Cerebrum Article

Glimpsing Promise in the Drug We Love to Hate

Smoking is the most lethal common practice human beings have inflicted on themselves. Linked, seemingly inextricably, with this tragedy is nicotine, with its psychoactive, powerfully addictive properties. Powerful they certainly are—affecting neurotransmitters that regulate some of the brain’s basic functions—but scientists are now examining nicotine’s potentially positive effects when brain functions such as memory processing falter as a result of neurological or psychiatric disease. Can the drug with the world’s worst image also do some good? Bioethicist Mark Parascandola probes the problems along with the apparent potential.

Published: April 1, 2003

During its long history in human society, and before evidence of its lethal health consequences began to mount in the 1950s, tobacco smoking had its proponents. In the 16th century, North American explorers reported that Native Americans believed tobacco to have beneficial cognitive properties: “The smoke, they say, gives them intelligence, and enables them to see clearly through the most intricate matters.”

As a result of Christopher Columbus’s voyage to America in 1492, tobacco was introduced into Europe. Nicotine—the toxic alkaloid found in tobacco—derives its name from Jean Nicot, a French ambassador to the Portuguese court from 1559 to 1561. The story is that the 30-year-old diplomat paid a visit to a famous Portuguese horticulturalist, Damiao de Goes, who gave him leaves from a strange plant reputed to have marvelous effects. Nicot dried the leaves, crushed them, and sent the powder back to the queen mother, Catherine de Médicis, who suffered from severe headaches. Reportedly, the remedy worked, and the tobacco plant quickly gained popularity in France, making Nicot something of a celebrity. The plant came to be called the Herb of Nicot. Interestingly, tobacco had been brought to France a few years earlier, by one André Thevet, but had gained little attention. Thevet had not described it as a medical remedy; Nicot, by contrast, engaged in some early brand-name marketing.

Early claims about tobacco, pro and con, rested solely on anecdotal evidence. Tobacco users reported that they could think more clearly and felt more relaxed after smoking, while opponents reported that smoke was noxious and unpleasant. Neither side had any medical evidence. It was not until after World War II, with the introduction of advanced methods for analyzing large-scale epidemiological data, that scientists could demonstrate conclusively that smokers were at higher risk for many deadly diseases, particularly lung cancer.

A turning point came in 1964 with the U.S. Surgeon General’s report, Smoking and Health, an indictment of cigarette smoking that linked it to lung cancer, chronic bronchitis, laryngeal cancer, and probably heart disease, and urged “appropriate remedial action.” Tobacco smoke contains more than 4,000 different chemicals, many known to be toxic (such as carbon monoxide, formaldehyde, and ammonia), and a variety of cancer-causing agents (such as nitrosamines, benzo[α]pyrene, benzene, vinyl chloride, and nickel). Some of these occur naturally in the tobacco plant; others are produced during the process of combustion. Nicotine is not directly implicated in the dire health effects of smoking, but it is the most pharmacologically active ingredient in tobacco smoke and the primary agent responsible for addiction to smoking.

Nicotine’s strongest effects are on the nervous system, increasing heart rate and blood pressure. At very high doses these effects can be dangerous, even fatal, but so far there is no conclusive evidence that modest doses of nicotine—like those received from a nicotine patch—are detrimental to health. And while nicotine, like any drug, can have unwanted effects, there may be some therapeutic situations, such as in using a nicotine patch to quit smoking, where benefits outweigh the potential risks.

Interestingly, the 387-page Surgeon General’s report included a one-page discussion of “beneficial effects of tobacco,” which lobbyists like Clarence Little of the Tobacco Industry Research Committee had fought hard to insert. Epidemiological studies did indeed show some modest benefits, notably improved bowel habits and reduced obesity, but these seemed inconsequential in the shadow of the hazards described in the other 386 pages. There were also published reports describing cognitive and emotional benefits of smoking, but many derived only from the clinical impressions of individual doctors. The authors of the Surgeon General’s report were skeptical: “The purported benefits on mental health are so intangible and elusive, so intricately woven into the whole fabric of human behavior, so subject to moral interpretation and censure, so difficult of medical evaluation and so controversial in nature that few scientific groups have attempted to study the subject.”

