased vulnerability to addiction are unknown, new scientific opportunities are bringing us closer to the possibility of identifying and characterizing the genes underlying addiction. In the past year, NIDA-supported researchers merged technologies from the imaging and genetic fields to discover that the number of brain dopamine D2 receptors an individual has may be correlated directly with his or her experience of the "pleasantness" of a drug. This is the first evidence in humans revealing a direct association between receptor levels in the brain and the pleasurable effects of a psychostimulant, such as methylphenidate. These findings have significant implications for understanding what determines individual differences in how much a person likes a drug and may represent a critical component in the neurobiological basis for drug abuse and addiction vulnerability.
Understanding the role that genetics, environment and their interaction play in shaping an individual's susceptibility to drug addiction allows us to greatly accelerate progress in developing more targeted drug abuse prevention and treatment strategies. We have already made great advances in outlining the fundamental principles of effective drug abuse prevention. These principles, however, are ready to be taken to a new and greater level of specificity. New research is needed to ensure that drug use prevention efforts are responsive to the special characteristics of different locales and settings, and to differences in the needs and responses of audiences that often vary in gender, ethnicity and age. Given that the greatest risk for initiating drug abuse occurs during the adolescent years, prevention research is vitally important to securing the future of our Nation.
Of course all of these prevention and treatment findings actually evolve from the progress made from our basic neuroscience and behavioral research portfolios. As drug abuse/neuroscience researchers elucidate the sites and mechanisms of action of drugs of abuse, our understanding of the function and structure of the brain continues to move dramatically forward. Science advances (discussed in more detail in the "Science Advances" section of this document), such as the identification of a chemical that can block the brain damage that is caused by methamphetamine; and the discovery that a brain chemical known as anandamide is involved in regulation of movement, will not only be beneficial to individuals affected by addiction, but may be useful to researchers in other disciplines. NIDA will continue to disseminate its research findings to the broadest community possible, including other scientists, treatment and prevention providers, the general public, and policy makers.
One particularly dramatic result of how neuroscience serves as the backbone of all our efforts, especially those that can be translated to the clinical setting, is the expected approval of the new anti-heroin medication, buprenorphine-naloxone. This medication was developed jointly by NIDA and a pharmaceutical company. Its unique chemical properties as a partial opiate agonist combined with an opiate antagonist make this drug the first medication likely to be used very effectively in traditional medical settings such as in doctors' offices (see "Science Advances" section of this document). The concept of blending these compounds into a new medication was driven by advances in understanding the neurobiology of opiate addiction and represents a major therapeutic advance for those treating addictions.
It is only through supporting and disseminating high quality science that we will ever succeed in replacing the ideologies and myths that so pervasively surround drug abuse and addiction. We have taken a giant step in this regard in the past year with the October 1999 release of the Nation's first ever research-based guide to drug addiction treatment. "Principles of Drug Addiction Treatment" outlines the essential components of drug addiction and its treatment based on decades of scientific research. It is hoped that these treatment principles will serve as a foundation for replacing dogmas about drug addiction with science-based treatment. We have made much progress toward this end, but the journey continues.
New Initiatives and Priority Areas for Drug Abuse Research
National Treatment Improvement. Through NIDA's Treatment Research Initiative, great progress has already been made in the treatment arena, although much more work still needs to be done. NIDA will continue to support research that brings new behavioral and pharmacological treatments to our Nation's forefront. Given some of the recent increases in stimulant abuse, particularly methamphetamine, NIDA will make medications for cocaine and methamphetamine major priority areas for its medications development program. The very rapid pace of discovery in the neurobiology of drug abuse is providing many new molecular targets and novel approaches that could be exploited to speed up medication development. NIDA will also simultaneously tap into the advances being made in the behavioral science and cognitive neuroscience fields to bolster NIDA's Behavioral Therapies Development Program. Once the behavioral and pharmacological treatments are tested and proven to be safe and effective in the laboratory setting, NIDA will test these science-based treatments in community-based treatment programs that are part of NIDA's newly launched National Drug Abuse Treatment Clinical Trials Network. The net effect of this initiative will be a marked improvement in the quality of drug addiction treatment in this country.
Transition from Drug Use to Addiction. NIDA-supported research has revealed a tremendous amount about both the biological and behavioral differences between a voluntary drug user and an addict, and it is clear these states are distinct from each other. There is a tremendous gap, however, in understanding the mechanisms that underlie the actual transition from one state to the other. This topic has been identified by the National Advisory Council on Drug Abuse as a major area requiring new, intensive, focused attention, since preventing the transition from being a voluntary drug user to being a compulsive user, an addict, would, of course, be a major health advance. Thus, NIDA-supported researchers will study this transition in detail. For example, they will work to determine whether the change from drug use to addiction is gradual or precipitous and will attempt to determine how taking a drug repeatedly over time changes the brain in such a way as to lead to the compulsive, self-destructive patterns of drug use that characterize addiction. NIDA will significantly expand its research portfolio to study the behavioral and neurobiological events that underlie this critical period as well as identify the genetic and environmental factors that make the individual more or less likely to move from one state to another.
