Apoorva Mandavilli is Nature Medicine's news
editor
Could the
long-standing villain in tobacco yet prove a hero in medicine?
Mounting evidence suggests that nicotine can help in certain
diseases—but researchers are wary of giving cigarettes a good name.
Apoorva Mandavilli reports.
Edward Sulzer began smoking when he was a teenager. He
puffed his way through the army and continued to smoke when he
became a professor of psychology at Southern Illinois University in
Carbondale. In his late thirties, Sulzer developed lung cancer.
After a year of hospitalization, at age 39, he died.
"You can see
why I'm very anti-smoking," says David Sulzer, who was 13 when his
father passed away. But two weeks ago, Sulzer, now a neurobiologist
at Columbia University, published a paper that in part explains how
nicotine might benefit some people (Nat.
Neurosci. 7, 581–582; 2004).
"I think there are a lot
of drugs like that, that have some clinically beneficial effects,"
says Sulzer, whose primary interest is in understanding how synapses
work. "But the health risks of smoking far, far, far outweigh the
benefits."
Just as with the opiate morphine a few decades ago,
nicotine is tapping into some uncomfortable contradictions in public
health. On one side is the near-unanimous portrait of the drug as
the addictive component of cigarettes. But evidence is slowly
building that nicotine also has unmistakable positive effects in
illnesses as diverse as schizophrenia, attention deficit and
hyperactivity disorder (ADHD), Alzheimer and Parkinson diseases,
ulcerative colitis and Tourette syndrome.
I'm not sure there's a hugely
bright future for just the compound nicotine. But
I think there's a lot of potential for modifying
the nicotinic system.
John
Dani professor of
neuroscience, Baylor College of
Medicine
The debate on nicotine is further complicated because,
unlike morphine, nicotine is available over the counter. Many
scientists who study the drug's beneficial effects are wary that
their pro-nicotine comments may be distorted as pro-smoking by the
media or by those with specific agendas. One researcher flat-out
refused to grant an interview, and others were careful to word their
comments in terms of nicotine-like compounds, rather than nicotine
itself.
"Nicotine as a drug has some benefits. But if you ask me,
'Is nicotine a good drug?' No," says Sherry Leonard, professor of
psychiatry and pharmacology at the University of Colorado. "We just
have to find [compounds] that do the same thing as
nicotine."
Where there's smoke...
Difficult as it may be to
untangle the rewards of nicotine from the ravages of smoking, much
of the evidence for nicotine's benefits actually derives from
epidemiological studies of the effects of smoking. For instance,
smokers appear to have a lower risk of developing Alzheimer disease,
Parkinson disease and ulcerative colitis.
Smoking gun: Large numbers of
mentally ill smokers may be lighting up in an attempt to
'self-medicate' their
symptoms.
In the 1960s, nearly half of the US
population smoked cigarettes. That number is down to about 22%, a
group that Yale University researcher Tony George calls "hard-core"
smokers. Among the mentally ill, however, the proportion of smokers
is much higher: up to 90% of schizophrenics, 70% of those with
bipolar disorder and more than 50% of depressed individuals smoke.
Some studies estimate that a third of those who smoke have at one
time battled a mental illness. "Smoking is a marker for psycho
pathology," says George, who is director of the Program for Research
in Smokers with Mental Illness at the Connecticut Mental Health
Center. "What I like to say is, 'Where there's smoke, there's
fire.'"
Smokers often say that after a cigarette, their thinking is
clearer, calmer and more focused. This effect is particularly
prominent in those with a mental illness, such as schizophrenia or
ADHD. "What we find is that nicotine and/or smoking seems to have
positive effects," says George. Many studies suggest that people
with mental illness smoke because they are trying to 'self-medicate'
and relieve the symptoms of their disorder, he says.
For instance,
schizophrenics have trouble filtering important or 'salient' stimuli
from unwanted noise. As a result, their brain is flooded with
sensory overload, which could account for some of their paranoia and
delusions. This 'gating' deficit is inherited, and about half of the
first-degree relatives of schizophrenics have the same difficulty.
Studies have shown that nicotine can normalize the ability to filter
out noise in both schizophrenics and their first-degree
relatives.
Depending on the type of incoming stimulus, dopamine
neurons fire either at a slow 'tonic' rate or in rapid bursts. Most
sensory inputs cause background or tonic firing, but certain salient
stimuli come through as buzzes.
When people smoke or take
nicotine in some other way, the nicotine binds to receptors in the
brain, releasing dopamine and desensitizing the receptors. In that
state, the receptors are no longer responsive to tonic signals. But
high-frequency stimuli, such as food and sex, can override the
desensitization and induce rapid firing. In essence, by filtering
out extraneous noise, nicotine enhances the signal-to-noise ratio.
"It cuts out nonsalient stimuli, so you experience it as a sharper
phenomenon," says Sulzer. "It's not hard to imagine how that might
help someone with delusions." Low levels of methylphenidate
(Ritalin) and amphetamines may do the same thing, Sulzer
says.
Based on anecdotal and epidemiological information,
researchers have also stumbled onto some unexpected effects of
smoking, for example in preventing ulcerative colitis, a chronic,
debilitating and largely incurable inflammation of the large
intestine. Nonsmokers are five times more likely to develop the
disorder than are current smokers; former smokers are at even
greater risk.
