Posted on 04/08/2014 4:55:27 AM PDT by jjsheridan5
Every drug of addiction must have its day. Morphine remains one of the most potent painkillers ever discovered. Cocaine’s chemical cousin lidocaine is still used by physicians and dentists as an effective local anesthetic. Even demon alcohol, when taken in moderation, cuts the risk of heart attacks, osteoporosis, rheumatoid arthritis and a hodgepodge of other ailments.
Now comes nicotine, perhaps the most unlikely wonder drug ever to be reviled.
If dozens of human and animal studies published over the past six years are borne out by large clinical trials, nicotine — freed at last of its noxious host, tobacco, and delivered instead by chewing gum or transdermal patch — may prove to be a weirdly, improbably effective drug for relieving or preventing a variety of neurological disorders, including Parkinson’s disease, mild cognitive impairment (MCI), Tourette’s and schizophrenia. It might even improve attention and focus enough to qualify as a cognitive enhancer. And, oh yeah, it’s long been associated with weight loss, with few known safety risks. (Although, in truth, few safety studies of the increasingly popular e-cigarettes have yet been published.)
Nicotine? Yes, nicotine.
In fact, the one purpose for which nicotine has proven futile is the very same one for which it’s approved by the Food and Drug Administration, sold by pharmacies over the counter, bought by consumers and covered by many state Medicaid programs: quitting smoking. In January 2012, a six-year follow-up study of 787 adults who had recently quit smoking found that those who used nicotine replacement therapy in the form of a patch, gum, inhaler or nasal spray had the same long-term relapse rate as those who did not use the products. Heavy smokers who tried to quit without the benefit of counseling were actually twice as likely to relapse if they used a nicotine replacement product.
And therein lies the conundrum that physicians and regulators will have to wrestle with if the promising studies about nicotine’s benefits hold up: how to endorse a drug linked to one of the greatest public health scourges the world has ever known.
“I understand that smoking is bad,” says neuroscientist Maryka Quik, program director of the Neurodegenerative Diseases Program at SRI International, a nonprofit research institute based in California’s Silicon Valley. “My father died of lung cancer. I totally get it.”
Yet over the years, she has published dozens of studies revealing the beneficial actions of nicotine within the mammalian brain. “The whole problem with nicotine is that it happens to be found in cigarettes,” she says. “People can’t disassociate the two in their minds.”
Tweaking the Brain
The first hint of nicotine’s curious benefits came from a study published in 1966 by Harold Kahn, an epidemiologist at the National Institutes of Health. Using health insurance data on 293,658 veterans who had served in the U.S. military between 1917 and 1940, Kahn found the kinds of associations between smoking and mortality that had already become well known. At any given age, cigarette smokers were 11 times as likely to have died of lung cancer as nonsmokers, and 12 times as likely to have died of emphysema. Cancers of the mouth, pharynx, esophagus, larynx — on and on. But amid the lineup of usual suspects, one oddball jumped out: Death due to Parkinson’s disease occurred at least three times as often in nonsmokers as in smokers.
The neurotransmitter dopamine sends signals related to pleasure, reward and motor function across neurons in the brain. A lack of dopamine has been linked to movement disorders such as Parkinson's disease. ©2013 Delilah R. Cohn
Following up, researchers expected the finding to be just a statistical aberration in Kahn’s data, but instead quickly confirmed it. Grasping at a final possible alternative to the inconvenient notion that smoking could have a healthful benefit, experts theorized that the association was due only to smokers dying young of cancer, heart disease and lung disease before the age when they might otherwise have developed Parkinson’s. (The neurodegenerative disorder affects about 1 percent of people by age 60, rising to about 4 percent by age 80.) But in 1971, epidemiologists Irving Kessler and Earl Diamond of Johns Hopkins University published a study comparing the smoking history of living Baltimore residents recently diagnosed with Parkinson’s with age-matched controls. Sure enough, they found that the Parkinson’s patients were much less likely than other residents to have ever smoked.
So what was it about tobacco that ravaged the heart, lungs, teeth and skin but somehow guarded against a disease of the brain? In 1979, UCLA neurobiologist Marie-Françoise Chesselet showed that nicotine increases levels of dopamine, a neurotransmitter essential for boosting attention, reward-seeking behaviors and risk of addictions, from gambling to drugs. Dopamine also helps control movement. Nicotine receptors in the striatum, the comma-shaped structure near the center of the brain where movements are planned and controlled, are located near the terminals that regulate and emit dopamine. Even a small dose of nicotine, Chesselet found, stimulates the release of dopamine in the striatum, putting the brakes on movement that otherwise would go uncontrolled.