Eliminating Health Disparities. Research has shown that individuals whose lives are marked by poverty, illiteracy, malnutrition, and other unhealthy environmental conditions are also at high risk for drug abuse. These individuals, as well as those in minority populations, are also at increased risk for many of the diseases associated with drug abuse, such as hepatitis. NIDA is intensifying efforts in all areas of its research portfolio, including basic, clinical, and epidemiological research to increase our understanding of the link between drug abuse and various diseases that predominantly affect underserved populations so that we can develop treatments, interventions, and prevention programs that are gender, age and culturally relevant to these populations. A special feature of the Clinical Trials Network will be its ability to recruit large numbers of subjects from very diverse background and locales. This will provide a particularly useful vehicle for analyzing some health disparities issues. NIDA is also expanding its efforts to increase the number of scholars from underrepresented groups participating in drug abuse research.
The Role of Stress in Drug Abuse and Addiction. Stress is thought to be involved in the development of many psychiatric and health disorders. It is not surprising that stress can be a critical factor in both the initiation of drug use and as a precipitating factor in relapse to drug use following periods of abstinence. There have long been behaviorally-oriented theories to explain these phenomena, but there is now increasing evidence that some behavioral sequelae of exposure to stress are actually biologically mediated. For example, corticotrophin-releasing factor (CRF), a stress-released peptide in the brain that can actually cause anxiety reactions by itself, is being found to be a mediating mechanism in stress effects on drug use and relapse. This relationship will be studied in much greater detail, but is already suggesting new targets for the development of anti-addiction medications, targets directed at manipulating the biological stress response systems. NIDA is working actively with pharmaceutical companies to evaluate medications that modulate stress, such as CRF antagonists for their potential utility as addiction treatments.
Treatment for Adolescents. New opportunities exist for identifying and developing effective treatments that are specifically geared towards adolescents. While many treatments currently exist, virtually all were developed on and for adults. Thus, there is a tremendous need for the development of new treatments focusing specifically on the special circumstances of adolescent patients. To address this important area, NIDA has developed an initiative on addiction treatment for adolescents that will focus on the development of treatments that are sensitive to the unique needs of youth, as well as co-morbidity with other illnesses and its treatment implications; matching each youth to the most appropriate treatment available; evaluating existing treatment programs; and testing the efficacy of new behavioral treatment approaches.
Prenatal Drug Exposure and the Neurobiology of Development. Years of research have confirmed that some children who are prenatally exposed to drugs have problems with aspects of motor skills, intelligence, fussiness and consolability, and attention span. Executive function, the ability to gather and use information in pursuit of one's own aims, may also be compromised. However, there still remains much to be learned about the impact of drugs on the developing human brain. To further our understanding of prenatal drug effects and to exploit the opportunities now provided by the emergence and availability of noninvasive imaging technologies, NIDA proposes to launch a "Neurobiology of Development Initiative." This initiative will allow researchers to determine the effects of drugs on brain development and plasticity at all ages. It will be particularly useful as we attempt to see if there are neuronal correlates for the behavioral patterns we are seeing in children and adolescents who were prenatally exposed to drugs. This initiative will also focus on researching the types of assistance that are needed for children to overcome difficulties from fetal drug exposure.
Emerging Drug Abuse Epidemics: Club Drugs. Some of our Nation's best epidemiological monitoring mechanisms are beginning to alert us to an increase in the use of "club drugs" such as methamphetamine, MDMA or "ecstasy," gamma hydroxybutyrate (GHB), ketamine, and rohypnol. These drugs are becoming increasingly available and popular with various sectors of the population, predominantly with young adults and adolescents who attend all night dance parties such as "raves" or "trances." NIDA will increase its efforts to identify, understand the neurobiology of these drugs, and develop effective prevention and treatment strategies. In December 1999, NIDA officially launched its "Club Drug Initiative" and sponsored a scientific meeting on this topic that helped identify research gaps that need to be addressed.
Methamphetamine Research. NIDA will continue to support research that focuses on methamphetamine abuse. Specifically, NIDA will work to clarify the mechanisms underlying the dramatic neurotoxic effects that have been recently reported in human methamphetamine abusers. Pursuing medications to aid in the treatment of methamphetamine addiction and overdose, developing prevention approaches that are tailored to the specific needs of individuals will continue to be a high priority for NIDA, as well as supporting more research to understand how methamphetamine produces its toxic effects and how to reverse the neurotoxic damage. Also, to better understand the effects that methamphetamine has on the developing child, NIDA has also launched a Methamphetamine Fetal Development Initiative.
