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Nicotine: It may have a good side

Published: March, 2014

It gets people hooked on cigarettes, but researchers hope that nicotine and related compounds will have therapeutic uses.

Nicotine is rightly reviled because of its associations with smoking and addiction. But the rogue substance has a wide range of e ects on the
brain, which may include some healing properties. Researchers are testing nicotine and related compounds as treatments for Alzheimer's
disease, Parkinson's disease, attention de cit/hyperactivity disorder (ADHD), and other conditions.

Self-medicating with cigarettes

Epidemiological studies have hinted at nicotine's therapeutic potential. During the 1980s, several found that smokers had lower rates of
Parkinson's disease than nonsmokers. Epidemiologists also validated what many mental health practitioners have long noticed: The smoking
rate among people with schizophrenia, depression, and anxiety disorders is far higher than average. It's widely believed that people with certain
mental health problems are self-medicating with cigarettes because the nicotine helps their minds function better.

A most rewarding experience

Although the number of smokers is decreasing, smoking still accounts for roughly 1 in 7 deaths in the United States (1 in 3 between the ages of
35 and 70). And tobacco — particularly when smoked — is highly addictive. The cigarette sends the nicotine straight to the lungs, where it's
absorbed by the blood, carried to the heart, and pumped up to the brain. One aspect of addiction is withdrawal, and the symptoms of nicotine
withdrawal usually begin within hours and consist of craving, irritability, anxiety, restlessness, and increased appetite. The craving may last for
months — even years.

The psychological e ects of nicotine at rst seem contradictory: increasing alertness while providing a sense of relaxation and calm. One
possible explanation is that the e ect varies with the user's initial state. For someone who's agitated, nicotine has a calming e ect. For someone
who isn't, it heightens alertness. This di erence may also help explain why nicotine, unlike many other addictive drugs, doesn't behave in a
simple additive manner as the dose increases.

Nicotine is addictive because it triggers a reaction in the brain's reward system, the structures responsible for giving us pleasurable sensations.
More speci cally, the drug intensi es the activity of the neurotransmitter dopamine in a part of the brain called the nucleus accumbens. Cocaine
and amphetamines do much the same thing; nicotine is tame in comparison. But experts theorize that it may have an added e ect because the
drug ampli es the brain's response to the behaviors associated with smoking. In other words, it's not just nicotine, but the pleasurable
sensations it confers on behaviors associated with smoking that make nicotine so addictive.

Express delivery

Cigarettes are addictive because they are so e cient at delivering nicotine to the brain.

Nicotine can be addictive without cigarette smoke. For example, people become addicted to the nicotine in chewing tobacco and "dip" that is
tucked next to the gums. As a rule, though, most drugs of abuse are not as addictive if they are delivered more gradually. In South America, coca
leaves are chewed or used to make tea as a mild stimulant. Whatever the harmful e ects, they're a far cry from snorting cocaine.
Methylphenidate (Ritalin) is chemically more or less the same drug as the injectable amphetamines made in illicit laboratories. But in pill form for
treatment of ADHD the e ects on the brain are so much milder that it changes the character of the drug, despite the chemical similarities.

E ects outside the brain

Nicotine does have some negative cardiovascular e ects, raising blood pressure and causing arteries to constrict, but it's debatable how
signi cant they are. Doctors were initially quite concerned about prescribing the nicotine patch and other so-called nicotine replacement
therapies for smokers with heart disease. But several studies in the mid-1990s showed that the nicotine replacements didn't increase the
number of heart attacks and strokes in these high-risk patients, so those worries have ebbed. Still, those were short-term studies, so
cardiovascular harm from long-term use might be a problem.

Most experts say nicotine itself does not cause cancer. It's addictive, which gets people hooked on cigarettes, but the prevailing view has been
that it is other substances in tobacco smoke (polycyclic aromatic hydrocarbons, tobacco-speci c nitrosamine) that cause DNA damage and
therefore cancer. But researchers at Stanford and elsewhere have conducted experiments that show nicotine may stimulate angiogenesis, or the
formation of new blood vessels. Tumors release angiogenic chemicals that create blood vessels so they have more blood to fuel their growth. A
number of cancer treatment drugs are angiogenesis inhibitors, designed to block those chemicals. Moreover, angiogenesis may play a role in the
formation of the plaques inside arteries that lead to heart attacks. If nicotine is angiogenic, then it may play a more direct role in causing, or
perhaps accelerating, cancer and heart disease than previously thought.

