Gold Forecasts and Describes Cocaine Vaccine, Smoking Addiction Research

July 1, 1997

In 1962, fewer than 4 million Americans had ever tried illegal drugs. By 1983, that number had risen to 80 million. Drug use peaked in 1985 and dropped until 1992. Since then, use has been increasing steadily, particularly among teenagers. This increase is partially a result of a trend back toward glorification of drug experimentation and legalization, and also because there's a general resurgence of smoking. Whether it's marijuana, tobacco, opiates or cocaine, it's still smoking.

Mark S. Gold, M.D., professor of neuroscience, psychiatry, community health and family medicine at the University of Florida (UF) College of Medicine has for more than two decades been at the forefront of the substance abuse field.

In addition to writing more than 700 articles for medical journals, he founded the first national drug hotline (800-COCAINE) in the United States and is board member of five of the nation's major drug prevention organizations-the American Council for Drug Education, PRIDE, D.A.R.E., National Drug Prevention League and National Families in Action.

An advisor to the White House, Justice Department and White House Office of Drug Policy during the Reagan and Bush administrations, Gold also worked closely with the Drug Enforcement Administration after producing with colleagues the first medical report on crack smoking. An invited participant at the Clinton administration's 1993 National Summit on U.S. Drug Policy, he was appointed as consultant to the White House Office of National Drug Control Policy in 1995.

Gold, an honors graduate of the UF College of Medicine, began his drug research in that institution's department of neuroscience in 1972. His studies of amphetamines and the role of the locus ceruleus led him to further studies of this brain region and other drugs of abuse. While at Yale University School of Medicine, his research culminated in the discovery of clonidine (Catapres), the first nonaddicting, nonopiate treatment for opiate withdrawal, and a development of brain noradrenergic (locus ceruleus) theory for opiate effects and withdrawal-pioneering work which has had impact on two decades of scientific and treatment developments.

In 1984, after interviewing thousands of cocaine addicts, Gold and colleagues proposed a novel dopamine theory to explain cocaine addiction and withdrawal. Like the locus ceruleus theory, this hypothesis remains the predominant theory and has led to new addiction treatments.

Gold has also had a major impact on substance abuse education as author of a series of highly acclaimed primary care medicine textbooks, Drugs of Abuse. Commenting in a review on Tobacco (Plenum 1995), his latest addition to that series, the Journal of the American Medical Association (DuPont RL. JAMA. 1996;275:16.) called Gold "the most prolific and brilliant of the addiction experts writing today."

Today, Gold's research focus is on cigarettes, with emphasis on the different brain systems involved in cigarette smoke versus nicotine, and what that means for improving treatment success. In an interview with the Psychiatric Times, he discussed his overall research and views on substance abuse.

PT: What changes have you seen in substance abuse nation-wide and what underlies those changes?

Gold: In 1962, fewer than 4 million Americans had ever tried illegal drugs. By 1983, that number had risen to 80 million. Drug use peaked in 1985 and dropped until 1992. Since then, use has been increasing steadily, particularly among teenagers. This increase is partially a result of a trend back toward glorification of drug experimentation and legalization, and also because there's a general resurgence of smoking. Whether it's marijuana, tobacco, opiates or cocaine, it's still smoking.

It's clear that drug use and addiction are this nation's No. 1 one public health problem, with cigarette smoking and dependence being the single most common preventable cause of death. Overall, so prevalent are drug problems that it'd be difficult to imagine insulting a patient by asking about tobacco, alcohol and other drugs. Yet even though these drugs produce numerous medical problems commonly treated by physicians, only recently have physicians begun to identify and vigorously treat the causative problem.An important concept that's been poorly studied is age of first use. People use these potent substances earlier and earlier, and there's a chance that effects for early users are quite different than if the same drugs were first used by older people. In younger people, those drugs could induce changes that make continued use more likely. Many neurobiological models could be useful in helping explain why childhood and adolescence are the very worst times for tobacco, alcohol or other drug use.

While we don't know a great deal, we do know that brain cells learn and adapt and can change in a way that makes reversion to predrug state less likely to occur. Brain trauma has effects at the point of trauma and also on all later development that's contingent on that area of the brain. So in younger people, drugs have the capacity to make far greater changes and maybe even retrain the brain in a pathological sense, and that wouldn't be the case were use delayed.

It really does appear that if you didn't smoke a cigarette before the age of 25, the pathological attachment is quite different than if you smoked at age 12. And it can't be coincidence that we've had this tremendous increase in illicit drug use among adolescents almost coinciding with the epidemic in eating and sexual disorders, at the same time neuroscientists are saying drugs of abuse access brain sites normally used for species survival reward.

PT: What was the significance of your early research on cocaine?