Combating Nicotine Addiction. Twenty-five years of NIDA research has provided the basis for understanding the addictive properties of nicotine and has led to the development of both pharmacological and behavioral treatments for nicotine addiction. Nonetheless, the use of tobacco products remains one of the Nation's deadliest addictions. To continue to address this major public health problem, NIDA has teamed with the National Cancer Institute and the Robert Wood Johnson Foundation to establish Transdisciplinary Tobacco Use Research Centers (TTURC). The TTURCs will facilitate a transdisciplinary approach to the full spectrum of basic and applied research on tobacco use, including: initiation of tobacco use (including the impact of advertising and marketing), prevention of tobacco use, addiction to tobacco, treatment of tobacco use, the identification of biomarkers of tobacco exposure, and the identification of genes related both to addiction and susceptibility to harm from tobacco. This transdisciplinary approach should lead to increased opportunities for understanding how nicotine acts in the brain and body and for developing new strategies for treating nicotine addiction and preventing tobacco use, particularly by teens and younger children.
Medical Consequences of Drug Use. Although we are learning much about the role that behaviors and patterns of drug use contribute to other public health consequences, particularly the spread of infectious diseases, including HIV/AIDS, tuberculosis, and hepatitis, there is much to be learned. In marked contrast to other addictions, particularly nicotine addiction and alcoholism, relatively little is known about the medical and health consequences for the individual who has been using illicit drugs over a prolonged period of time. With the recent establishment of NIDA's Center for AIDS and Other Medical Consequences of Drug Abuse, NIDA will begin a major new research initiative focusing on the short and long-term health consequences associated with drug abuse and addiction. NIDA will be particularly interested in preventing hepatitis C in the general population and in increasing access to care. NIDA will also be more closely examining the interaction between AIDS treatments and drugs of abuse.
Story of Discovery: Methamphetamine Abuse: Confronting a Public Health Crisis
Methamphetamine -- what was in the 1930s a promising new treatment for nasal congestion, is now in the 1990s, a growing public health menace. We now know that methamphetamine is not only a powerfully addicting stimulant, but a drug that it is highly toxic to human brain cells when abused. These properties, coupled with the fact that it is easy to make with commonly available ingredients make it a looming public health problem for our country.
Methamphetamine was first developed in 1919 as an amphetamine derivative by a pharmacologist in Japan. However, it was not until the 1930s that the pharmacological properties of the amphetamine family of compounds were discovered. Initially, amphetamines were found to have potent vasoconstrictive properties. In fact, amphetamine was initially marketed in 1932 as Benzedrine, an inhaler designed for the relief of nasal congestion. Users of these over-the-counter inhalers soon discovered that the amphetamine contents of these inhalers were powerful central nervous system stimulants because, as scientists later discovered, of their ability to activate the dopamine system in the brain. Soon abusers were disassembling the inhalers to retrieve the amphetamine containing paper inside, since these drugs activate the reward or pleasure circuit.
There have been several waves of amphetamine and methamphetamine abuse in this country since then. During the 1950s and 1960s, methamphetamine and amphetamines were being diverted from pharmaceutical products and being abused by truck drivers, students, and housewives as insomniac and weight loss agents. Intravenous use of methamphetamine became popular among white, young adults, particularly in the Haight-Ashbury district of San Francisco in the late 1960s and early 1970s. As a result of the increasing abuse, the Controlled Substance Act was passed in 1970 and dramatically changed the availability of pharmaceutical amphetamines. As pharmaceutical supplies of amphetamines became more difficult to obtain, the purity of street methamphetamine declined dramatically, with caffeine and ephedrine often substituted or sold as methamphetamine. Because the production of methamphetamine does not require special knowledge or expertise in chemistry, there began to be a reemergence of the illicit use of methamphetamine in the 1980s.
The use of methamphetamine was confined in the 1980s primarily the West Coast. A number of indicators, including those from the National Institute on Drug Abuse's (NIDA) Community Epidemiology Work Group (CEWG) and a new Multi-site Assessment of Methamphetamine Use, are clearly showing that the abuse of this drug is now spreading throughout the Midwest and into other areas of the country and emerging in cities and rural settings thought previously to be untouched. Not only is it spreading to new areas, but its use is increasing among populations not previously known to use this drug. Recipes for methamphetamine have been available and circulated among numerous sources. In the 1990s, the Internet has increased access to recipes and instructions for producing methamphetamine, and has also contributed to its spread.
The increasing use of this drug is of particular concern because of recent research from a number of sources demonstrating the neurotoxic effects of the drug. In addition, because of sloppy production, what is often sold as methamphetamine can contain a number of toxic contaminants including lead, chloroform, and sulfuric acid. In the 1980's evidence was accumulating that methamphetamine was toxic to dopamine and serotonin containing neurons in animals given relatively high doses. In 1997, it was shown that non-human primates exposed to methamphetamine doses routinely used by human abusers, resulted in profound damage to both the brain's dopamine and serotonin neurotransmitter systems. These effects also appear to be long-lasting, in the rhesus monkey, for example, there are data showing that changes persist for over 3 years. There is now alarming evidence of toxicity in humans. In 1998, using state-of-the-art neuroimaging technology, investigators found that methamphetamine abusers who have been abstinent from methamphetamine for several years show significant decreases in the numbers of brain dopamine transporters, similar to the data that were first seen in non-human primates. These long-lasting neurochemical effects may be partly responsible for the severe behavioral abnormalities that accompany prolonged abuse of this drug.