And that effect suggests why nicotine could help treat Parkinson’s disease. Called “the shaking palsy” in an 1817 essay by the English physician James Parkinson (after whom the disease was later renamed), Parkinson’s is marked by shaking and difficulty with walking, coordination and all other movements. Although its ultimate cause remains unexplained, neuroscientists have long known that as symptoms worsen, dopamine-producing neurons in the striatum die out. Since the 1960s, the gold-standard treatment for the disease has been the drug levodopa, also known as L-dopa, a dopamine precursor that can cross the blood-brain barrier. But the drug is not perfect: L-dopa treatment eventually induces dyskinesia — quick, involuntary movements of the hands, and sometimes of the head and trunk.
Putting together the emerging lines of evidence, Quik decided to treat Parkinson’s disease in squirrel monkeys by administering nicotine. In a landmark 2007 paper, she reported that the monkeys had 50 percent fewer tremors and tics, and that nicotine had reduced dyskinesia 35 percent in those already receiving L-dopa. Studies by Quik and others involving rats, mice and nonhuman primates have since found similar effects. In short, by driving dopamine, nicotine appeared to ease the tremors and tics caused by Parkinson’s, and even the movement disorder induced by the major Parkinson’s drug.
Waiting for Human Evidence
Given the findings, one might reasonably ask how many clinical trials of ordinary over-the-counter nicotine patches or gum as either a treatment or preventative for Parkinson’s have been published in the medical literature. “In humans, none,” says neurologist James Boyd of the University of Vermont College of Medicine. That will change soon. Boyd is now running two such studies. The first, begun in 2010, is a small, randomized 12-week trial of whether a nicotine patch can reduce another problem often associated with Parkinson’s: impulsivity.
A 2007 study suggests that nicotine treatment could help alleviate the dyskinesia often experienced by Parkinson's patients being treated with L-dopa (left). Chart: Allison Mackey/Discover after Quick, et al. "Nicotine and Parkinson's Disease: Implications for Therapy."
Remember, Parkinson’s involves a loss of dopamine, a neurotransmitter that regulates not only movement but also addictive behaviors. It has long been observed that people who develop Parkinson’s tend to be more low-key and risk-averse than average, as if their innate dopamine levels have always been on the low side. When they take L-dopa, however, some have been known to swing to the other side of the reward-seeking spectrum, developing gambling or sexual addictions. Boyd hopes nicotine might push such patients back to a middle ground.
He is also the principal U.S. investigator for a randomized trial that began late last year in Germany and is now being conducted here to test the value of nicotine as a therapeutic drug. The study seeks to answer whether ordinary over-the-counter nicotine gum or patches can halt the progression of Parkinson’s. To get at the answer, one component the study will look at is whether the chemical can relieve the writhing, twisting movements that eventually beset almost every Parkinson’s patient taking L-dopa.
Beyond Parkinson's
While researchers await the results of the Parkinson’s studies, they look beyond to nicotine treatments for other disorders as well.
“Nicotine has separate mechanisms by which it may protect brain cells, aside from its influence on dopamine,” Boyd says. “One of the functions of nicotinic receptors is to moderate the entry of calcium into cells. The presence of nicotine increases the amount of intracellular calcium, which appears to improve cellular survival.”
And nicotine may have an antioxidant effect, serving to mop up the toxic free radicals produced as a byproduct of metabolism, thus protecting the brain. The neuroprotective effects of nicotine were studied in a randomized clinical trial involving 67 subjects in the early stages of Alzheimer’s disease, where memory was slightly impaired but decision-making and other cognitive abilities remained intact. They received either a 15-milligram nicotine patch or placebo for six months. The results found “significant nicotine-associated improvements in attention, memory and psychomotor speed,” with excellent safety and tolerability.
Other studies suggest that nicotine may be as effective at enhancing attention as methylphenidate (Ritalin) and the wakefulness-promoting drug modafinil (Provigil). In 2008, Paul Newhouse, director of the Center for Cognitive Medicine at Vanderbilt University School of Medicine in Nashville, compared performance on a series of cognitive tasks in 15 nonsmoking ADHD patients while wearing either a 7-mg nicotine patch or a placebo patch. After just 45 minutes with the nicotine patch, the young adults were significantly better at inhibiting an impulse, delaying a reward and remembering an image they had seen.
Even people without any diagnosed disorder might benefit from nicotine. Psychologist Jennifer Rusted of the University of Sussex in Britain calls the drug “the most reliable cognitive enhancer that we currently have.” In addition to improving visual attention and working memory, nicotine has been shown by Rusted to increase prospective memory: the ability to remember and implement a prior intention. (When your mother asks you to pick up a jar of pickles at the grocery store on the way home, she’s saddling you with a prospective memory challenge.)