This was a fair characterization at the time. It has taken scientists several decades to begin to understand how nicotine affects the brain by binding to specific receptors (called nicotine cholinergic receptors) on the surface of brain cells. This stimulates the cells to release neurotransmitters such as acetylcholine, epinephrine, and dopamine. Epinephrine provides the fast “kick” to the smoker, causing a release of glucose and an increase in heart rate, blood pressure, and breathing. Dopamine is fundamental to reward and pleasure pathways in the brain and is boosted by addictive drugs such as cocaine and heroin, as well as by nicotine.

The fast action of inhaled nicotine makes cigarette smoking (along with direct intravenous use) the most addictive route for administering nicotine, which reaches the smoker’s brain less than 10 seconds after inhalation. Because inhaled nicotine reaches the bloodstream so quickly, it produces an intense but short-lived spike in its levels. In contrast, nicotine from a skin patch works its way into the bloodstream slowly, over about three hours, and never reaches the peak levels that inhaled nicotine does, even when the overall dose is the same. Nicotine nasal spray and nicotine chewing gum fall somewhere in the middle. Not surprisingly, smokers report that their habit is highly reinforcing (they want to keep repeating the experience), but they do not have the same enthusiasm for the nicotine patch.

Stressful or Relaxing?

Even today, smoking has its share of defenders. Richard Klein, author of Cigarettes Are Sublime (1993), managed to quit smoking, but only after composing this tribute to its pleasures. Cigarettes, he wrote, “are a source of consolation, particularly in times of loss. They provide a powerful antidote to anxiety.” Many smokers seem to agree—even while reporting that they would like to quit. Scientists have been puzzling over these perceived psychological effects since at least the 1960s.

Sociologist Daniel Horn at the U.S. National Clearinghouse for Smoking and Health, a federal government office opened after the 1964 release of the first Surgeon General’s report, conducted some early research on why people smoke. He and his colleagues asked 2,000 smokers whether they agreed with various statements about their smoking habits. Eighty percent agreed with statements such as “Smoking cigarettes is pleasant and relaxing” and “When I feel uncomfortable or upset about something, I light up a cigarette.” For many, it seemed, smoking was a way to reduce feelings of anxiety and anger.

Skeptics suggested another interpretation. Perhaps this perceived benefit of smoking was simply the result of reversing the effects of nicotine deprivation. After a smoker has gone a few hours without a cigarette, it is no surprise that smoking lifts his mood. Smokers often report that the first cigarette of the day, following a night of abstinence, is the most satisfying. Skeptics also pointed to a paradox in the claim that smoking has major calming properties since, in the body, nicotine appears to act more as a stimulant than a sedative, increasing the smoker’s heart rate and breathing through its effects on the nervous system.

Only later did studies suggest a potential mechanism by which nicotine may act in the brain to reduce feelings of stress and anxiety. David Gilbert, a researcher at Southern Illinois University who worked for the R. J. Reynolds Tobacco Company early in his career, has been studying the behavior and attitudes of smokers for several decades. He and his colleagues report that nicotine appears to quiet areas of the brain’s right hemisphere that are active in anxious, emotionally unstable, or depressed individuals. We know, in fact, that the right hemisphere is associated with emotional responses to stressful situations. By inhibiting negative emotional responses such as anxiety, nicotine users may be better able to carry out left hemisphere-based problem-solving that would otherwise be overwhelmed by negative emotions. Psychologist John Kassel at the University of Pittsburgh suggests that “nicotine may act so as to reduce individuals’ attention to internal states (cognitions, affect) that, if otherwise attended to, would promote feelings of stress or tension.”