In addition to characterizing the toxicity, researchers have also been striving to understand the causes of toxicity. Research in cell culture and animal models has proposed several mechanisms of cellular toxicity and has identified many compounds that seem to protect animals against methamphetamine toxicity. NIDA is pursuing the development of these compounds into medications that may be effective in treating methamphetamine addiction.
Understanding how methamphetamine's biochemical and pharmacological actions can lead to cell death is critical to restoring cognitive function to methamphetamine-impaired individuals, developing medications for reversing or treating addiction, and may also have far-reaching effects in the treatment of stroke, Parkinson's disease and other neurodegenerative diseases in which the common neurotoxicity mechanism is operative.
Story of Discovery - 1930's Mystery Solved with Modern Day Technologies: New Prevention Principle Unveiled
What was one of the great mysteries of the prevention research world in the 1930s has been brought to new light with 1990s technology and knowledge. The "Cambridge-Somerville" intervention mystery of the 1930s was finally solved when researchers in the 1990s equipped with videocassettes, sophisticated coding schemas, and other state-of-the art equipment, began to understand why a modern day intervention program that was based on established prevention principles was also showing negative results. The "Cambridge-Somerville" study was designed to counteract the negative influences on boys growing up in high crime neighborhoods. The intensive, individually tailored intervention that involved family support lasted 5 _ years and even by today's high standards, would be considered cutting edge. However, despite the excellent study and program design, the results of a 30-year follow-up evaluation showed the surprising outcome that the intervention actually produced more negative, outcomes (such as a higher prevalence of individuals who were convicted of crime, diagnosed with alcoholism, schizophrenia, or manic depression) in those who received the intervention then those who did not. Also, the greatest negative effects were found with those individuals who were most engaged in the program, another completely unexpected, certainly counter-intuitive result.
Similarly, researchers were completely baffled when the modern day Adolescent Transitions Project in Oregon, a comprehensive school-based prevention program with a very strong parent component, showed negative outcomes for the high-risk youth who engaged in the intervention versus the comparison groups who did not. Researchers had to ask themselves why this was happening. It seemed like they were doing everything right. They were tailoring the program to the needs of the middle and junior school students, they were actively engaging parents in the programs, yet the results were showing that some teens who participated in the intervention used tobacco more frequently, and were rated by teachers as more delinquent than the teens who did not participate in the program. They also found that older youth with the highest initial levels of problem behavior were most susceptible to the negative effect.
To investigate this further, scientists examined the results from other research at the Oregon Social Learning Center, including a study that was researching anti-social behavior in boys by videotaping their interactions with peers. These videotapes revealed a sequence of interactions researchers termed "deviancy training." They observed that teens were inadvertently being positively encouraged through smiles and laughter when references were being made to deviant behavior. Further, when both boys in the pair were characterized as antisocial, almost all positive reactions were to deviant talk. On the other hand, less deviant adolescents often ignored or failed to reward such talk. Researchers began seeing a pattern, they began to suspect that how students were grouped in programs had an effect on the results of the study.
In follow-up research, the intervention was modified to address the problem of deviancy training. Researchers ensured that the groups were carefully supervised to discourage this direct encouragement of problem behavior. Yet, despite the supervision, grouping these boys again resulted in negative effects. Videotapes of the intervention sessions further suggested that age might be an additional factor of importance. Older boys, and more physically mature boys, seemed to be able to mobilize more group attention more effectively than younger, less deviant boys.
Moreover, attention may have come less from the content of discussions and more from dress, behavior, and nonverbal expressions.
These studies have taught us an important lesson -- youth at high risk should not be grouped together because it can worsen problem behaviors including those behaviors related to school and drug use. Realizing this principle, researchers then began to look at research from past studies for similarities with negative effects, including the Cambridge-Somerville intervention.
Researchers realized that the same grouping phenomenon had occurred in that study as well, thus ending the 60-plus year mystery. Moreover, these findings have led to the development of new analytic techniques and observational methods that have produced a better understanding of why the negative effects occurred and what prevention designers can do to protect against them. Determining that youth at high risk for behavior problems should not be placed in prevention programs with other high risk youth is one of the new prevention principles that NIDA-researchers have unveiled. This revelation has implications far beyond the drug abuse community. This is a finding that is relevant to other disciplines as well, including clinical and correctional settings.