“It’s a small effect, maybe a 15 percent improvement,” Rusted says. “It’s not something that’s going to have a massive impact in a healthy young individual. But we think it’s doing it by allowing you to redeploy your attention more rapidly.” In short, the drug seems to work by helping users shut out irrelevant stimuli so that important information can come to the fore.
The ability to shut out stimuli could also turn nicotine into a treatment for schizophrenia, where afflicted individuals are overwhelmed by sights, sounds and thoughts that most of us would either ignore or quickly dismiss. Studies in the United States, Canada and Germany have shown that nicotine improves the ability of people with schizophrenia to focus their attention and recall recent events. In addition, the potent antipsychotic haloperidol often causes dyskinesia, which Quik’s 2007 study proved nicotine can relieve.
Not the Great Satan
Perhaps most surprising is that, in studies by Boyd and others, nicotine has not caused addiction or withdrawal when used to treat disease. These findings fly in the face of nicotine’s reputation as one of the most addictive substances known, but it’s a reputation built on myth. Tobacco may well be as addictive as heroin, as some have claimed. But as scientists know, getting mice or other animals hooked on nicotine alone is dauntingly difficult. As a 2007 paper in the journal Neuropharmacology put it: “Tobacco use has one of the highest rates of addiction of any abused drug.” Paradoxically it’s almost impossible to get laboratory animals hooked on pure nicotine, though it has a mildly pleasant effect.
The same study found that tobacco smoke itself is necessary to amp up nicotine’s addictiveness. In 2005, for instance, researchers at the University of California, Irvine, found that animals self-administer a combination of nicotine and acetaldehyde, an organic chemical found in tobacco, significantly more often than either chemical alone. In 2009, a French team found that combining nicotine with a cocktail of five other chemicals found in tobacco — anabasine, nornicotine, anatabine, cotinine and myosmine — significantly increased rats’ hyperactivity and self-administration of the mix compared with nicotine alone.
In short, the estimated 45.3 million people, or 19.3 percent of all adults, in the United States who still smoke are not nicotine fiends. They’re nicotine-anabasine-nornicotine-anatabine-cotinine-myosmine-acetaldehyde-and-who-knows-what-else fiends. It is tobacco, with its thousands of chemical constituents, that rightly merits our fear and loathing as the Great Satan of addictiveness. Nicotine, alone: not so much.
Despite the potential benefits and apparent safety, researchers like Boyd want more evidence before they’ll recommend a nicotine patch for anything other than its FDA-approved (but seemingly useless) purpose, smoking cessation. “Nicotine has potential drug interactions. It can interfere with blood pressure medications. To recommend something for which there is no good long-term safety data — it’s just wrong,” Boyd says.
To Quik, the upside is clear. “People have tested all their favorites to help treat Parkinson’s and other neurological disease,” she says. “Now nicotine’s time has come.”
I hear you. I remember, not too long ago, playing basketball all day, often all weekend, only taking a break every hour or so to grab some water and a quick cigarette. When I quit smoking, however, it was like suddenly I couldn’t even walk up the stairs without coughing and pain. On those occasions where I did go back to smoking, I was shocked at how easy it was.
E-cigs definitely result in some mild irritation. Personally, I find that it goes away within a few days, but for others, it seems to be a permanent feature. One thing that may help me, and you may want to try, is that I drink a ton of water (an old habit from weightlifting days).
Some good information mixed with some absolute falsehoods.
Nicotine is addictive all by itself.
Nicotine without combustion byproducts does affect microcirculation, the consequences of those changes are not well researched.
Straight nicotine probably does have positive effects but the risk versus benefits are not known and it would be unwise to subject yourself to a lifelong addiction without fully knowing that it will provide more benefit than harm over the long haul.
” I still use the legal delivery system for my daily dose of Ol’ nic”
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Mt too,having one right now with good,strong black coffee.
Been doing this for 60 years.
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Tobacco is not cured with ammonia. Wherever you read that or whoever told you that does not know what they're talking about. Ammonia occurs naturally in tobacco leaves. The curing process "sweats" this naturally-occurring ammonia out of the tobacco leaves, removing it, leaving the finished golden brown product with that vaguely spicy, warm scent for which tobacco is known and loved.
Smoked my entire adult life (35 years). Slowly developed violent coughing bouts every night. Feared I could not quit.
My Dr prescribed one month of Wellbutrin (Anti Depressant) and the patch.
