Imagine a new class of drugs that can blunt serious psychiatric disorders, repel the onset of Alzheimer's and improve attention in ADHD-afflicted teens, as well as relieve a range of physical ailments, from ulcerative colitis to chronic pain. If tests were already being done in humans, you would probably have heard about it on the evening news, right? Did I mention that these compounds might help you lose weight too?
Not only does this potential medical breakthrough exist, but it comes from a most unlikely source, one generally associated with addiction, sickness and death: nicotine. What's stranger still is that much of the relevant research into nicotinic compounds comes from Big Tobacco, the makers and marketers of one of the most addictive substances on the planet and the single most preventable cause of death. Researchers even believe that understanding nicotine may lead one day to an effective "cure" for smoking.
The negative health risks of cigarette smoking are so overwhelming that its beneficial effects have been largely ignored. But as every smoker knows, lighting up can sharpen concentration and elevate mood. Over the decades, doctors have also observed that smokers have below-average rates of certain diseases, including Parkinson's and ulcerative colitis.
Psychopharmacology has demonstrated nicotine's capacity as an all-around cognitive enhancer, increasing the brain's learning and memory functions.
Meanwhile, deep in the tobacco fields of North Carolina, R.J. Reynolds and other tobacco companies had spent many millions of dollars on nicotine research. Their chemists worked to breed a more powerful and flavorful tobacco leaf. They also infused cigarettes with additives that would maximize the addictiveness of their product. Some estimates count 4,000 chemical additives in modern cigarettes. In the process, Big Tobacco's labs -- and, in particular, that of tobacco giant Reynolds -- became the world's leading repository of knowledge about nicotine as a drug.
Medical investigation into these matters began in earnest only in the late 1990s when a pure, harmless form of nicotine became available via delivery methods developed for smoking cessation, like the nicotine patch and Nicorette gum. At the time, however, few were willing to listen to good news about nicotine. The government was fighting a "war on tobacco" against a corporate cabal that was not above renewing its consumer base with child-friendly marketing campaigns, involving the likes of Joe Camel and Marlboro Miles, and come-ons that offered alluring prizes in trade for tabs torn off smoked-out cigarette packs.
In this atmosphere, getting funding for nicotine research was a hard sell, longtime nicotine researcher Paul Newhouse, M.D., of the University of Vermont College of Medicine told The New York Times in 1997: "The problem with nicotine is that it is tied to cigarettes and therefore seen as bad. A lot of people have difficulty in being convinced that nicotine is potentially valuable." The government funded basic research into the chemical's activity in the brain, but not into studies of its potential beneficial uses. It was left to Reynolds to pony up the bucks. In conjunction with university scientists, the company's research section, headed by toxicologist Don DeBethizy, synthesized every known nicotinic compound and published 300 reports in 15 years on the workings of nicotine in the body and brain.
As the "war on tobacco" shows signs of success across the developed world, the public's capacity to identify nicotine apart from cigarette smoking has increased. There is a growing awareness of the chemical as a "drug" in the therapeutic, rather than the strictly addictive, sense.
Anecdotal and observational information has been confirmed and explained by advances in neuroscience. Studies routinely claim that upward of 80 percent of schizophrenics smoke, compared with around 20 percent of the general population. (People with depression and with ADHD also have higher rates of smoking.) This is likely due to the fact that smoking releases bursts of dopamine in the brain. "Schizophrenia is a disorder largely of the dopamine system," John Dani of Houston's Baylor College of Medicine told PLOS-Biology in 2004. "It's thought that schizophrenics have a hard time separating background information from important bursts [of information]. Nicotine helps to normalize that signaling by depressing the background but letting the bursts through well."
Nicotine works by binding to nicotinic cholinergic receptors, which lie on the surface of many cells throughout the body and brain. By keeping these receptors switched on, it stimulates various types of neurotransmitters, especially dopamine, which helps regulate the brain's pleasure and reward centers and plays a key role in addiction. The "dopamine burst" effect also explains nicotine's potency as a cognitive enhancer or potential "smart drug." An analysis of 41 studies in 2010 found that nicotine increases motor skills, alertness, attention and response time, as well as short-term and working memory.