Science Advances
Unearthing the Switch: Two Brain Chemicals Have Been Found to be Important in the Transition to Addiction. Although the frequency that cocaine users take cocaine before becoming addicted may vary from several times to several years, there is a certain point at which their use becomes compulsive and they have great difficulty quitting. Determining what happens in the brain at this point has been a major goal for scientists seeking to understand the mechanisms of cocaine addiction. One component of the switch from infrequent to frequent use appears to be the activation of a gene that codes for the production of a protein called delta-FosB. To learn more about the role of delta-FosB in the addiction process, researchers developed a new strain of mice with an extra delta-FosB gene that, when activated, produced large quantities of the chemical in the nucleus accumbens. The researchers found that adding the extra delta-FosB gene caused the mice to become more sensitive to the pleasurable, or rewarding, effects of cocaine, a change that is thought to play an important role in the development of cocaine craving and addiction. This suggests that increases in delta-FosB levels that occur during long-term cocaine administration may be partially responsible for the increase in cocaine reward. But how does delta-FosB make cocaine more rewarding? In studying these animals, the scientists found that switching on the delta-FosB gene increased the production of one of the brain's glutamate receptor subunits designated GluR2. To determine whether an increase in GluR2 production might increase sensitivity to cocaine reward, the researchers transfered a GluR2 gene directly into the nucleus accumbens of one group of mice and found that cocaine reward was dramatically enhanced. Knowing the factors that contribute to the compulsive behaviors that are the hallmark of addiction will enable the design of effective treatment strategies to reverse the long-lasting brain changes that occur as a result of chronic drug exposure.
Long-term Methadone use May Actually Normalize the Addicted Brain. Using data from state-of-the-art imaging techniques (phosphorous magnetic resonance spectroscopy), researchers have found that patients who are on prolonged methadone maintenance for heroin addiction, may have improved neurochemical functioning compared to addicts just entering methadone treatment. Methadone maintenance therapy, one of the most effective treatments for heroin addiction, has been shown in numerous studies to reduce drug use and improve psychiatric symptoms, as well as improve overall health. This study is showing signs that the brains of long-abstinent, methadone treatment opiate abusers actually begin to normalize when compared with shorter duration methadone maintenance patients, particularly when one looks at their metabolic levels. The study demonstrates that the cerebral phosphate metabolites of long-term methadone maintenance patients are similar to those of non-drug users, suggesting that methadone maintenance may allow a normalization of brain function in abstinent opiate addicts over the course of their treatment. Further studies are needed to determine the functional significance of this important observation.
Why Do Some People Find Addictive Drugs Particularly Pleasant? One of the most challenging problems in addiction is to understand why after their initial drug experience some individuals continue to abuse drugs whereas others do not. It has recently been suggested that brain levels of the dopamine D2 receptor, which is involved in the communication among dopamine containing cells, may predict which individuals are more vulnerable to abusing and becoming addicted to drugs. Using positron emission tomography (PET) neuroimaging techniques, scientists have measured both the amount of brain dopamine D2 receptors in the brain as well as measured the subjective responses to the drug methylphenidate in the same individuals. Methylphenidate is a psychostimulant drug that works in the brain in a similar manner to cocaine, but does not have the same powerful euphoric effects that cocaine does. Scientists found that those individuals with relatively lower levels of brain dopamine D2 receptors found methylphenidate to be "pleasant." Individuals with more brain dopamine D2 receptors on the other hand found methylphenidate to be "unpleasant." The findings reported in this study are the first evidence in humans revealing a direct association between dopamine D2 receptor levels in the brain and the pleasurable effects of psychostimulants. That is, for the first time, the number of receptors has been correlated directly with the "pleasantness" of a drug. These findings have significant implications for individual differences in how much a person likes a drug and may represent a critical component in the neurobiological basis for drug abuse and addiction vulnerability.
Substance Abuse Treatment Is Cost-effective. There is a common belief that unlimited substance abuse benefits would dramatically increase health care costs. Because of these concerns, some employers have started to separate mental health and substance abuse benefits. To calculate the impact that substance abuse parity has on health care costs, researchers conducted a study of substance abuse treatment utilization and costs in a number of plans managed by a large managed behavioral health care company. In this analysis, researchers compared "no limit" plans to plans with annual limits on substance abuse treatment. The researchers found that changing even stringent limits on annual substance abuse benefits had only a small absolute effect on overall insurance costs under managed care, even though a large percentage of substance abuse patients were affected. For example, removing an annual limit of $10,000 per year on substance abuse treatment was estimated to increase insurance payments about by $0.06 per member per year. Removing an annual limit of $1,000 was estimated to increase payments about $3.40. This study demonstrated that concerns about rising health care costs are unfounded and that parity benefits under managed care would be affordable.
Chemical Identified That May Block Brain Damage Caused By Methamphetamine. Research has clearly shown that methamphetamine can cause long-term damage to brain nerve cells that contain the neurotransmitter dopamine. Scientists have now identified a chemical that may help combat this damage. This chemical, known, as [D-Ala2,D-leu5]enkephalin (DADLE) is similar to a chemical, enkephalin, normally produced by the brain. Research in animals has now shown that DADLE can block the damage to dopamine containing nerve terminals due to subsequent use of methamphetamine. Additionally, experiments with cells grown in culture indicate that the protective actions of DADLE in promoting cell survival are long-acting and potent. These exciting results identify for the first time a potential means of preventing nerve cell damage caused by drug use. This has important implications for treating drug addicts and the sequelae of problems that result from drug use.
