Biennial Report of the Director

Research in Diseases, Disorders, and Health Conditions
Chronic Diseases and Organ Systems
Substance Abuse and Addiction

Nearly four decades of research supported by NIH have proven addiction to be a complex brain disease characterized by compulsive, at times uncontrollable, drug craving, seeking, and use that persists despite potentially devastating consequences. Once addiction takes hold in the brain, it disrupts a person's ability to exert control over behavior, reflecting the compulsive nature of this disease. In fact, many of the drug-induced brain adaptations can be long lasting, which is, in part, why addiction is considered a chronic disease. And like the more classic chronic diseases (e.g., diabetes, hypertension, and heart disease), most addicted patients require long-term treatment, and relapse (or symptom re-emergence) may occur during the treatment or recovery process.230

NIDA’s and NIAAA's diverse research portfolios, reflected in their strategic plans,231 are geared toward preventing the initiation of drug and alcohol use and their escalation to addiction; developing successful treatments for drug and alcohol abuse and addiction; and improving treatment accessibility and implementation. NCI also supports research in this area, particularly with regard to smoking cessation and tobacco control. In addition, research on the cycle of substance abuse naturally extends to the critical research needed to address the medical (e.g., HIV, fetal alcohol syndrome), social, and legal consequences of both substance use in the short-term, and the disease of addiction.

Research on the prevention of substance abuse and addiction includes research on genetics, development, and basic neurobiology, as well as the effects of environment and social/policy interventions on the risk of drug and alcohol use initiation and its transition to addiction. Large-scale epidemiological studies (over 40,000 respondents in a data collection cycle) such as NIDA's Monitoring the Future Survey of 8th, 10th, and 12th graders and NIAAA’s National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) provide information on substance use and co-occurring conditions that can help to inform prevention efforts to target the areas and populations of greatest concern.

In terms of genetics, research shows that about half of an individual's risk of addiction depends on his or her genes and the dynamic interactions between genetics and the environment. Locating and identifying the individual genes that affect risk for substance use and addiction can help tailor prevention approaches and identify targets for medications development. A compelling example was the discovery of a cluster of nicotinic acetylcholine receptor genes on chromosome 15, implicated in early initiation of smoking, the transition to nicotine dependence, and vulnerability to lung cancer and peripheral artery disease. The alpha 5 nicotinic receptor gene within this cluster was identified as a potential medication target and shown to be involved in nicotine’s aversive properties (e.g., withdrawal symptoms, which are a major trigger of relapse in tobacco users). 

NIDA is supporting research designed to uncover neural correlates of risk and protection that influence brain development and substance use trajectories. For example, using functional magnetic resonance imaging (fMRI), the brain can be scanned in its resting state to generate maps of regions that operate together (i.e., functionally connected). Recently created resting state fMRI maps of healthy volunteers will help establish critical benchmarks against which researchers will be able to compare patients with brain disorders or identify those at greater risk for addiction and other psychiatric disorders based on telltale “signatures.” Such signatures, or “biomarkers,” could become the basis of new diagnostic approaches that allow for the early detection and/or monitoring of psychiatric disorders, including addiction. 

Abuse of prescriptions drugs, primarily opiate pain medications, ranks second (after marijuana) among illicit drug users. Notably, unintentional poisoning deaths involving prescription pain relievers has more than quadrupled from 1999 through 2009 and now outnumber combined deaths involving heroin and cocaine. NIDA supports a variety of strategies to prevent prescription drug abuse, including epidemiological studies of the patterns, trends, and motivations underlying prescription drug abuse; development and testing of prevention interventions that have an impact on prescription drug abuse; studies of the effectiveness and impact of prescription drug monitoring programs; and development of pain medications with diminished abuse potential. The latter could reduce the need for highly addictive opioid medications, along with their availability for diversion and abuse.

Early identification of young people at risk for drug and alcohol use as well as identification of those already drinking or using drugs are key to the prevention of more serious problems later. NIDA and NIAAA will continue to support research evaluating the effectiveness of screening, brief intervention, and referral (SBIRT) for alcohol and other drug use in pediatric and primary care settings. In 2011, NIAAA released a simple, easy-to-use, developmentally appropriate, and empirically based alcohol screening guide.232This guide is helping health care practitioners identify children at elevated risk for using alcohol as well as those children and adolescents who have already experimented or are more heavily involved with alcohol.

