I have received few comments about
this blog post on smoking.
Most of the comments refer to the fact that smoking kills.
Is it so?
Let's have a read.
Nicotine as Therapy
I am copying from this PLOS Biology paper (bold sections are my choice)
Nicotine is an alkaloid in the tobacco plant
Nicotiana tabacum,
which was smoked or chewed in the Americas for thousands of years
before European invaders also succumbed to its pleasures and shipped it
back to the Old World. N
icotine has always been regarded as medicinal
and enjoyable at its usual low doses. Native Americans chewed tobacco to
treat intestinal symptoms, and in 1560, Jean Nicot de Villemain sent
tobacco seeds to the French court, claiming tobacco had medicinal
properties and describing it as a panacea for many ailments.
Higher
doses are toxic, even lethal—which is why nicotine is used around the
world as an insecticide. Yet few of the horrendous health effects of
smoking are traceable to nicotine itself—cigarettes contain nearly 4,000
other compounds that play a role. Until recently, nicotine research has
been driven primarily by nicotine's unparalleled power to keep people
smoking, rather than its potential therapeutic uses.
Nicotine locks on to one group of receptors that are normally targeted
by the neurotransmitter acetylcholine.
Nicotinic acetylcholine receptors
(nAChRs) are ion channels threaded through cell membranes.
When
activated, either by acetylcholine or by nicotine, they allow selected
ions to flow across the cell membrane.
In vertebrates nAChRs are all
over the autonomic and central nervous sytems and the neuromuscular
junction. A nAChR is composed of five polypeptide subunits (
Figure 1),
but there are many nAChR subtypes made of different subunit
combinations, a diversity that helps explain why nicotine can have so
many different physiological and cognitive effects.
 |
| Figure 1. Schematic Illustration of an Acetylcholine Receptor (Illustration: Giovanni Maki) | | | |
Nicotine and the Brain
People
with depressive-spectrum disorders, schizophrenia, and adult ADHD
tend
to smoke heavily, which suggested to researchers that nicotine may
soothe their symptoms. Common to all these disorders is a failure of
attention, an inability to concentrate on particular stimuli and screen
out the rest.
Nicotine helps.
Researchers at the National Institute on
Drug Abuse have shown via functional magnetic resonance imaging that
nicotine activates specific brain areas during tasks that demand
attention (
Box 1).
This may be because of its effects, shared with many other addictive
drugs, on the release of the neurotransmitter dopamine. “Schizophrenia
is a disorder largely of the dopamine system,” says John Dani of the
Baylor College of Medicine in Houston, Texas. Dopamine signals in the
brain occur in two modes—a kind of background trickle, punctuated by
brief bursts. “It's thought that schizophrenics have a hard time
separating that background information from important bursts. We've
shown that nicotine helps to normalize that signaling by depressing the
background but letting the bursts through well,” he says. “I'll be
surprised if there's not a co-therapy [to help schizophrenics] that
takes advantage of nicotine systems in less than a decade.”
Box 1. Nicotine's Effect on Attention
Using
functional magnetic resonance imaging, scientists at the National
Institute on Drug Abuse provided the first evidence that
nicotine-induced enhancement of parietal cortex activation is associated
with improved attention. They compared brain activity during a task
demanding sustained attention—rapid visual information processing
(RVIP)—with that during an undemanding sensorimotor control task (Figure 2).
Group results from 15 smokers (right) illustrate the effects of
nicotine and placebo patches in left and right parietal cortex (1 and 2)
and left and right occipital cortex (3 and 4). Nicotine significantly
increased activation in occipital cortex during both the control and
rapid visual information processing tasks, suggesting a general
modulation of attention. In contrast, nicotine increased activity in the
parietal cortex only during rapid visual information processing,
suggesting a specific modulation on task performance.
[...]
Smokers also have lower rates of neurodegenerative disorders, and
nicotine improves cognitive and motor functioning in people with
Alzheimer disease and Parkinson disease. The prevailing hypothesis is
that nicotine increases release of neurotransmitters depleted in those
diseases. Dani and his colleagues have recently shown that
acetylcholinesterase inhibitors—which block the degradation of
acetylcholine and hence prolong its action—used to treat Alzheimer
disease also stimulate dopamine release.
