Smoking may be bad for you, but researchers and biotech companies are quietly developing pharmaceuticals that are decidedly good for brains, bowels, blood vessels and even immune systems – and they're inspired by tobacco's deadly active ingredient: nicotine.

Nicotine acts on the acetylcholine receptors in the brain, stimulating and regulating the release of a slew of brain chemicals, including seratonin, dopamine and norepinephrine. Not surprisingly, the first scientific work that identified these chemicals and how they affect the body came out of nicotine research – much of it performed by tobacco companies.

Now drugs derived from nicotine and the research on nicotine receptors are in clinical trials for everything from helping to heal wounds, to depression, schizophrenia, Alzheimer's, Tourette Syndrome, ADHD, anger management and anxiety.

"Nicotine is highly stigmatized – and for good reason, because the delivery system is so deadly," says Don deBethizy, CEO of Targacept. "But the drug itself and the research generated by studying its effects on the brain both show great promise for helping us improve our physical and mental health."

DeBethizy worked for R.J. Reynolds Tobacco Company for 15 years – he was one of the first to publicly declare that tobacco is addictive – before he spun Targacept off as a separate company. RJR retains a 4 percent share of the Winston Salem biotech, which has one mission: to develop drugs that target the so-called "nicotinic receptors" in the human central-nervous system.

Nicotine performs that function to an unhealthy extreme. "Nicotine itself is hugely potent and not specific enough," says Linda Gretton, Targacept's director of communications. "But the research we have allows us to take the best therapeutic qualities of nicotine and develop treatments that target receptors."

With funding from pharma giant AstraZeneca, Targacept is headed into Phase II clinical trials for a compound that could help overcome cognitive deficits in people who have Alzheimer's or schizophrenia. The company is also in Phase I trials for a compound that treats pain from molar extractions. The drugs both resemble nicotine in their molecular makeup, but are missing nicotine's addictive properties and toxicity.

Research into the medicinal qualities of nicotine was spurred in the 1990s by the availability of nicotine skin patches. For the first time clinical researchers had a form of nicotine that would deliver a reliable dose for study, and could be paired with placebos in blind trials.

Patients suffering from ulcerative colitis – a bowel disease – were subjects of some of the first studies, following observations of unusually low rates of smoking among those with the condition. A 1982 article in the British medical journal The Lancet was titled, "Non-smoking: a feature of ulcerative colitis." Researchers subsequently found that the nicotine in cigarette smoke reduced occurrences of ulcerative colitis, though the drug wasn't an ideal treatment.

"It was somewhat effective, but as a long-term treatment it has its drawbacks, systematic side effects and difficulty administering effective doses," says Dr. William Sandborn, of the Mayo Clinic. "Still, there was a time that we had patients using nicotine patches as off-label therapy."

More nicotine surprises followed. In 2000, Stanford researchers who set out to prove that nicotine damages blood vessels found just the opposite: it prompts the growth of new blood vessels. "It may be the reason smokers' cancers are so aggressive, says Dr. Scott Harkonen, CEO of drugmaker CoMentis. "But it also raises the question: where would you want to promote new blood-vessel growth?"

The answer, it turns out, was found in diabetes patients, who too often lose a lower extremity to amputation after a wound becomes gangrenous – a result of poor blood circulation. Rates of amputations have steadily increased, Harkonen says, and nicotine could be a key to reversing that trend. Now CoMentis is in Phase II studies for "a gel that contains nicotine that's applied directly to the wound site," says Harkonen.

CoMentis is also working with a European company to study the effects of nicotine on the immune system, where it seems to quiet immune responses that go haywire with certain immune disorders.

None of the nicotine-based drugs and molecular siblings have yet come to market, and the stigma attached to nicotine may cause patients to recoil. But "the idea of nicotine-based drugs is alive and well," says the Mayo Clinic's Sandborn, a gastroenterologist who's watching from the wings. "There aren't any approved drugs yet, but I believe they're coming."

"There will be a variety of nicotine-based drugs coming out," agrees Ed Levin, a nicotine researcher at Duke University, who's done groundbreaking research on improving mental function in schizophrenia, Alzheimer's patients and people with ADHA. Levin believes the drugs are something to look forward to.

"There will be great progress when the nicotine sister drugs come to market," he says. "About half the cigarettes in this country are bought by people with psychiatric problems – high percentages of people with depression and schizophrenia smoke, for example.

"When we can give people their medicine in a form that doesn't kill them, it will be real progress."

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