Surprising twist

In laboratories across the country, nicotine — widely vilified as one of the greatest threats to human health — is undergoing a makeover.

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.

“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?

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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.”

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Wide-ranging studies

At Targacept, whose name stands for “targeted receptors,” numerous versions of nicotine-like drugs are being tested on a range of disorders. One compound, called TC-2403, is being tested for safety and effectiveness in treating patients with ulcerative colitis. Earlier studies by Sandborn showed that using nicotine patches helped control the symptoms of the disease, such as diarrhea and abdominal pain.

Promising studies on nicotine for various brain disorders are underway at Targacept and other drug companies, as well as among private researchers. Newhouse has published studies showing that nicotine injections can improve the cognitive function of Alzheimer’s and Parkinson’s patients. In a new study, Newhouse has been granted $1.5 million by the National Institute on Aging to explore whether use of the nicotine patch can treat mild cognitive impairment, a condition characterized by forgetfulness that may be a precursor to Alzheimer’s disease.

“There are places in the brain that are involved in learning and memory, and these nicotinic receptors show a pretty dramatic decline in function in people with Alzheimer’s disease,” says Levin, who pioneered much of the research on nicotine and cognition in laboratory animals. “The idea is that you replace some of this nicotinic receptor stimulation with nicotine.”

Nicotine may do more than alter the temporary release of neurotransmitters that affect learning and memory. In a study presented last year, Scripps Research Institute scientists found evidence that a byproduct of nicotine appears to prevent the formation of the harmful protein plaques associated with Alzheimer’s disease.

In November, Newhouse announced the results of a study showing that nicotine patches helped improve the concentration of teenagers with ADHD. The nicotine seemed to work specifically on one aspect of the disorder — the inability to control impulsive behavior.

“Nicotine corrects a specific cognitive deficit that kids with ADHD have,” he says. “We think we’ve stumbled onto a potential mechanism for why these kids take up smoking at very high rates. It looks like nicotine can robustly correct this inability to control the impulsive aspects of behavior.”

Other research has showed that the nicotine patch can help reduce use of the drug Haldol in children with Tourette’s syndrome, which is characterized by tics and behavioral and attention problems. Preliminary studies also have begun on nicotine for schizophrenia and depression. And Targacept, which has a phase II study on ADHD, has recently launched studies on nicotine for pain. Scientists have known since the 1930s that nicotine can block some types of pain. However, as in other uses of nicotine, the chemical must be altered to reduce side effects before it could be used for pain relief.

“For learning and memory problems, nicotine looks as good or better than almost anything out there,” Newhouse says. “The question has been, can we get the good benefits of nicotine without the toxicity? We think we can do this.”

Researchers are adamant that people shouldn’t use the nicotine patch or, worse, take up smoking as a way to treat a disease.

Studies have not proved that nicotinic drugs can be both safe and effective, especially for long-term use. Nor should healthy people think that using nicotine, either in patch form or by smoking, can temporarily boost their brain power or memory, Newhouse says. Studies show that normal people’s cognitive skills probably won’t benefit from nicotine.