They suspect that
malfunctioning of the dopamine system may be affecting noncognitive
aspects of dementia such as depressed mood, and that this might be
alleviated by nicotine.
[...]
Nicotine and Pain
Nicotine's
salutary effects in patients with neurodegenerative and mental
disorders have been studied a lot and are fairly well known. Two much
newer topics of academic research are nicotine's potential for pain
relief and for treating obesity.
Nicotine itself has provided modest pain
relief in animal studies.
Although the analgesic effect of drugs that
mimic acetylcholine were originally attributed to a different class of
receptors,
it is now clear that nAChRs play an important role in the
control of pain.
For instance, epibatidine, a drug that is extracted
from the skin of an Ecuadorian frog and that acts at nAChRs, has been
shown to be 200 times more potent than morphine at blocking pain in
animals. Current animal research is aimed at discovering just where,
how, and which classes of nAChRs work against pain, with the aim of
developing more selective drugs.
Meanwhile,
nicotine is also being investigated as an
analgesic in humans. For
example, Pamela Flood, an anesthesiologist at Columbia, is investigating
nicotine's future as a postoperative analgesic. She recently completed a
pilot study of 20 women undergoing gynecological surgery. All the women
had access to unlimited morphine and also got either a single 3-mg dose
of nicotine nasal spray or a placebo.
The placebo group had peak pain
scores of eight out of a possible ten in the first hour after surgery.
Women who got nicotine averaged a pain score of five. Despite the small
sample size, Flood says, the results were highly significant. “As far as
I know this is the first clinical study to use nicotine for analgesia,
and it was much more successful than I ever would have imagined.”
[...]
Nicotine's Future
Developing
new drugs that selectively target specific subtypes of nicotine
receptors is an expensive, albeit potentially lucrative, proposition.
And therein lies a question. Will nicotine-based therapy consist mostly
of costly new drugs from the pharmaceutical industry? Or can less
expensive nicotine products like the patch, chewing gum, and nasal
spray—which are generally intended for smoking cessation but widely
available, usually without prescription—find their way into the world's
medicine cabinets?
“It's
a little early to call whether nicotine will be used itself as a
therapeutic agent or whether these more specific drugs that are being
produced or maybe even used in combination with other drugs may be the
most important way to go,” says Dani. But he doesn't see the medicinal
use of plain nicotine as very likely. Dani points out that the body's
own agent, acetylcholine, acts over milliseconds to activate nicotinic
receptors, whereas nicotine itself stimulates these receptors for hours.
That lengthy action means that, although nicotine activates the
receptors, it then often turns particular receptor subtypes off again, a
process called desensitization. “It's hard to predict inside of a body
what you're getting. Am I getting an activation or am I turning the
receptors off?”
Yet
much of the work to date showing nicotine's effectiveness on a huge
range of disorders has involved products available at any drugstore and
intended to help people quit smoking. Newhouse is using patches for mild
cognitive impairment. Flood has demonstrated pain relief with nasal
spray and will use patches in her next study. And Role feels that gum
hasn't been adequately explored for its therapeutic potential. Nicotine
gum, she notes, is a better imitator of smoking than the patch because
it delivers brief hits rather than a steady supply. She's also uncertain
whether natural nicotine has been studied enough. But Role also points
out that nicotine has its serious problems—addictive potential,
cardiovascular damage, and (especially when delivered through the
mucosa) cancer.
Dani
says, “People are probably going to have to find creative ways to
understand which subtypes of nicotinic receptors they're turning on and
which ones they're desensitizing. Maybe drug delivery methods will
matter. Maybe subtype specificity will matter. It's less than a decade
that we've known how important nicotinic receptors are. Now we have to
move forward from there.”
“We've
made an enormous amount of progress on understanding the biology of
these receptor systems and how to target them. What has been trickier
has been to develop an appropriate pharmacology that allows one to
selectively target agents for particular therapeutic purposes with an
adequate safety index,” Newhouse says.
“But some of the drugs that are
coming on in human trials now are very promising. So I'm cautiously
optimistic that we're on the road to developing some useful nicotinic
therapies.”
 |
Figure 2. The Brain on Nicotine (Image: Elliot Stein, National Institute on Drug Abuse)
|