There is some evidence to suggest that
nicotine exerts a protective effect in the colon by inhibiting the
production of ineterleukin-8 and other inflammatory cytokines.
Nicotine may also enhance the production of a mucus layer between
cells and the components of stool, and may have some effect on the
nerves of the gut.
In patients with ulcerative colitis, 50%
of those who began or resumed smoking after a flare-up went into
remission. Patients who improved smoked twice as many cigarettes as
patients who did not improve. Proof-of-concept studies suggest that
delivering nicotine via transdermal patches can relieve ulcerative
colitis symptoms, albeit with a lot of side effects (Ann. Intern.
Med. 126, 364–371; 1997)
...there's
fire
Despite its promise, developing nicotine as a treatment is
fraught with pitfalls. Apart from its addictive nature and its
action as a psycho-stimulant, nicotine influences the release of
many neurotransmitters, including dopamine, GABA, glutamate and
acetylcholine. "It's kind of a dirty drug because it does many, many
things," says Edythe London, professor of psychiatry and
pharmacology at the University of California in Los
Angeles.
When smokers abstain from cigarettes,
there is greater blood flow as measured by fMRI—meaning
their brains have to work harder—to perform the same
working memory task.
Edythe London,
UCLA
Addiction is primarily a concern only
with cigarettes, which, by all accounts, are not an option for
treatment. When people smoke, there is a rapid rise in blood levels
of nicotine, which corresponds to a spike in brain concentration,
and then the levels fall off rapidly, rising again with the next
cigarette. That sort of rapid cycling is what is thought to drive
addiction.
With the patch, peak blood levels are about 60% of those
seen with smoking. Gradually increasing nicotine doses through the
patch relieves symptoms, but evidence thus far suggests that it does
not stimulate the central nervous system enough to become addictive.
In nonsmokers, however, the patch is not well-tolerated and can have
many side effects, including increased heart rate, lightheadedness,
sweating and nausea. Blood levels with nicotine gum are even lower
than with the patch, but chewing gum is too variable and difficult
to monitor to be a viable treatment alternative.
"I'm not sure
there's a hugely bright future for just the compound nicotine," says
John Dani, professor of neuroscience at Baylor College of Medicine.
"But I think there's a lot of potential for modifying the nicotinic
system."
In the brain, nicotine binds to receptors of the
neurotransmitter acetylcholine. Eleven subtypes of these nicotinic
receptors—combinations of ten alpha and four beta subunits—have thus
far been found throughout the central nervous system. Because there
are several classes of receptors, levels of nicotine in the blood
can have a wide variety of effects. Dani and others suggest that the
receptors could be good targets for drug development. Understanding
which receptor subtype is important in a specific disorder could
help scientists design nicotine-like drugs that selectively bind to
a specific subtype.
For instance, gene expression analysis
has shown that in schizophrenics, nicotinic receptors, particularly
the alpha-7 subtype, are expressed at lower levels. The gene for the
alpha-7 receptor has also consistently been implicated in genetic
studies of schizophrenia and, to a lesser extent, of bipolar
disorder.
Smoking reduces levels of
monoaminooxidase, an enzyme that controls dopamine
levels in the brain.
Courtesy of Brookhaven National
Laboratory
A clearer understanding of nicotine's
therapeutic effects might also help combat addiction to it and other
drugs. Although nicotine influences the release of many
neurotransmitters, its effect on the dopamine system, which is
important in reward-based learning, memory and addiction, has
recently taken center stage. "We think that nicotinic receptors are
an important part of the reward pathway," says Dan McGehee, a
neurobiologist at the University of Chicago. "If you block the
receptors generally using an antagonist, you can maybe limit the
rewarding effects of other drugs of abuse."
Ifs, ands or
butts
As scientists unravel the components of the nicotinic
system, it is increasingly clear that there are large holes in the
understanding of the biology of nicotine, addiction, mental illness,
stress—and how all of those things are tied together. "I don't want
to say I'm not optimistic," says McGehee. "But there are many things
we need to look at in more detail."
Until recently, for
instance, clinical trials in schizophrenia often used nonsmokers as
controls. Because most schizophrenics are smokers and nicotine has
profound effects on the brain, including all combinations of
participants might yield significantly different results.
The biggest
challenge from a public health perspective, many researchers say, is
that people might misinterpret evidence of nicotine's effects in
certain disorders as an excuse to smoke or to not quit
smoking.
On the contrary, in most people, nicotine might have
harmful effects beyond those associated with smoking, says Sulzer.
In people with schizophrenia, ADHD or other disorders where
performance is suboptimal, nicotine raises the ability to filter
stimuli to 'normal' levels. Except under extreme task demands,
"normal people don't need this because their signal-to-noise ratio
is already pretty good," Sulzer notes. In fact, several studies show
that in healthy controls, nicotine either has no effect or, in some
cases, can worsen performance.
But "if some idiot or drug company is
going to twist things around," that important distinction might get
lost, says Sulzer. "The only thing that would come out of [this
research] that I'd be horrified by is if people used it to advocate
smoking," he says. "I think it would be a real travesty if that
happened."
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I'm not sure there's a hugely
bright future for just the compound nicotine. But
I think there's a lot of potential for modifying
the nicotinic system. 
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