But consider a puzzling piece of counter evidence. Standard psychological testing scales reveal that, on average, smokers actually experience higher stress levels than nonsmokers. If smoking is relaxing, why are smokers more stressed? One hypothesis is that smokers differ constitutionally from nonsmokers. In others words, people with higher anxiety levels to begin with may be more likely to become habitual smokers (and addicted to nicotine). Indeed, smokers do differ from nonsmokers in many ways. Epidemiological studies have shown that smokers are more likely to drink alcohol and coffee, be involved in traffic accidents, change jobs, get divorced, and fail in school. No one suggests that smoking causes these things; the idea is that there are differences, on the whole, between people who smoke and people who do not. In this context, it may make sense that those who are already jittery would be more inclined to take up smoking as a way to bring them back to “normal.” An alternative hypothesis is that addiction to nicotine may increase overall stress levels, which are then relieved (briefly) by a nicotine fix. Despite what smokers themselves perceive, the psychological benefits from smoking remain elusive.

Smoking and Cognitive Performance

Shortly before the smoking and health debate began in earnest in the early 1950s, the American Tobacco Company was financing studies at the Medical College of Virginia in Richmond on the biological effects of nicotine. Pharmacologists Paul Larson, Jack K. Finnegan, and Harvey B. Haag were aware of some isolated reports in the medical literature describing the effects of smoking on vision—a clue that something in cigarette smoke affects the nervous system. To test the effect of smoking on visual acuity and alertness, they designed an experiment using a well-known phenomenon called flicker fusion frequency. Our optical nervous system can perceive that a light is flickering on and off; if the flickering is too rapid, however, we perceive the light as continuously on. This “flicker fusion” occurs sooner (at a slower rate of flickering) when the observer is tired and later (at a faster rate of flickering) when the observer is given a stimulant drug. Larson and colleagues found that smokers could detect a faster flicker immediately after smoking a cigarette, but that this effect was most pronounced when the cigarette came after several hours of abstinence (for example, the first cigarette of the day). They also found that the effect did not occur when the subjects smoked a low-nicotine cigarette; thus the effect seemed to result from nicotine.

By the 1970s, active research on the cognitive effects of smoking suggested that smoking a cigarette increased one’s level of alertness and cognitive functioning. Psychological researchers began studying the effects of smoking on reaction time and the performance of mental tasks. One series of studies looked at the effects of smoking on reaction time, simple mental tasks, and learning. Not surprisingly, much of this work has been sponsored by the tobacco industry. One of the early researchers, David Warburton, became an outspoken advocate for the psychological benefits of nicotine and even formed an organization called ARISE (Associates for Research into the Science of Enjoyment), which has been funded largely by the tobacco industry. Nicotine and tobacco researchers disagree on the propriety of scientists’ accepting tobacco industry funding, even with no strings attached. Drug companies, of course, also have vested interests in the outcome of research that they sponsor, but the tobacco industry has drawn heightened suspicion because of its decades-long public relations campaign to deny the hazards of smoking and fund research that diverts attention toward other, unrelated causes of disease. Nevertheless, the industry has supported some reputable scientists conducting legitimate research projects. Today, the leading scientific journals routinely require authors to disclose any potential conflicts of interest, which for nicotine researchers includes any financial relationships with a tobacco company.

The mechanism by which nicotine appears to boost cognition is a plausible one. By binding to the cholinergic receptors on brain cells, nicotine mimics the effects of the neurotransmitter called acetylcholine. Acetylcholine is our most abundant neurotransmitter, with a pivotal role in the brain’s intercellular communication and in the release of other neurotransmitters. This makes it important for motor behavior, memory, and learning.

Recently, researchers have used electroencephalography (EEG) to study and compare the brain function of smokers and non-smokers as they respond to various stimuli. Edward Domino at the University of Michigan recruited 20 volunteers to participate in an experiment to measure the effects of smoking on tasks requiring mental discrimination. (This particular project was supported by the National Institute on Drug Abuse, part of the NIH, but the scientist earlier received industry support for other work.) Domino theorized that nicotine might aid the required concentration by enhancing the brain’s “stimulus barrier” against irrelevant stimuli. Because we are bombarded with visual and auditory signals throughout the day, our brain’s ability to sort out those we want to attend to from those we do not is crucial to our everyday functioning. Volunteers were told to listen to a series of tones and count the “oddball” tones, which were higher in pitch than the others. Meanwhile, the researchers monitored the volunteers’ brain-wave activity with an EEG machine, measuring the strength of the P300 wave that represents the brain’s discrimination between important and unimportant information. Smokers deprived of their cigarettes had the weakest response, suggesting they had more difficulty focusing on the oddball tones; but smokers who had just had a cigarette showed a stronger response to the oddball tones and a decreased response to other, irrelevant tones, compared with nonsmokers.