A Chemical Produced in the Brain May Offer New Insights into Tourette's Syndrome and Parkinson's Disease. In the early 1990's researchers isolated a chemical produced by the brain that interacts with the specific sites where )-9-tetrahydrocannabinol, the active ingredient in marijuana, acts. This chemical, named anandamide, was found to be involved in a variety of biological activities, such as analgesia, sedation, memory and cognition. In a recent study using rats, researchers have discovered that anandamide also helps regulate movement. Movement is a very complex function that involves many brain areas and different neurotransmitters, including dopamine. In this study, the researchers determined that in normal rats dopamine caused the release of anandamide from nerve cells. The released anandamide then reduced the amount of dopamine released by other neurons which resulted in a reduction in movement. This system of checks and balances appears to be integral to controlling and fine-tuning muscle movement. These results suggest that anandamide may hold clues to better understanding disorders such as schizophrenia, Tourette's Syndrome and Parkinson's Disease, all of which appear to involve dysregulated dopamine neurotransmission. Furthermore, since all drugs of abuse produce their effects through the dopamine system, an increased understanding of how anandamide regulates and interacts with dopamine may open new avenues for treatments for drug addiction
Chronic Marijuana Smokers Seem to Undergo Withdrawal When They Quit. Two scientific studies published in 1999 suggest that cessation of marijuana smoking may also produce an unpleasant withdrawal state. In one study, researchers provided frequent marijuana smokers with cigarettes treated with the active ingredient in marijuana )-9-tetrahydrocannabinol (THC). After the volunteers smoked these cigarettes in a residential laboratory environment for four days, they reported feelings of "irritability" and "stomach pain" when the cigarettes were no longer available. They also reported feeling less "social" and "talkative" during this abstinence period. In another study, researchers found that long-term marijuana users brought into the hospital and denied access to the drug displayed more aggressive behavior on a computer test of aggression at three to seven days after discontinuing marijuana use. These scientific observations have profound implications for how we think about marijuana smoking. They clearly demonstrate that long-term marijuana users can experience withdrawal symptoms and that effective treatments to alleviate these symptoms are needed. They also suggest that continued use of marijuana may be an effort to alleviate an unpleasant abstinence syndrome. Lastly, these findings suggest that there is a complex set of physical and subjective variables directing the continued abuse of smoked marijuana, similar to what has been found for other drugs of abuse.
Dopamine: More than Just the Pleasure Molecule. Dopamine's role in addiction may be not quite as simple as previously thought, that is as the brain's "feel-good" chemical. Using state-of-the-art technology, researchers can now measure the role of dopamine in drug reward with finer resolution. Voltametry, which uses a specially treated carbon fiber tip to detect minute amounts of neurochemicals, represents a major advance over microdialysis in the measurement of neurotransmitters in the brain. New findings in animals suggest that in addition to promoting feelings of well-being, dopamine also seems to have an alerting function, helping animals to notice what is new in their environment. It may act to make new experiences more pleasurable, that is it may serve as a predictor of a reward or pleasurable sensation, but once the pleasurable task is learned, dopamine's role is diminished. Because dopamine's role may be more varied and complex than previously thought, drug treatment approaches need to be designed that focus on more than just blocking dopamine.
New Insights into Opiate Addiction. Opiate drugs such as morphine and heroin are the most effective pain relieving compounds known. However, their usefulness in treating pain is limited because of the profound tolerance that develops during their chronic use as well as their addictiveness. Opiates have been shown to exert their physiological effects by their ability to activate the brain's naturally occurring opiate receptors. It has been known for some time, that opiates, upon binding to these receptors can cause them to be deactivated and to be removed from the cell surface or "internalized." though the potential relationship between internalization and tolerance has not been clear. Using cell culture technology, researchers were able to calculate a "RAVE" measure for a number of different opiate drugs. RAVE is a measure of the relative effectiveness of each drug at activating the opiate receptor versus the ability of the drug to induce opiate receptor internalization. What they found was that methadone and etorphine, both of which have low propensities to induce tolerance also had low RAVE values. On the other hand, morphine, which has a very marked propensity to induce tolerance has a high RAVE value. In addition, methadone and morphine differ in their abilities to produce addiction. This research suggests that taking into account a drug's ability to both activate the opiate receptor as well as induce receptor internalization enables predictions about its analgesic effectiveness and tendency to produce tolerance.
