Nicotine, the Wonder Drug?

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.

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.)

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.”

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.

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.

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.

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.”

To help counter the never-ending onslaught of misguided myths about nicotine:

Nicotine clearly has health benefits. But what is really interesting is that nicotine is not addictive, despite common perception:

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.

Coupled with the myth about toxicity (covered in many different publications -- the current "official" toxicity is a never proven wild-a**-guess made 100 years ago, and never challenged, despite ample evidence that it was incorrect by a substantial margin), and we find that the anti-nicotine movement is a fraud, all the way through.

Nicotine is not addictive (on its own), carries no real health risks (unless it is in the form of tobacco), and has non-trivial health benefits.

The hysteria about nicotine is, like most left-wing movements, all about money and power, with no concern at all for scientific accuracy.

My Dad died of complications related to Parkinson’s. Turns out it is one of the strangest illnesses in the world. Parkinson’s almost seems to prevent cancer - except for melanoma - which is worse in Parkinson patients. And according to my Dad's main doctor, there is a vaccination against Parkinson’s - smoking. He said in more than twenty years he could only remember one smoker with Parkinson’s.

Not sure smoking is worth all the other risks, but there are apparently a few good things that come from it.

I actually wish the Doctor hadn't told us that, because my Mom had convinced my Dad to give up smoking right after they were married. You can imagine how that made her feel.

I’m offended, on behalf of tobacco, for it being called “noxious”. When will the insults and bullying stop? :>} I still use the legal delivery system for my daily dose of Ol’ nic. I know. I’m a bad person.

No health risk? No such thing as nicotine poisoning?

I mentioned nicotine toxicity, so this was clearly not a well-thought out question. Nicotine toxicity exists, just as toxicity exists for every chemical. But the levels of toxicity usually cited are comically low, being derived from a 100 year old self-experimentation, resulting in a wild-a**-guess about the level of toxicity. While this level has never been challenged formally, there is a wealth of anecdotal data that suggests that nicotine toxicity is only a realistic problem in extreme cases. By way of example, most attempts to commit suicide via nicotine ingestion have merely ended up with nasty cases of nausea, despite being well above the "official" level of toxicity.

I’m offended, on behalf of tobacco, for it being called “noxious”.

I agree with you. Tobacco in and of itself is quite good (although today's cigarettes, with all of the added chemicals, may qualify as "noxious"). Apparently, it is also quite tasty. I know that at least one avant-garde restaurant actually makes dishes with sauteed tobacco leaves, and that native tribes consumed it as a leafy green. I wouldn't do that with tobacco grown for cigarettes, however.

Ever smoker that I personally know insists that the patches do nothing to help with cravings. (One of my friends said that it made them much worse.)

I’ve been saying for years that there’s something else in a cigarette that’s being overlooked. Kind of nice to have that validated.

I found the same thing. The patch (and the gum) both result in a weird uncomfortable feeling, one that would be best resolved with a cigarette. There are probably three things going on: first, as the article alludes to, there are thousands of other chemicals in tobacco, and it appears that it is some magic combination of chemicals resulting in addiction. Second, the chemicals used in curing also play a role — snus, which are cured with salt water, are much less potent than ammonia cured tobacco. Third, combustion itself results in a more rapid and concentrated delivery of these chemicals to the brain.

But really, we don’t know what is really going on. The one thing we can say with a reasonable degree of confidence is that if nicotine is addictive, it is only trivially so.

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.

As a former smoker, former by switching to e-cigarettes, I find this not to be the case entirely.

Perhaps e-cigs aren't pure nicotine, but there is a definite withdrawal issue with them. It's not as bad as tobacco, but it's still there.

Several times I've run out of e-cig juice and fallen back onto analogs because of the withdrawal cravings.

It’s the thing’s you associate with smoking that are addicting. Quit for 5 1/2 years and one day the phone rang and before I answered it I grabbed an ash tray and pulled it closer. After dinner, sitting on the patio, taking a break from garden work, those were the tough times.

“So what was it about tobacco that ravaged the heart, lungs, teeth and skin... “

It is the WILD ABUSE of cigarettes that causes all the problems. Abuse ANYTHING to the degree that smokers abuse cigarettes and you’ll have big health problems.

I’d be willing to bet that 1 or 2 cigs a day wouldn’t hurt almost anyone and may even help most in certain ways.

Correlation doesn't imply causation. I, too, have observed this. There are a couple of possibilities: one is that once you have become addicted to the cocktail of chemicals in tobacco, there is some change in the brain that makes us susceptible to addiction of nicotine (in other words, for a non-smoker, nicotine is not addictive, but for a life-long smoker, it is). The more likely explanation is this, in my opinion: nicotine has a number of positive benefits. When you stop smoking (which you are addicted to), you are struggling with "withdrawal". Nicotine's positive benefits make that withdrawal tolerable. So when you remove nicotine, it isn't that you are suffering from withdrawal from nicotine: rather, it is that the chemical which was helping you deal with withdrawal is now absent, and you are now fully exposed to the underlying addiction.

This dovetails with other studies that show that tobacco (and presumably nicotine), are highly beneficial for people dealing with any addiction. So much so, that it used to be conventional wisdom to provide drug addicts with tobacco to help them deal with cessation.

I remember my doctor telling me years ago that anything less than 10 cigarettes per day was unlikely to cause problems down the road. Unfortunately, I was fully brainwashed by years of PSA’s informing me that there was no “safe” level of smoking, so I did what everyone else did: smoke like a chimney with the intention of quitting at a later date.

So you are probably correct. It is the abuse of cigarettes that is most likely the underlying culprit.

Another thing I find interesting, purely from my observation...

I have a hard time tolerating e-cigarettes. Especially the propylene glycol based juices, but even the vegetable glycerine ones often cause me to cough and eventually wheeze.

I don’t have any problem at all tolerating regular cigarettes. The last time I had any unpleasant side effects while using was about a decade ago during an extremely stressful time when I got up to over a pack a day, and then I had a cough. Normally, cigarettes seem to have something in them that helps cover up the irritation they cause. It’s only when you try to stop using them and the mollification is taken away, that you realize the damage they have been doing.

That makes switching awfully difficult going from regular cigarettes to e-cigs, while it’s extremely easy to go from e-cigs back to regular cigarettes. Going the first way gets you double the discomfort while going backwards gives instant gratification while removing all irritation.

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