In 2000 R.J. Reynolds made news when it spun off its research section into an independent biotech company called Targacept, with DeBethizy at the helm. Targacept's stated mission was to explore the medical uses of nicotine. "The reason Targacept exists is the fact that we have a lot of knowledge and expertise on nicotine," Seth Moskowitz, a Reynolds spokesman, told The Wall Street Journal. "We decided it would be worth our while to apply our expertise." The move got the pharmaceutical industry thinking of nicotinic compounds as "the next big thing." The firm was subsequently flooded with hundreds of millions of dollars from private equity firms, but its biggest investor has been AstraZeneca, the British-based drug firm.
Big Tobacco is in no position to design, develop or test nicotinic compounds; that's Big Pharma's risky business. While cigarettes are no longer a booming industry in the developed world, Big Tobacco has little reason to fret about its profitability when it has made huge inroads into the developing world: By 2025 an estimated 85 percent of smokers will live in poor countries. Philip Morris, the world's largest cigarette manufacturer, saw its Asia revenue soar from $5.6 billion in 2007 to nearly $11 billion in 2011. Even so, the patents Reynolds holds on all those molecules targeting different nicotinic receptors are as good as gold to any drug company pursuing this class of drug.
The idea of Big Pharma and Big Tobacco working hand in hand might give some pause. Among Big Tobacco's most infamous attempts to boost sales were ads that bamboozled smokers by using pseudomedical jargon. For decades cigarettes were peddled with claims that smoking assisted digestion and elevated mood. "More doctors smoke Camels than any other cigarette," boasted a 1950s multimedia campaign that featured leading-men types in white coats puffing away happily. Physicians also confirmed the benefits of Lucky Strikes as "your throat protection against irritation and cough," while smoking was pitched to women as the key to "keep a slender figure."
Tobacco-company executives repeatedly lied to Congress about how much they knew about the deadly effects of their products on the country's collective health. Pushing back against the FDA's efforts to regulate cigarettes as a drug-delivery device, the industry spun its science in an attempt to portray the pharmacological effects of nicotine as no more significant than carrots.
Ironically, those words came back to haunt Targacept's DeBethizy, who resigned from the company two years ago after its most promising nicotinic-receptor molecules failed in a Phase III trial for depression. So far, the pharmacological effects of nicotine as a drug in humans are indeed no more significant than carrots. A second Targacept compound failed in tests against ADHD. Other companies -- they have names like Memory, EnVivo and NeuroSearch -- have had equally dispiriting results.
The initial promise of nicotinics as a wonder drug for major serious diseases with cognitive-based symptoms or causes remains unfulfilled. None of the nicotinic-receptor targeters has been able to replicate in humans the beneficial effects seen in the lab and in animal testing. This is not surprising, as the brain presents science with its greatest therapeutic challenge. Companies are seeing more success in testing their nicotinics against below-the-brain conditions like ulcerative colitis.
At the time of its Targacept spinoff, Reynolds stated that it had no interest in using its research to find a treatment for nicotine addiction. But given the size of the potential market for such a drug, Big Pharma does have an interest.
Chantix (varenicline) is the only pharmaceutical approved specifically as a smoking-cessation therapy. It was developed by Pfizer with an apparent appreciation of how buprenorphine (Suboxone) works to control opiate addiction. Just as bupe is a "partial agonist" of opiate receptors, Chantix partially binds to nicotinic receptors, reducing cravings while simultaneously making smoking less pleasurable. Yet Chantix can have serious negative psychiatric side effects, including depression, violence and suicide -- a sign of the fundamental difficulty in developing brain drugs. Every type of nicotinic receptor is likely to play a role in a wide range of brain functions, so when you block, blunt or stimulate one, it causes a whole cascade of undesired effects.
"There's been an explosion of knowledge about the molecular receptors of nicotine, and we're finally going to be coming up with a whole new class of medications in the next six to 10 years," Jed Rose, a psychopharmacologist and chief of the nicotine-research program at the Duke University Medical Center, told The Wall Street Journal in 1999. "As our understanding of what nicotine does in the brain improves, the treatments will accelerate."
Rose's lab came up with the original nicotine patch; his most recent invention was a user-friendly form of inhaled nicotine, which some experts believe will be more effective than the vapor method of e-cigarettes. Still, his prediction about a new class of nicotinics has not come true -- not yet. But our understanding of what nicotine does in the brain has improved a lot since 1999. It's a safe bet that this dirty drug that has wreaked such havoc on public health is saving its best act for last.
Matt Harvey is an award-winning freelance journalist whose writing has appeared in Black Book, the New York Post and the New York Press, among other publications. His previous piece for Substance.com was about how addiction was used as a scapegoat in an anti-Semitic murder spree.