Treating Chronic Pain With Fewer Side Effects. Although opiate medications such as morphine are critical for the treatment of chronic pain, their usage remains limited by the development of tolerance and physical dependence. One promising area of research attempts to modify opiate compounds so that they maintain their analgesic properties, while reducing the undesirable side effects. This research has lead to the development of a new opiate compound called DIPP-NH2. DIPP-NH2 can both activate and inhibit receptors, the sites in the brain where opiates act, simultaneously; meaning it likely has low abuse potential. When this molecule was tested on laboratory rats, it was found to be three times more potent at producing analgesia than morphine. Furthermore, it produced no physical dependence and less tolerance than morphine when given chronically at high doses. The production of this compound opens exciting new avenues into the treatment of chronic pain and could have far reaching effects for the millions of people who suffer from chronic pain. An additional benefit of this compound is its potential as a research tool. Because it produces analgesia without dependence, it will be a very useful tool in understanding the basic brain mechanisms that are involved in addiction. This could in turn facilitate the development of more effective treatments for addiction to opiates such as heroin.
Gene Therapy for Chronic Pain. Chronic pain is a major health problem that can substantially diminish quality of life and reduce an individual's productivity. It is much more difficult to treat than acute pain which may be because it may cause changes in the brain and spinal cord that actually help to maintain and even increase the pain. Researchers have recently developed a new method of pain control using a novel genetic therapeutic approach. Briefly, researchers applied to the skin of mice a genetically engineered virus that contained genes that code for the production of enkephalins. Enkephalins are chemicals that are naturally produced in the brain and spinal cord and have a function in helping to control pain. The virus was then picked up by nerves and carried to a part of the spinal cord that is involved in sensing pain. Once at this site, the virus began producing a large amount of enkephalins. Following the treatment, the mice appeared normal, and responded normally to acute pain. However, the animals showed a dramatic reduction in their response to chronic pain. While more studies are needed, these results indicate that this type of treatment can successfully treat chronic pain while not impacting an animal's ability to respond to acute pain situations. This approach may eventually lead to a noninvasive, safe, and effective treatment of chronic pain in humans.
Researchers Discover How Long HIV Can Survive in Drug Paraphernalia. Specific information about how long HIV can survive in drug paraphernalia, such as the syringes, cookers, water and filters that are typically used by injection drug users has long been needed. (Cookers are used to dissolve the powder form of drugs, such as cocaine and heroin, into an injectable form.) Using a variety of laboratory simulations and newly developed microculture assays, researchers were able to determine that HIV was found to survive for periods in excess of 4 weeks in blood within the lumen of the syringe. Syringes with detachable needles were found to harbor more blood between their plunger and base, indicating that they may be riskier for HIV transmission than syringes with needles that do not detach. Survival of the HIV in the cookers was found to be dependent on the temperature achieved during preparation of drug solutions. HIV was found to be inactivated once the temperature exceeded on average 65OC. Heating the cookers for 15 seconds or longer reduced viable HIV below detectable levels. This information about the length of time that HIV can survive in drug paraphernalia can be used by the prevention community to decrease the spread of HIV and other infectious diseases in drug users who continue to inject.
Maternal Smoking During Pregnancy Increases The Risk That Offspring Will Have Conduct Disorders, ADHD And Will Use Drugs. Over the years there has been much speculation about the long-term health and behavioral effects of children born to mothers who smoke during pregnancy. In a 10-year longitudinal study, researchers examined the relationship between attention-deficit/hyperactivity disorder (ADHD), major depression, and other illicit substance use disorders to the onset and severity of nicotine dependence. Among other things, the researchers found that female offspring of mothers who smoked 10 or more cigarettes per day during pregnancy were 5 times more likely to develop drug abuse or addiction during adolescence than were offspring of mothers who did not smoke during pregnancy. Among boys, maternal smoking during pregnancy was associated with a 4-fold increase in the risk of conduct disorder. Major depression and ADHD have also been found to contribute to the severity of nicotine dependence in delinquent adolescents. Clinically, the findings underscore the need for smoking prevention and cessation programs in women during pregnancy.
A New Drug Application For a Medication to Treat Heroin Addiction. NIH-supported scientists have been working with a pharmaceutical company to develop a new treatment medication for opiate addiction. Scientists have determined that the partial agonist buprenorphine can be combined with naloxone to produce a tablet, which will safely, and effectively treat heroin and other opiate addiction, have low diversion potential, and be aversive to injection. A number of recent studies have shown that buprenorphine maintenance is an effective treatment for heroin addiction. Expected to be approved by the FDA soon, buprenorphine combined with naloxone will be a major therapeutic advance in the treatment of opiate addiction. This product has less abuse potential than methadone, has a ceiling effect (increasing doses do not produce dose related respiratory depression) against overdose, and will generally induce withdrawal if injected (reducing the opportunity for HIV and hepatitis infection through needle sharing behaviors).
Effects Of Behavioral Therapy For Cocaine Addiction Can Be Long-Lasting. This study provides the first demonstration that using vouchers to reinforce periods of cocaine abstinence during treatment can produce sustained abstinence for one year after the termination of treatment. Scientists have demonstrated that patients who received vouchers for having cocaine-free urines were more likely to have sustained cocaine abstinence during outpatient treatment than a comparative group that received incentives regardless of urinalysis results. This shows the long lasting effects that behavioral treatments can have and the valuable role behavioral therapies can play in treating addictions.