Skeptics will again raise the issue of nicotine deprivation. Is nicotine simply bringing habitual smokers back to a “normal” level of functioning? Many studies have shown, predictably, that smokers deprived of nicotine perform very poorly at tasks that require concentration. Countering this, however, some studies have shown that exposure to nicotine increases alertness and cognitive functioning in nonsmokers as well as smokers.

Amid the Peril, Therapeutic Promise

None of these researchers recommends that nonsmokers use nicotine to enhance their cognitive performance. Nicotine is a powerful drug with adverse effects as well as modest benefits for performance; in healthy individuals, those benefits do not outweigh the potential risks from nicotine’s effects on the cardiovascular system. The calculation may be different, however, for people suffering the severe impairment of cognitive functioning inflicted by neurological disease. Here we confront the tantalizing promise—and dangers—of the world’s most maligned legal drug.

Alzheimer’s Disease

In 1986, scientists at the National Institute of Mental Health began experimenting with intravenous doses of nicotine for Alzheimer’s patients. They knew from autopsies that patients with Alzheimer-type dementia have fewer cholinergic receptors in their cerebral cortex and make less acetylcholine. They also knew that nicotine functions as an agonist (response-booster) at cholinergic receptors throughout the brain; they were familiar with studies of smokers suggesting that nicotine may improve information processing and learning. It seemed reasonable to try to ascertain whether nicotine might reverse some of the cognitive damage of Alzheimer’s disease. Some animal studies had supported that conclusion, but the real test would be in humans.

The first volunteer was a 57-year-old man with probable Alzheimer’s disease who had never smoked. The researchers gave him, on different days, three different doses of nicotine dripped into his bloodstream via an intravenous tube. The first two doses caused no problems, but a half hour after he received the third and highest dose, the patient started to panic. He reported “overwhelming anxiety bordering on terror, a desire to flee the room, and feelings of impending doom.” As with many drugs, the dose makes the poison; very high doses of nicotine can have serious adverse effects, including mental confusion, irregular pulse, breathing difficulty, and even death. This experiment served as a reminder that the dose at which the drug was given must be carefully modulated.

The research team, led by neuropharmacologists Paul Newhouse and Trey Sunderland, tested the treatment in five more Alzheimer’s patients the same year. All were given a list of words to memorize and also the task of thinking of words in a category like “kitchen appliances.” At the medium dose, patients performed better at free recall of words and were less likely to include irrelevant words. At the highest dose, however, patients did not perform as well; some experienced strong mood changes. Although the high dose had been tested earlier in healthy volunteers and showed no adverse effects, the researchers reasoned that Alzheimer’s patients might have increased sensitivity to nicotine because of disease-related changes in their brains. Overall, the study suggested promise for nicotine therapy, as long as a less toxic form of the drug could be developed.

Research on nicotine as a treatment for Alzheimer’s continues. Edward Levin at Duke University has been experimenting with nicotine-like compounds in rats with Alzheimer’s-like brain lesions. His strategy is to administer the drug over a longer period to try to avoid acute negative effects. A preliminary human trial with eight patients who were given nicotine patches demonstrated significant improvements in their attention and reaction time. Pharmaceutical companies are exploring the potential for nicotine-based drugs for Alzheimer’s, but this work is in the very early stages.

Parkinson’s Disease

In the 1960s, epidemiologists in the United States and United Kingdom observed an odd phenomenon. Patients who died of Parkinson’s disease were mostly nonsmokers. Richard Doll and Richard Peto found in their long-term study of 34,000 British physicians that nonsmokers were in fact three times more likely to die of Parkinson’s disease than smokers. At the time, the significance was far from clear. Doll and Peto speculated that loss of muscle control might make smoking more difficult, so that over time people with Parkinson’s tended to give up the habit. This explanation, however, dissolved under more detailed statistical analysis. Apparently the effect was real, but the researchers remained puzzled, writing, in 1976: “No ready explanation exists, however, by which cigarette smoke could exert a beneficial effect on the central nervous system.”