NIH research is also focused on reducing college drinking and drug abuse and their many social and health consequences, including cognitive impairment, poor academic performance, assault, drug and alcohol poisoning, injuries, drunk and drugged driving, addiction, and even death from overdose. Research encompasses epidemiological surveys of college populations, as well as individual and environmental approaches to reducing substance use and associated consequences.

Treatment approaches under investigation include research on development of medication and behavioral treatments, screening, and intervention practices, as well as comparative research to evaluate the effectiveness of treatment strategies for addiction.
Despite the enormous burden that drug abuse and addiction exact on our society, few medications are yet approved to treat substance use disorders. This disconnect has made the development of medications a top priority for NIDA. NIDA’s strategy in this regard has been to “de-risk” compounds so that they can become attractive to the pharmaceutical industry. To accelerate clinical trials for medications development, NIDA is offering greater up-front support to grantees for a shorter period of time. This shift was prompted in part by the highly successful clinical trials of Probuphine, supported using ARRA funds. Probuphine is a buprenorphine medication implanted under the skin, which allows continuous medication delivery for six months after a single treatment that is expected to improve adherence and reduce the possibility of diversion. Another strategy is a novel public-private partnership to develop, test, and bring to market safe and effective anti-smoking medications. NIAAA has made substantial progress in testing potential new medications for alcohol dependence. The inclusion of DNA collection and analysis as part of clinical trials makes it possible to move treatment for alcohol dependence closer to personalized medicine.

230 See Drugs, Brains, and Behavior, The Science of Addiction: https://www.drugabuse.gov/publications/science-addiction.
231 For more information, see https://www.drugabuse.gov/about-nida/2010-strategic-plan and https://www.niaaa.nih.gov/AboutNIAAA/Interagency/Pages/progressreport.aspx.
232 For more information, see https://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/YouthGuide.

Behavioral treatments continue to be a critical component of addiction treatment. For example, in the largest trial of its kind, NCI-funded researchers from the Fred Hutchinson Cancer Research Center found that telephone counseling using motivational interviewing and cognitive behavioral approaches significantly improved six-month smoking cessation rates in older teens. This finding is noteworthy, given that 20 percent of American high school seniors smoke cigarettes, and few strategies have been effective in sustaining cessation among teen smokers. NHLBI, NCI, and NIDA have also partnered to co-fund research on smoking cessation in hospitalized patients, and NCI recently funded two special initiatives to improve effectiveness of smoking cessation interventions among low-income adults and prevent and reduce smokeless tobacco use. Finally, NIDA is supporting research to expand the availability of behavioral therapies by developing interventions using alternative delivery formats, such as Web-, computer-, PDA- or text-based modalities, all of which may benefit hard-to-reach populations and increase access to treatment options for millions of smokers.

Recognizing that only a small percentage of individuals with alcohol or drug abuse and addiction problems seek help, NIDA and NIAAA are facilitating the implementation of substance abuse screening and brief intervention into the primary healthcare setting. In addition to its youth screening guide, NIAAA has developed and disseminated its Clinician's Guide: Helping Patients Who Drink Too Much233 that provides standard guidelines for SBIRT in primary care and mental health settings. Through the NIDAMED initiative234—NIDA’s outreach to practicing physicians, physicians in training, and other health professionals—NIDA continues to encourage physician screening of tobacco, alcohol, and illicit and prescription drug abuse. NIDA’s Web-based Drug Use Screening Tool (now mobile and accessible via smartphones and tablets) provides a single question Quick Screen to identify recent patient drug use, followed by the NIDA-Modified Alcohol, Smoking, Substance Involvement Screening test, which guides clinicians through a series of screening questions, and based on the patient’s responses, generates a substance involvement score that suggests the level of intervention needed.