Gold: Our experience with patients and dopamine hypothesis reconciled addict and user reports with a neurobiological hypothesis which challenged the prevailing notion that cocaine was neither addicting nor dangerous. In the early '80s, many experts naively believed cocaine was not dangerous and that addiction was defined by the presence of an observable abstinence syndrome. Users' and addicts' experiences changed these ideas and changed the way psychiatrists diagnosed addiction. By the time of the DSM-IV, withdrawal complaints and tolerance weren't even necessary [criteria for substance dependence] and just a small part of the picture.

Researchers and clinicians had believed that cocaine was simply a reuptake inhibitor, and the drug was even being tried as an antidepressant based on that. They thought cocaine increased catecholamines, especially dopamine, and they didn't differentiate acute from chronic use. But we had the benefit of talking to large number of patients, demonstrating prolactin increases in males and giving dopamine challenges. It became clear to us that when cocaine was taken for a long time or as a binge, it produced decreased rather than increased interest in sex, and rather then being euphoric, was anhedonic. So we explained cocaine abstinence on the basis of dysphoria and dopamine depletion.

It's important to understand that addiction to all drugs of abuse is a brain disease, with drugs being taken for positive, specific brain-rewarding effects. Opiates are targeted at endogenous opioid systems, marijuana at endogenous cannabinoid systems, benzodiazepines and alcohol at the GABA receptor complex, and cocaine at the dopamine reuptake transporter. Ultimately, all drugs attempt to gain rapid access to brain areas that produce intense pleasure and reward. These hardwired dopamine, or DA, brain reward circuits can be stimulated in studies and accessed and stimulated by drugs of abuse. So the cause of addiction can best be understood by these brain reward effects, which override negative side effects, toxicities and negative consequences.

PT: What's the significance of these findings from a treatment standpoint?

Gold: Since the target of all drugs of abuse is the brain, the treating physician needs to consider that these targets have been altered by years of potent drug use. No one drinks for the effects of alcohol on the gastric mucosa, nor sniffs cocaine for effects on the nasal septum or smokes for effects on the lung. Changes in brain are both acute and prolonged and in some patients may be permanent. Recent advances involving in vivo voltameter and microdialysis make it possible to monitor synaptic levels of brain dopamine in nucleus accumbens of freely moving animals. These studies show that drugs of abuse are powerful in changing behavior and reprogramming the animal or human subject because they produce more powerful increases in dopamine than any natural rewards, even sex or food.

These potent actions in the brain's primitive motivational circuits evolved and were fixed long before the first occurrence of addiction. The susceptibility of lower animals to drug dependence is a function of prior use, dose and route of administration as well as of the drug itself. So if the drug can get to the primitive mesotelencephalic dopamine reward system in the brain of an animal or a human being, it can cause the organism to pay attention and attribute species-specific survival significance to the drug self-administration event. Cocaine and other psychostimulants are particularly powerful in that they're more likely to be used to death than other rewarding drugs of abuse. This work emphasized the role of dopamine in cocaine abuse, dependence and in other drug addictions.

Treatment models have evolved from a primary focus on detoxification as the sine qua non of treating addiction. But if detoxification is regarded by itself as a stand-alone treatment, then it's not very effective. That's because detoxification is just the first step in a long process of neuroadaptative and behavioral change. Overall treatment must target the drug dependence, relapse, and behavioral, family and social problems, in addition to diseases masked by the drug use and diseases acquired by the addict.

It should also be noted that current detoxification protocols are short-term and targeted at acute abstinence. But protracted withdrawal complaints are recognized for many drugs. Those complaints are quite prolonged and clearly not limited to immediate effects of drug absence. The cocaine addiction model is so important because it emphasizes the dysphoria, relapse and need for addiction treatment rather than detoxification.PT: Given the high toll that cigarettes are taking, what are the best treatments available today and why do so many people fail to quit?

Gold: Smoking is an intensely addicting illness. A typical smoker who inhales 30 cigarettes a day and takes eight to 10 puffs per cigarette smokes at least 240 times a day, or 87,600 times a year, and in toto has smoked in 20 years at least 1,752,000 times before coming in for treatment. If someone injected heroin that many times, there'd be no needle site left. Inhalation is an extremely powerful route of drug self-administration, more similar to intravenous use than oral use, so compelling brain reward and pathological attachment is very strong. But when we see someone smoking, we don't think of a needle sticking out of their arm. We've been desensitized to smoking behavior and aren't as alarmed as we should be when we see it.

We've been very interested in why people fail in treatment. If you're a smoker, you're being told how easy it would be to quit now that there's the over-the-counter gum and patch, you see people all around you who have quit, and there's also the tremendous social stigma. But the fact is, the attachment to the smoking itself is intense, and people trivialize positive effects delivered in smoke and overemphasize the importance of detoxification.

Since physical withdrawal isn't like heroin withdrawal, which is very difficult to ignore, one important advance in thought is that physical withdrawal from nicotine is decreasing in importance as a relevant factor in outcome. The second advance is the idea that the strength of the pathological attachment might be affected by host factors, such as acquisition in utero of smoking preference from a mother who smoked then, induction of changes from starting to smoke in adolescence, or family history or personal history of depression.