Nicotine's imitators
Nicotine binds to the nerve cell receptors known as nicotinic or nicotinic acetylcholine receptors. Depending on the receptor and other factors,
that binding may speed up the signaling between nerve cells or slow it down. There are at least a dozen nicotinic receptors; their functions are
varied and overlap but often involve the processing of thoughts.

The molecules that snuggle into these receptors needn't come from tobacco or nicotine. Dr. Paul A. Newhouse, director of the University of
Vermont's Clinical Neuroscience Research Unit and for two decades a leading researcher in this eld, says that one set of compounds under
investigation comes from a toxin in nemertine worms.

Drug companies are investing in nicotine-related compounds. Abbott Laboratories' ABT-418 has shown promise in treating ADHD. Taiho
Pharmaceuticals has licensed a drug, code-named DMXB-A (also known as GTS-21), that is in early trials for the treatment of schizophrenia.
P zer's novel antismoking pill, Varenicline, is supposed to turn on nicotinic receptors just enough so smokers don't go through withdrawal, but
not enough to cause addiction.

Why so slow?
Researchers have been talking about nicotine-related drugs for decades, but none are on the market yet. Part of the problem is reputation. One
researcher has suggested that nicotinic drugs be termed "cholinergic-channel modulators" to avoid the stigma. And it isn't just image. Nicotine
researchers have accepted money from tobacco companies. Targacept, a biopharmaceutical rm that focuses exclusively on this area of research,
was part of R. J. Reynolds until 2000.

Even without these problems, designing nicotine-related drugs is tricky. Researchers must nd compounds that are selective. "Nicotine is a
pretty promiscuous drug," Dr. Newhouse explains. "It hits a lot of things at once. But for e ective medications, we want to target speci c receptor
subtypes." Another obstacle is that nicotine-related compounds often have a fairly narrow therapeutic index: There isn't much di erence
between a dose that's helpful and one that's toxic. That isn't insurmountable, but it slows down clinical development.

Finally, the possibility that nicotine has angiogenic properties may put a damper on the research. In a review article on nicotine and
angiogenesis published in 2004 in the Annals of Medicine, researchers John P. Cooke and Haim Bitterman said there was little reason to be
worried about short-term use. In their opinion, nicotine gums and patches are safe and e ective when "used as directed." But they called on
scientists investigating the therapeutic potential of nicotine-like drugs to take the "potent angiogenic e ects of nicotine" into account. Dr.
Newhouse says the angiogenesis evidence comes largely from animal studies, so it doesn't necessarily apply to humans. He also points to the
good safety record of the patch and other nicotine replacements, while noting that there has been some legitimate concern about the
development of insulin resistance.

Successful patchwork
Investigators are seeing if the nicotine patch might have other uses besides helping smokers quit. In 2004, one trial found that the patch
improved cognitive performance in patients with schizophrenia. A 2003 study investigated the e ectiveness of nicotine patch therapy in
nonsmoking patients diagnosed with depression. And a 2001 study reported promising results for treatment of Tourette's disorder with a
combination of the nicotine patch and the antipsychotic drug haloperidol (Haldol).
In a 2004 Psychopharmacology article, Dr. Newhouse and Alexandra Potter, Ph.D., reported that the high smoking rate among adolescents and
adults with ADHD could be explained by their discovery that nicotine improves aspects of their mental functioning. Potter is recruiting people
for two ADHD trials — one involving nicotine and the other a drug called mecamylamine, which blocks certain nicotinic receptors.

An especially promising area of research involves cognitive impairments that are a precursor to Alzheimer's disease. In 2004, Duke University
researchers published a small study on the e ect of the nicotine patch in people with such impairments. They reported signi cant improvement
in decision-making ability and attention (but not motor function or memory) in 11 subjects. Those results led to a larger study funded by the
National Institute on Aging.

Dr. Newhouse believes people are already using nicotine patches on their own for memory problems. "We get e-mails and letters inquiring
about this almost every day," he says. "We still don't have the data to recommend it. But we're excited at the prospects and think the strategy
looks pretty promising."

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