Separated from cigarettes, molecularly tweaked and carefully administered, nicotine holds promise as a powerful treatment for a variety of illnesses, from Alzheimer's disease to depression to schizophrenia, many scientists now believe. Even more surprising, perhaps, is the improbable source of the research that is helping to fuel scientists' optimism about nicotine's potential to heal: the much-maligned tobacco industry itself.
Not surprising in terms of profit motive, perhaps. But surprising that an industry responsible for health problems is now working on improving health.
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"This is tobacco biology that has been taken out of Big Tobacco and put into health research," says Dr. William Sandborn, a nicotine researcher at the Mayo Clinic in Rochester, Minn.What began more than a decade ago as a smattering of small studies has become a major research effort involving the federal government, the tobacco industry, a half-dozen pharmaceutical companies and dozens of private researchers. Some experts predict that the first nicotine-based medicine may reach the market in a few years.
Nicotine's potential therapeutic value has been recognized for years, but the drug's connection to smoking has dissuaded many scientists from exploring the field, says Edward Levin, a behavioral pharmacologist and nicotine researcher at Duke University in Durham, N.C. Development of the nicotine patch, which the FDA approved for smoking cessation use in 1991, provided a way to test the effects of nicotine apart from smoking. "We could see there was a therapeutic use for nicotine," Levin says. The smoking-cessation patch remains the only FDA-approved medical use for nicotine.
Nicotine is addictive and toxic and can constrict blood flow, raising one's heart rate and blood pressure. However, studies conducted for approval of the nicotine patch, and information culled from people who have used the patch, have shown that nicotine, when taken in small doses, appears safe and does not contribute to dependency. Many of the serious health problems associated with smoking — cancer and heart disease — are caused not by the nicotine itself but by the tars and carbon monoxide in cigarettes, Sandborn says. By itself and in low doses, nicotine appears free of major side effects.
"The nicotine patch is a proof of concept that you could get a benefit without all the baggage that comes with smoking," he says. "But we still needed a way of further improving nicotine itself to take it all the way to being a good medical therapy."
That is what many researchers are working on; tobacco giant R.J. Reynolds, for instance, created a small biotech company to develop nicotine-based therapies. Reassured by the patch's safety record, scientists are fixing their attention on some long-standing questions concerning nicotine use: Why are smokers less likely to develop Parkinson's disease or ulcerative colitis? Why do almost 90% of schizophrenics smoke — three times the rate of the general population? Why do teens with attention deficit hyperactivity disorder, or ADHD, smoke at higher rates than their peers?
Clues to behavior
Doctors have long suspected that people with schizophrenia and ADHD are self-medicating — that is, they try to alleviate their symptoms by smoking. Recent research is providing clues that would explain this behavior.
Early laboratory work, much of it by scientists working for cigarette manufacturers, has yielded a more sophisticated understanding of how nicotine acts in the body, says Dr. Paul Newhouse, director of the Clinical Neuroscience Research Unit at the University of Vermont. Scientists hope that knowledge will lead to medicines that can capitalize on nicotine's benefits while curtailing side effects.
Scientists have found that nicotine connects to specific cell receptors called acetylcholine receptors. Acetylcholine receptors are prominent throughout the body, which is one reason high doses of nicotine cause a wide range of side effects. Acetylcholine receptors play a particularly large role in the brain, where they act as gatekeepers for the release of other brain chemicals such as neurotransmitters, which have an effect on learning, memory and emotion.
When someone is addicted to nicotine, stimulating these receptors tends to increase concentration, dampen appetite and produce a sense of calm — effects many smokers would recognize. By changing the nicotine molecule, however, scientists hope to produce a chemical that is safer and nonaddictive, because it would work only in specific areas of the body, Levin says.
"Most people are interested in a nicotine agonist — a sister drug that mimics nicotine's benefits without the deleterious side effects to avoid the addiction problem and stresses on the cardiovascular system," he says.
Different kinds of nicotinic receptors exist in the body, and scientists are trying to target receptors in specific areas with nicotine-like drugs, Newhouse says. That's why nicotine could end up being useful for an array of disorders, from brain disorders to pain to intestinal problems.
For example, Newhouse notes that in patients with ulcerative colitis, the nicotinic receptor in the lining of the intestine is different from those in the central nervous system. That suggests a drug could be developed that would target only the receptor in the intestine. "Increasingly," he says, "people are trying to come up with compounds that are highly selective, that only do what we want them to do and don't do other things."
One of scientists' biggest hurdles in working with even low doses of nicotine has been reducing nausea. Studies using the nicotine patch in nonsmokers with various disorders have revealed high rates of nausea, vomiting and diarrhea. In one study of Parkinson's disease patients, almost half of the people dropped out of the trial because of nausea. But progress in controlling that problem has allowed work on nicotine to proceed.
"We've had to learn to target subtypes of the receptors in the brain and avoid receptors that produce nausea," says J. Donald deBethizy, president and chief executive of Targacept, the North Carolina-based biotech company that grew out of a research unit at R.J. Reynolds. "That was the key. Now the question is: Do these drugs treat patients? We've already proven safety."