It's so obvious to me from all my current research that it's not the smoking patients who are deficient; it's the treatments that are deficient. Whether it's nicotine, opiates or cocaine, when treatments fail the patients, my point of view is the treatments are in need of repair rather than the patient being in need of blame.

Regarding that initial withdrawal, our recent meta-analyses on efficacy of nicotine replacement therapies from nearly 18,000 subjects on randomized trials of nicotine gum, patches, sprays and inhalers have strongly suggested that all are effective smoking cessation aids. Still, relapse rates are high both during and after detoxification, with only about 15% staying abstinent for a year.

Research offers some explanation for this, in that data utilizing positron emission technology demonstrated that nicotine administration isn't equal in all ways to smoking tobacco. Smoking cigarettes induces changes in the brain's monoamine oxidase activity, which suggests smokers get significant antidepressant effects from smoking. So these data help explain treatment resistance and commonplace multiple failures. Many cigarette smokers, like alcoholics and opiate addicts, have a protracted abstinence syndrome lasting a year or more. And finding an antidepressant effect of cigarette smoke may also explain the withdrawal boredom and depression, high prevalence of depressives, and family history positive for depression among smokers.Since nicotine replacement and detoxification is limited in efficacy, non-nicotine medicines that reduce relapse are necessary, including antidepressants like fluoxetine (Prozac) and bupropion (Wellbutrin), nortriptyline (Pamelor, Aventyl), and even naltrexone (ReVia). And as in alcohol and opiate withdrawal, clonidine has been used to reverse autonomic signs and symptoms seen in cigarette smoking discontinuation or nicotine abstinence. Again, as in opiate and alcohol relapse prevention, naltrexone may have an important role. We've been using these relapse prevention treatments to improve the success of our smoking cessation interventions and have finished a second sponsored study of naltrexone in cigarette abstinence. Naltrexone-related decreases in dropouts and relapse would be a welcomed addition to the treatment armamentarium and further support a common neurobiology of addiction and relapse.

I'm also very interested in the idea that one of the reasons people fail is there's no maintenance alternative offered, which some people may need, because as I already said, some changes in the brain resulting from smoking are long-lasting and some may even be permanent. If that's the case, a smoker might ask, "What's the least-risk healthiest alternative at this point given the realities of my addiction?" I think we've minimized severity of cigarette dependence by not testing or giving a maintenance option.

A talk show host used to joke that he started the gum and years later was still chewing it. But it may be that there'd be relatively no negative health consequences of doing that. People are definitely confused about what the difference is between smoking and nicotine. There's no doubt to me that there are some factors in the smoke that have physical effects, including metabolism, which are slower to recover. Nicotine itself-if not in large doses-is not the problem, so what's to say that some people shouldn't be offered nicotine patch or gum replacement for years?

PT: What new developments are on the horizon?

Gold: Regarding cocaine, it's been demonstrated that dopamine systems in general and cocaine's dopamine transporter binding site in particular is necessary for cocaine to produce its psychostimulant effects. Molecular cloning has identified a single gene encoding the dopamine transporter and explaining the binding of cocaine to the carrier protein. Anti-cocaine antibodies targeted at cocaine reinforcement sites on the dopamine transporter may yield a cocaine vaccine. Catalytic antibodies to cocaine facilitate the breakdown of cocaine to inactive ecgonine methyl ester and benzoic acid. So developing bovine and other cholinesterases may provide us with new cocaine metabolizing agents for overdose treatment, and a number of cocaine vaccines are intensively being studied at the present time.

Now this is a major conceptual leap. Until very recently, when experts talked about prevention, they talked about grassroots community organizations, "just-say-no" campaigns, and things like that, so the idea we could have immunological prevention like we have prevention against measles or mumps is such a conceptual leap, and we'll have to adjust to these advances. With inoculations on the horizon, it wouldn't be difficult to think we could have treatment for cocaine overdose on the basis of providing people with cocaine metabolic enzymes, or we could give treatment for marijuana dependence by interfering with marijuana access to endogenous cannabinoid systems, or we could treat nicotine dependence by pharmacological treatment that quickly and effectively returned the brain's nicotine responsive system to the state it was before the first cigarette. And all these are things being researched now in one form or another. To take it even further, positive effects of these dangerous drugs of abuse at the same time are being studied and will yield a whole new generation of new and important treatments for medical illnesses for which no effective treatment exists. For example, research suggests that nicotine has a positive effect, especially during critical periods in facilitating flow of information, and people are now doing animal studies using nicotine gene transfer for memory enhancement and possible applications to Alzheimer's disease or other brain disorders. So science gives us the potential to dissect out the positive and turn that into a therapeutic agent, without the smoke.

Anyway, the good news is that we are learning all the time, and more often than not, recognizing that addiction is a brain disease and that treatment after detox makes one- and five-year abstinence more likely to occur.