In time, as the effects of nicotine on the brain were understood, the phenomenon seemed less surprising. Although the mechanism by which nicotine may protect against Parkinson’s remains obscure, scientists do know that nicotine facilitates the release of dopamine from neurons in the brain’s basal ganglia region. In Parkinson’s patients, this is the area that loses dopamine-containing neurons; and drugs such as L-dopa that increase dopamine reduce symptoms of the disease. This suggests that nicotine may combat the effects of Parkinson’s by making more dopamine available.

Paul Newhouse and his colleagues at the University of Vermont, with partial funding from Japan Tobacco, conducted a small pilot study, reported in 2000, in 15 elderly patients with a moderate form of Parkinson’s. First, patients were given nicotine intravenously over half an hour. During and just after the nicotine exposure, the subjects showed improvements in attention and arousal, including faster reaction times, compared to a control group. Next, the patients wore a nicotine patch 16 hours a day for two weeks, after which their basic motor skills were tested. They showed substantial improvements in dexterity and movement, but the improvements disappeared one to two weeks after the nicotine patches were removed. One of Newhouse’s patients described his reaction to the nicotine treatment on National Public Radio: “I felt like a three-way light bulb that was on the 50-watt setting, and then, with the nicotine, it switched me almost instantly to the 100-watt setting.” Newhouse cautions that the long-term effects are unclear.

Tourette’s Syndrome

Neuroscientist Paul Sanberg at the University of South Florida Medical School, with funding from the National Institute of Neurological Disorders and Stroke and the Tourette’s Syndrome Association of America, has been studying the effects of nicotine on children with Tourette’s syndrome. Tourette’s patients usually are treated with one of the powerful tranquilizers, like Haldol, to reduce the involuntary twitches, tics, and blurting of obscenities that characterize the disease; but a major side effect of such tranquilizers is a severe slowing of the patient’s ability to move and think. After discovering in experimental animals that nicotine enhanced the effectiveness of an anti-Tourette’s drug, Sanberg and his colleagues gave Nicorette gum to several patients, all children, along with Haldol. Within half an hour, many of the children’s tics had stopped and parents reported that the children were focused better on their homework. On the downside, the gum tasted so awful that some kids became nauseated. The scientists decided that the next test would be with a nicotine patch.

To convince others, however, Sanberg and his colleagues needed a formal placebo-controlled clinical trial. They enrolled 70 patients, age 8 to 18, from their clinic. Half got a 7-mg nicotine patch (similar to those used to aid in smoking cessation) along with their Haldol; the other half got a dummy, or placebo, patch with no nicotine. Those who received the nicotine patches had fewer tics. Most important, even when these children received only half their usual dose of Haldol, they still did better than those getting the full dose of Haldol with no nicotine. University of South Florida psychiatrist Archie Silver explained: “Not only was the nicotine patch effective, but a much smaller dose of the medication [Haldol] could be given. That’s especially important when treating children and adolescents.” Of course, treating children with nicotine, even in a less addictive form, raises ethical concerns even though such research may pave the way for drugs that mimic the beneficial effects of nicotine without its unwanted properties.

Schizophrenia, Depression, and ADHD

For some time, scientists have known that heavy cigarette smoking is common in certain neurological and emotional disorders. For example, nine out of ten patients with schizophrenia are very heavy smokers; if they stop, their symptoms appear to worsen. Psychiatrists have suspected that these patients discovered by experience that smoking cigarettes was a form of self-medication. As we have seen, cognitive testing shows that nicotine helps the brain focus on important stimuli and to filter out unwanted stimuli. People with schizophrenia tend to have a hard time with such focusing and are easily distracted by background noises that unaffected people usually ignore, such as the humming of a refrigerator or a computer. Robert Freedman, director of the Schizophrenic Research Center at the Denver Veterans Administration Center, has found that people with schizophrenia seem to lack the normal version of a gene important in development of cholinergic receptors in the brain. If someone with schizophrenia is unable to make enough acetylcholine, then nicotine, by mimicking the effect of acetylcholine, may help overcome the deficit.