Cost Effective Addiction Prevention Program for Rural Families. Parents can play a critical role in combating adolescent drug abuse. Research has shown that family-based prevention interventions that focus on improving parents' communication and disciplinary skills can help children avoid drug use. A short-term family intervention for general populations called Preparing for the Drug Free Years (PDFY) has been developed that is designed to enhance general parenting skills and discourage child drug abuse. Two studies were conducted to determine the effectiveness of PDFY in rural family settings. PDFY uses five, two-hour, weekly sessions to teach parents how to establish and maintain rules, to be positively involved with the child, and to manage conflict and anger. Parenting behaviors improved in all families that participated in the PDFY program.
Adolescents Who Inhale Volatile Solvents (such as glue or spray paint) Are More Prone To Delinquent Behavior. The use of intoxicating inhalants by adolescents to get high, such as glue, spray paint, and lighter fluid, is a significant and increasing problem in the United States. Over the years several studies have attempted to determine if there were any associations between inhalant use and delinquency. Based on a cross-sectional survey of over 13,000 students in grades 7-12 researchers found that inhalant experimenters and regular inhalant users in grades 9-12 reported more minor criminal activity than other drug experimenters and users who did not use inhalants. Students using inhalants were more likely than those involved with other drugs to engage in some kinds of "trouble behavior," including being suspended from school, missing school due to alcohol or drug use, and getting into trouble at home because of alcohol or drug use. The findings of this study suggest that inhalant use is more strongly associated with delinquency than is use of other drugs.
NIDA Budget Policy
The Fiscal Year 2001 budget request for the NIDA is $496,294,000, excluding AIDS, an increase of $27,145,000 and 5.8 percent over the 2000 level. Included in this total is $4,900,000 additional for the following NIH Areas of Special Emphasis: $2,500,000 for Biology of Brain Disorders, $400,000 for Bioengineering, Computers, and Advanced Instrumentation, and $2,000,000 for Health Disparities.
One of NIH's highest priorities is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while providing new research opportunities. To control the growth of ongoing commitments and support planned new and expanded initiatives, the Fiscal Year 2001 request provides average cost increases of 2 percent over Fiscal Year 2000 for competing RPGs. Noncompeting RPGS will receive increases of 2 percent on average for recurring costs. This strategy will ensure that NIH can maintain a healthy number of new awards, especially for first time researchers.
Promises for advancement in medical research are dependent on a continuing supply of new investigators with new ideas. In the Fiscal Year 2001 request, NIDA will support 366 pre- and postdoctoral trainees in full-time training positions. Stipends will increase by 2.2 percent over Fiscal Year 2000 levels.
The Fiscal Year 2001 request provides for the National Drug Abuse Clinical Trials Network at the same level as in FY 2000 and includes funding for 21 research centers, 192 other research grants, including 3 new clinical career awards, and 78 R&D contracts. The mechanism distribution by dollars and percent change are displayed below:
Budget Mechanism Table
(Total Including AIDS*, Dollars in Thousands)
| Mechanism | FY 1999 Actual | FY 2000 Estimate | FY 2001 Estimate | |||
|---|---|---|---|---|---|---|
| No. | Amount | No. | Amount | No. | Amount | |
| Research Projects | ||||||
| Noncompeting | 791 | $256,613 | 872 | $278,933 | 940 | $325,001 |
| Administrative Supplements | (137) | 8,993 | (107) | 6,550 | (115) | 7,000 |
| Competing | 338 | 102,360 | 352 | 116,221 | 262 | 89,550 |
| Subtotal, RPGs | 1,129 | 367,966 | 1,224 | 401,704 | 1,202 | 421,551 |
| SBIR/STTR | 56 | 11,124 | 59 | 12,761 | 63 | 13,635 |
| Subtotal, RPGs | 1,185 | 379,090 | 1,283 | 414,465 | 1,265 | 435,186 |
| Research Centers | 34 | 50,622 | 38 | 56,239 | 38 | 66,005 |
| Other Research | ||||||
| Research Career Programs | 169 | 18,691 | 175 | 20,200 | 179 | 21,100 |
| Other Research Related | 35 | 17,705 | 43 | 36,994 | 44 | 37,470 |
| (Clinical Trials Network) | (11,000) | (28,700) | (29,000) | |||
| Subtotal, Other Research | 204 | 36,396 | 218 | 57,194 | 223 | 58,570 |
| Total, Research Grants | 1,423 | 466,108 | 1,539 | 527,898 | 1,526 | 559,761 |
| Research Training | 428 | 14,301 | 441 | 15,318 | 441 | 15,600 |
| R & D Contracts | 98 | 64,045 | 97 | 59,901 | 99 | 62,477 |
| Intramural Research | 41,312 | 50,529 | 52,550 | |||
| Res. Management & Support | 31,643 | 33,730 | 35,079 | |||
| Total, NIDA | 617,409 | 687,376 | 725,467 | |||
* Includes funding for AIDS: FY99 - $188,919; FY00 - $218,227; FY01 - $229,173.