by Floyd E. Bloom, M.D.
Professor emeritus, Department of Molecular and Integrative Neuroscience, The Scripps Research Institute
Director, Alkermes, Inc.
Director, Elan Pharmaceuticals, Inc.
No advances in brain research this year match the importance of those gains made in substance abuse research and treatment, detailed in the following chapter. Consider the recent development of several medications that can help drug-dependent individuals reduce their consumption of almost all of the legal and illegal drugs that humans administer to themselves. Such a feat merits special status even among the year’s biggest scientific findings. But the subject also has several important lessons to teach us about the process by which researchers uncover the brain mechanisms affected by drugs, and about the role of experience in developing an addiction. In addition, scientists’ improved understanding of the natural history of the disease of addiction—the average age of onset, the duration of dependence with or without treatment, and the influence of genetic and environmental factors in prolonging or shortening dependence—may help individuals decide when to seek treatment, and how.
Finding the Right Receptors
Recent surveys from the National Institutes of Health indicate that more than 22 million Americans have significant substance abuse problems, but fewer than 25 percent of these people receive treatment. More than 80 percent of federal and state prison inmates have been incarcerated for alcohol- or drug-related offenses. Those not treated while in prison are almost certain to return to addiction upon release.
Interest in drug addiction rose as a result of the intense use of heroin and marijuana by enlisted personnel in the Vietnam War, a trend that led President Nixon to create the Special Action Office on Drug Abuse Prevention in 1971. That step led the National Institute of Mental Health to increase research into both alcoholism and other forms of drug abuse. Epidemiological studies of the soldiers revealed that many of them were too young to purchase alcoholic beverages, whereas pure heroin and marijuana were cheap and readily available. At the time, scientists couched what little they knew about the intoxicating effects of beverage alcohol (ethanol) and the illicit addictive drugs such as heroin, cocaine, and marijuana in terms of indirect actions on the six neurotransmitters that were then under study (acetylcholine, dopamine, norepinephrine, serotonin, glutamate, and gamma-aminobutyric acid—GABA).
The newly stimulated research into addictive drugs first focused on the nature of the receptor at which opiate drugs initiated their effects in experimental animals. Once that receptor had been well characterized by several highly competitive groups of neuroscientists, some imaginative researchers began to consider why the brains of humans possessed such a drug receptor. In less than five years that train of thought yielded an astounding discovery: the opiate receptors existed because they represented the sites of action of previously unknown neurotransmitters, then termed “endorphins”—endogenous (naturally occurring) morphine-like substances. Eventually, scientists defined three separate endorphin gene families, expressed in three separate families of neuronal circuits together with three major kinds of endorphin receptors.
Attention Shifts to Alcoholism
These discoveries had two enormous effects on the neuroscience field. Some scientists took the discovery of an unknown transmitter whose receptors interacted with opiates as reason to suspect that other powerful central nervous system drugs, such as marijuana and benzodiazepines (drugs used to treat anxiety), produced their effects via receptors for other unknown transmitter systems in the brain. Not surprisingly, researchers soon identified endogenous cannabinoids, neurotransmitters whose cannabis receptors permit the actions of marijuana, while the effects of benzodiazepines were later attributed to a specific combination of the subunits that compose the receptors for GABA.
The second consequence of the discovery of the endorphin signaling systems concerned the scientific attention paid to alcoholism. Potent and selective antagonists that block opiate receptors had already been developed as a means to treat cases of opiate overdoses and addicts in federal prison hospitals. Experimentalists then began to look at other drugs whose basic workings were not yet understood, including alcohol.
Alcohol research in the 1970s suffered from a lack of interest from researchers. Compared to the potency of other sedative drugs, alcohol was considered quite weak in terms of potency, as grams of alcohol were required for the anxiety-reducing effects and tens of grams for the intoxicating effects. Yet, by the early 1980s, several groups of researchers had reported that opiate antagonists would suppress alcohol self-administration in animal models and would reverse the effects of low doses of ethanol on neurons in brain tissue samples.
These studies on alcohol then converged with scores of related studies that highlighted specific regions of the brain as a drug reward circuit—the dopamine neurons of the substantia nigra and a small cluster of neurons in the anterior hypothalamus known as the nucleus accumbens. These studies, well covered in the chapter that follows, replicated highly consistent findings that opiate antagonists could reduce alcohol self-administration in animal models. The results emboldened clinicians to try the drugs on alcohol-dependent human subjects, who evidenced an almost complete lack of side effects. Eventually, the FDA approved the use of opiate antagonists and other drugs that reduce the pharmacological effects of alcohol on cells for the clinical treatment of alcohol dependence.
Fighting Addiction Misinformation
To return to the enlisted men of the Vietnam War: In the 1970s, and indeed even now for many who consider themselves informed, drug addiction was considered by law enforcement officers and the criminal justice system to be instant and permanent, inducing a craving so powerful that no conscious effort could overcome it. To those addicts in withdrawal, overtly criminal behavior to acquire drugs was considered justifiable. However, when large samples of soldiers were reinterviewed one and three years after their service and compared with an age-matched group, the results were astounding. While initial interviews supported by urine testing indicated that nearly 80 percent had used marijuana, that half of all enlisted men had tried morphine or opium, and that nearly 20 percent were symptomatic enough to have been called dependent while in service, one year later only 5 percent of those who were addicted to opiates in the war zone were addicted in the United States. Of those not addicted, virtually none had received any treatment. Lee Robbins of Washington University in St. Louis, the lead epidemiologist of those studies, concluded that the availability of cheap drugs accounted for the high rates of drug use in wartime. Clearly, the common view of the addict—once addicted, addicted for life—was erroneous. Addiction was not a lifelong dependency; it could be interrupted by a change in environment. Perhaps with the right agent treatment was possible. For the veterans who exhibited deviant social behavior before serving in Vietnam, however, the rates of re-addiction and treatment failure were as high as in the civilian and federal prison populations.
In the case of alcohol dependence, the lifetime prevalence approaches 20 percent in the general population. (The genetic basis for vulnerabilities and resistance to addiction are another important, active area of work, but that is beyond the scope of this essay.) With regard to licit drugs, among the causes of deaths in the United States as listed in the Physicians and Lawyers for National Drug Abuse Policy 2008 report, smoking-related deaths are number one, and alcohol-related deaths are number three, after cancer.
The Road to Better Treatment
The development of drugs to treat alcohol-dependent subjects has opened the door to the search for medications to treat other dependencies. However, most physicians have never received training in the diagnosis or treatment of dependent patients. Subjects arrested for driving while intoxicated and brought to emergency rooms are placed in a double bind, since most health insurance policies by law in many states will not cover treatment of intoxicated subjects. Most physicians—if they have the time to speak with their patients, diagnose the dependency, and then decide to embark on a therapeutic course— may not believe that medication is either helpful or required, holding the view that counseling alone, by some third-party practitioner, will suffice. While opiate antagonists combined with group therapy in clinical trials have been reported to be quite effective for dependent populations who seek treatment, far more addicted individuals have not yet opted for treatment. Gaining access to a health care system unaware of the treatments that could be implemented is not much help. However, sufficient attention from the patients who recognize the problem in themselves or a significant other may ultimately bring these advances of medical treatment more effectively to the population at risk. Clearly this field has progressed significantly in recent years, thanks in no small part to biomedical research.