Heavy smoking is also more common among people with attention-deficit/hyperactivity disorder (ADHD) and depression. A few small pilot studies have tested the effect of nicotine patches on these conditions. Edward Levin and his colleagues at Duke University Medical Center found in 2000 that nicotine improved the attention span of 40 adults with ADHD. The researchers speculate that this effect may result from nicotine’s promotion of dopamine release. A study among only 15 depressed adults in Mexico, conducted in 2002 by Rafael J. Salin-Pascual at Universidad Nacional Autónoma de México, showed improvements after four days using the nicotine patch. These small pilot studies are intriguing, but they are only the first step.

Enter “Nico-Ceuticals”?

Given these multiple intriguing, albeit preliminary outcomes, it is not surprising that pharmaceutical companies are investigating nicotine-based therapies. They are surely aware that nicotine has significant adverse effects, such as its effect on heart rate, along with its therapeutic ones. Drug manufacturers are experimenting with nicotine analogs (man-made chemicals similar to nicotine) in search of agents that have the beneficial properties of nicotine without the hazards.

Thus, when a new drug for Alzheimer’s comes to market, it may be similar to nicotine, but with some important differences. There is an economic motive here because, as a naturally occurring substance, nicotine cannot be patented, but a synthetic nicotine analog could be.

In something of an about-face, some tobacco companies have become interested in developing their own nicotine-based drug products. When the Food and Drug Administration was attempting to regulate cigarettes in the 1990s on the grounds that they are drug-delivery devices, tobacco companies insisted that the pharmacological effects of nicotine were minor. They compared nicotine with caffeine, carrots, white flour, and even television and pinball machines in its ability to produce an effect on the body. Now, however, with a new market for nicotine on the horizon, they have suddenly become acutely aware of its pharmacological effects.

Most of these drugs are at least several years away from reaching the market. Meanwhile, scientists studying therapeutic uses of nicotine are quick to emphasize that they do not recommend that anyone begin smoking, or delay quitting, because of the possible therapeutic benefits of nicotine. Cigarette smoking is by far the most dangerous form of nicotine delivery. Scientists in any case caution against self-medication by smoking or using over-the-counter nicotine products (like the new nicotine lozenges) to treat disease symptoms. And nicotine may have adverse effects even beyond those identified to date. In January of this year, Phillip A. Dennis and colleagues at the National Cancer Institute reported that nicotine itself may contribute to lung cancer by interrupting the normal cell life cycle. The researchers caution that the findings are preliminary and do not demonstrate that conventional nicotine therapy for quitting smoking is unsafe.

Can nicotine ever overcome its deadly association with tobacco? Some tobacco-control advocates worry that even FDA-approved nicotine therapies may be troubling. They suggest that these products may aid the proliferation of nicotine in our society, and increased nicotine addiction may lead to increased cigarette smoking. Fortunately, regulators and the medical profession have an important advantage when it comes to pharmaceuticals. Although the Supreme Court ruled that the FDA does not have the authority to regulate tobacco products, the agency clearly does have jurisdiction over any nicotine-based products that are marketed and sold with health claims. Nicotine-based drugs will have to pass all the same tests that any new drug must pass before entering the market. In the end, ironically, the most beneficial nicotine-based products will be the most tightly regulated while the most dangerous—the cigarette—will remain untouchable because Congress has not given the FDA authority to regulate tobacco products.

Despite promising initial indications, an understanding of the effects of nicotine on the brain and nervous system is in its infancy. More research is needed on the potential uses of nicotine or its synthetic substitute in treating brain disorders. At the same time, tobacco-control advocates are right to be cautious; although nicotine is not the direct cause of tobacco-related deaths, nicotine addiction, because of its role in maintaining the smoking habit, remains one of our most daunting public health challenges. Nicotine simply cannot be separated entirely from its association with tobacco as long as smoking is common. Let the research continue, but always with the caveat that nicotine is no ordinary drug.