NIDA’s portfolio includes a significant investment in effectiveness and comparative effectiveness research that encompasses community treatment programs as well as the criminal justice system, where drug abuse problems are widespread. NIDA’s Drug Abuse Treatment Clinical Trials Network plays a key role in testing evidence-based treatments in community settings, optimizing their utility and cost-effectiveness and fostering their adoption. NIDA is taking a similar approach to enhance treatment for drug-addicted individuals within the criminal justice system through its Criminal Justice-Drug Abuse Treatment Studies network, an inter-agency collaboration aimed at bringing proven treatment models into the criminal justice system to help stop the vicious cycle of drug abuse and crime.

The study of the medical and social consequences of drug abuse and addiction requires a considerable continuing scientific investment in several areas. HIV/AIDS remains one of the most serious medical consequences of drug abuse, and its link goes well beyond injection drug use, because intoxication or addiction often leads to impaired decision making and/or risky sexual behaviors. Thus, NIDA supports research to improve HIV prevention among drug abusers, enhance screening and treatment access for HIV/AIDS and other co-occurring conditions, as well as uncovering and preventing any potential interactions between drugs of abuse, HIV/AIDS disease processes, and the medications used to treat both. For example, extensive research has demonstrated that drug abuse treatment is HIV prevention. Similarly, research is now showing that HIV treatment is also HIV prevention, in that patients treated with HAART not only have better health outcomes, but their decreased viral load and infectivity translates into decreased HIV transmission and incidence on a population level. A priority research area for NIH is to create the infrastructure and linkages needed to implement the “Seek, Test, Treat, and Retain” strategy, which seeks out high-risk, hard-to-reach vulnerable populations (e.g. substance abusers), tests them for HIV, begins treatment in those who test positive, and retains patients in treatment and monitors their care. Large-scale studies have revealed a high prevalence of alcohol use, abuse, and dependence among HIV-infected patients both in and out of care. NIAAA will continue to support research that develops and tests coordinated interventions to reduce alcohol use and alcohol-related consequences in HIV-impacted populations.

Virtually every organ system in the body is vulnerable to damage induced by excessive or chronic alcohol use, damage which results in a range of medical conditions that include liver disease, pancreatitis, heart disease, fetal abnormalities and brain damage. Liver disease claims 37,000 lives annually; alcohol is the underlying cause for approximately 40 percent of these deaths. In 2008, alcoholic liver disease was responsible for nearly 1 in 5 liver transplants in the U.S. NIAAA continues to support research on the underlying mechanisms of alcohol induced tissue and organ damage to identify potential targets for treatment, inform strategies to prevent damage and improve the prognosis for alcohol-related liver disease.

Given the prevalence of drinking, especially binge drinking among adolescents, the association between early alcohol use and later alcohol dependence, and other concerns about the effects of alcohol on the developing brain, NIAAA has funded a combination of human and animal studies to better understand how alcohol affects adolescent brain development and function.
Exemplary recent advances in addiction science include the development of a nicotine vaccine. Although studies have demonstrated proof of concept for nicotine vaccines, the vaccines’ inability to generate a sufficiently strong immune response has hindered their success. A 2011 winner of NIDA’s Translational Medications Avant-Garde Award is developing and testing a novel vaccine that induces a strong immune response against nicotine without the need for chemical enhancers. This innovation could result in a less expensive vaccine with fewer side effects. The vaccine will be administered intranasally, and is expected to enter clinical trials within the next five years.

Every hour, a baby is born suffering from opioid withdrawal, which can lead to multiple adverse maternal and neonatal consequences. Better treatment options could improve public health and reduce associated medical costs. To that end, a NIDA-supported study found that buprenorphine results in 43 percent less time in hospital, 60 percent shorter treatment duration, and 89 percent less morphine administered for withdrawal symptoms in neonatal abstinence syndrome compared to methadone. If buprenorphine were adopted as the standard of care for women of childbearing age, it could result in a savings of nearly $260 million per year.235

A cost-benefit analysis of the Communities That Care (CTC) drug abuse prevention system found long-term reductions in drug use and other risky behaviors as well as monetary benefits relative to the cost of conducting the intervention–a savings of between $5 and $10 for every $1 invested, with returns that increase over time. Benefits stem from anticipated reductions in smoking-related mortality, improved health, lower medical expenses, and lower criminal justice system and crime victimization costs over the life course of program participants.236

