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. Nicotine 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.
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.”
[...]
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 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.”
[...]
“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.”
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. Nicotine 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)
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