My cough was gone in two days. Knew I had quit in Four days.
Always felt Wellbutrin was the key. Talk to your Dr about Wellbutrin.
Should get a pipe. Much better tobacco without all the added chemicals and crap :)
When you quit after smoking fairly heavily for a long time, the years of accumulated "tar" begin to shed in your lungs and you start hacking it up. The worst of it passes in a week or so, but it may go on for weeks. The majority of any cumulative effect on the lungs typically clears up over a matter of a few months' time for most, leaving apparently healthy, pink tissue with little evidence other than perhaps some scarring. Due to this, some will still go on to develop emphysema and/or COPD later in life. If the repeated irritation caused sufficient cell mutation and that mutation begins to reproduce out of control, then you have cancer. The odds sound terrible for smoking-related diseases, ten times more likely, twelve, twenty times more likely than a non-smoker, but understand that it's minuscule in nonsmokers and slightly less minuscule in smokers. They've been called coffin nails since the eighteenth century, so it's not as if people weren't aware of negative health consequences from smoking heavily. But, there are benefits. Concentration, energy, mood, it's a very useful chemical or group of chemicals for everyday life. So, people still smoke.
You are entirely correct. I was actually referring to the fact that ammonia is added back in to tobacco after curing, at least for some cigarette manufacturers. I was using the word “curing” far too loosely, when I should have said “manufacturing”.
My grandmother lived until she was 93. My grandfather to 96. My grandmother played tennis twice a week until she was 72, when her doctor finally prevailed upon her to quit smoking. She did, and her health started failing almost immediately, and never really returned.
What is not commonly reported is that if you’ve been smoking for more than 30 years, and you are above age 60, they no longer tell you to quit, but to cut down.
Unfiltered Pall Mall’s. I used to mail home plug tobacco from North Carolina and Georgia, where you can still get Peachy Plug, and other of the older brands of plug tobacco. They would go out in the backyard in the sun and enjoy a slice.
Science is in bad shape.
Nicotine induces the same dopamine release pathways seen with other addictions. Physical and psychological withdrawal is seen with cessation just like with other addictions. Behaviour with use is the same as with other addictions. Addiction rate with use is significantly higher than with use of some other addictive substances such as alcohol.
The question is not whether it is addictive but whether it matters.
And from this you're willing to ignore the overwhelming amount of established science that tells us that nicotine is a highly addictive substance?
Cigarette smoking is more addicting that nicotine by itself, but to claim that nicotine isn't the main cause of addiction to tobacco requires some serious, and willful, avoidance of facts.
These researchers want to deny that nicotine is addictive by itself, and claim that animal and human studies support them, but that just isn't the case. People can say just about anything they want to say in these articles and there will always be a contingent of people who are willing and eager to buy into it hook, line, and sinker. Even I believe that they believe what they're telling you. But they are wrong. Very wrong.
Aside from the first sentence, is any of what you just said in reference to nicotine, or to tobacco? While you provide no sources, so I have to guess, you are in all likelihood referring to tobacco. This article is about nicotine, not tobacco.
Please answer the question, since you are clearly of the opinion that nicotine alone is addictive: why, if nicotine is addictive, do trial participants who ingest nicotine (not tobacco), not display any of the symptoms of addiction, even though their serum levels of nicotine are kept at elevated levels for months at a time?
It is a simple question. Absent an answer, it completely undermines the proposition that nicotine alone is addictive.
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My grandmother lived until she was 93. My grandfather to 96.”
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Sounds like my family.
I’m 81 and have told my doctor that I won’t stop smoking or having my daily,large cup of coffee. I have cut down on both,though.
I also have refused to have certain routine tests done because I feel they are a waste of time and money.
I have had the same doctor for 30 years and she tolerates me-—in fact we like each other.
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You have good genes. Enjoy your life and thank your parents. At 81, I think I would do the very same thing.
Final Report A recent theory of addiction suggests that the ability of a drug to activate and persistently sensitize the brain reward system is what makes it addictive. This ability creates a positive feedback cycle that enhances the psychologically rewarding effects of the drug and encourages repeated use. However, the effects of nicotine do not appear to be entirely consistent with this theory. Nicotinic receptors in the brain containing a4 and (32 subunits bind nicotine and stimulate the reward system of the brain. Chronic nicotine exposure increases the density of these receptors in the brain but it does not always lead to an increase in the brain nicotinic response. In fact, chronic nicotine exposure appears to irreversibly inactivate a large fraction of rat brain nicotinic receptors expressed in frog oocytes. Thus, chronic nicotine exposure does not always lead to sensitization of the nicotinic response. The specific aims of our research were to (1) characterize nicotine-induced irreversible receptor inactivation and (2) discover the biochemical mechanism responsible for inactivation.