A potential approach to treating cocaine addiction (or overdose) involves a naturally occurring enzyme called butyrylcholinesterase (BChE), which can metabolize, or convert, cocaine into other compounds through a chemical process called hydrolysis. Researchers have previously created BChE-based compounds with enhanced cocaine-metabolizing properties and have now extended their effectiveness though use of a virus (modified with the DNA for producing the cocaine-metabolizing enzyme) as a delivery method. Over a 6-month period, cocaine-dependent animals injected with the DNA-modified virus did not engage in cocaine-seeking behavior even when primed with cocaine injections, and they still had high levels of the enzyme in their bodies at the end of the study. Using a viral delivery system for a cocaine-metabolizing enzyme shows promise as a way to prevent relapse in cocaine addiction, particularly if combined with cocaine vaccines currently under study237

Most studies examining treatments for opioid dependence have been conducted with heroin-addicted patients at methadone clinics, so little data exist on treatment for patients addicted to prescription pain relievers, especially treatment delivered in the offices of primary care doctors. To help address this issue, NIDA's Clinical Trials Network launched the Prescription Opioid Addiction Treatment Study in 2007, which took place at 10 treatment sites around the country. In the study, more than 600 treatment-seeking outpatients addicted to prescription opioids received Suboxone (buprenorphine plus naloxone) in combination with substance abuse counseling sessions or brief standard medical management, in which physicians evaluated treatment effectiveness and recommended abstinence and self-help participation. While no difference occurred relative to the behavioral treatments, approximately 49 percent of participants reduced prescription pain reliever abuse during Suboxone treatment. However, this success rate dropped to 8.6 percent once the Suboxone was discontinued, indicating that medication maintenance is indicated for this population and that more research is needed to determine the required duration.238

233 See NIAAA Clinician’s Guide: Helping Patients Who Drink Too Much, https://www.niaaa.nih.gov/Publications/EducationTrainingMaterials/Pages/guide.aspx.
234 For more information, see https://www.drugabuse.gov/medical-health-professionals.
235 Jones HE, et al. N Engl J Med. 2010;363(24):2320–31. PMID: 21142534.
236Hawkins JD, et al. Arch Pediatr Adolesc Med. 2012;166(2):141–8. PMID: 21969362.
237 Anker JJ, et al. Biol Psychiatry. 2012;71(8):700–5. PMID: 22209637.

NIAAA supported a study to determine if the medication ondansetron, which blocks the transporter for the neurotransmitter serotonin, could reduce problem drinking in alcohol-dependent individuals. Ondansetron is currently used to treat nausea and vomiting, often following chemotherapy. Variants in the gene encoding the serotonin transporter, designated as LL and TT, were previously shown to be associated with heavy drinking. The study showed that subjects with the LL genotype who received ondansetron reduced their average number of daily drinks and had significantly more days of abstinence, relative to those who received placebo. Ondansetron’s effects were even more pronounced among individuals who possessed both the LL and TT gene variants, while subjects who lacked the LL variant showed no improvement with ondansetron.239

The accumulated scientific knowledge derived from these studies and many many others will be used to transform the way addiction is treated and how to prevent drug abuse or its escalation to addiction. Some exciting initiatives include:

NIAAA's Strategic Plan240 includes a focuses on a wide range areas. The following are a few examples:

A new funding opportunity announcement will promote research on 1) how chronic and acute alcohol consumption affect behavioral regulation processes at the epigenetic, cellular, systems (neurocircuitry), and behavioral levels; 2) how these effects lead to the propensity to develop alcohol dependence; and 3) the influence of genetic and environmental factors on behavioral regulation processes contributing to alcoholism risk.

238 Weiss RD, et al. Contemp Clin Trials. 2010;31(2):189-99. PMID: 20116457.
239 Johnson BA, et al. Am J Psychiatry. 2011;168(3):265-75. PMID: 21247998.
240 For more information, see https://pubs.niaaa.nih.gov/publications/StrategicPlan/NIAAASTRATEGICPLAN.htm.