To study inactivation, we expressed rat brain (c4p2) nicotinic receptors in Xenopus oocytes and measured their acetylcholine (ACh) response before and after a prolonged incubation in nicotine. The results showed that the x4(32 ACh response remained depressed for 24 h after a 1 or 12 h incubation in 10 pM nicotine, compared to controls incubated for an equal time in nicotine-free media. However, a 12 h incubation in 101 .LM nicotine did not affect the number of total or surface a4(32 receptors measured by [3H]epibatidine binding. Thus, a 12 h exposure to 10 [LM nicotine appeared to irreversibly inactivate brain nicotinic receptors expressed in oocytes. We initially hypothesized that receptor phosphorylation or de-phosphorylation was responsible for this irreversible inactivation. To test this hypothesis, we used biochemical techniques to demonstrate that rat a4P2 nicotinic receptors were phosphorylated in Xenopus oocytes. Then, we constructed a chimeric ocl/oc4 subunit that removed all the phosphorylation sites in the a4 subunit. Surprisingly, prolonged nicotine incubations still inactivated receptors formed from this chimera and wild-type (32 subunits even though all the phosphorylation sites were removed and the receptor displayed no detectable phosphorylation. These results suggested that changes in receptor phosphorylation were not responsible for nicotine-induced inactivation. We then hypothesized that nicotine uptake and release from the oocytes could cause apparent irreversible inactivation. Nicotine has a pKa of 7.84. Thus, it is only partially ionized at pH 7.4 (74%). Uncharged nicotine could diffuse across the plasma membrane and accumulate inside intracellular acidic vesicles because it is a weak base. Therefore, oocytes could slowly take up and release nicotine into the wash media. Because the equilibrium dissociation constant of a4(32 nAChRs for nicotine is small (4-7 nM), even minute amounts of nicotine released into the wash media could desensitize these receptors and make it appear, as if they were irreversibly inactivated. To test this hypothesis, oocytes expressing (x4(32 receptors were co-incubated with un-injected oocytes that were pre-soaked in 10 g.M nicotine for 12 h. The nicotine-soaked un-injected oocytes released enough nicotine to desensitize the (x4(32 receptors and account for all the apparent irreversible inactivation caused by a 12 h exposure to 10 pM nicotine. These results showed that nicotine release from the oocytes caused the apparent irreversible inactivation of nicotinic receptors following prolonged nicotine incubations. To confirm this hypothesis, we incubated oocytes expressing a4(32 receptors in a saturating concentration of ACh for 12 h or a very low nicotine concentration (5 nM) and measured the effects of the incubation on the ACh response. ACh is fully ionized at pH 7.4 and cannot easily cross the plasma membrane or accumulate inside acidic vesicles. A 12 h incubation in 300 pM ACh or in 5 nM nicotine (which resulted in negligible nicotine release from the oocytes) did not irreversibly inactivate (x402 receptors. We also measured the amount of nicotine released by nicotine-soaked oocytes using radioactive nicotine. Oocytes soaked for 12 h in radioactive nicotine released enough nicotine into the media to desensitize (x4(32 receptors. Finally, we showed that even continuous rapid rinsing with nicotine-fee saline fails to prevent nicotine-soaked oocytes from releasing enough nicotine at the surface of the plasma membrane to desensitize a4P2 receptors. Thus, our results conclusively show that nicotine does not irreversibly inactivate brain nicotinic receptors expressed in frog oocytes but, rather, desensitization caused by nicotine release from the oocytes into the wash media makes it appear as if the receptors are irreversibly inactivated.
The results of our research have several important implications for nicotine addiction. First, they show than nicotine-induced inactivation is not involved in nicotine addiction. Second, they suggest that nicotine is addictive because it persistently sensitizes the reward system of the brain by increasing the density of nicotinic receptors in the brain. Thus, the well documented finding that smoking increases the density of nicotinic receptors in the human brain suggests that chronic tobacco use sensitizes smokers to the effects of nicotine and creates a positive feedback cycle that promotes nicotine addiction. The next step in this research would be to study nicotine uptake and release in mammalian cells expressing brain nicotinic receptors.
You are playing with the banks money anyway at this point. I smoke cigars, chew leaf tobacco during baseball season, drink whiskey occasionally, and coffee most of the time.
I avoid anything ‘diet’. I am cutting down on carbs, and increasing proteins and fats. I’ve lost weight and feel better, especially with exercise.
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