The Science of Nicotine Addiction

There are 50 million nicotine addicts in the US, and one in five deaths results from smoking. According to the CDC, smoking is still the leading preventable cause of death. Here's why it is so hard to kick, and the treatments.

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Quitting smoking is hard, as any nicotine addict will tell you. So hard, in fact, that a popular 2011 article in The Fix reported that nicotine is the third most addictive substance, behind heroin and crack cocaine, in terms of how hard it is to kick.

The statistics surrounding nicotine are, indeed, grim. There are 50 million nicotine addicts in the US, and one in five deaths results from smoking. Not only is smoking—and related activities, like chewing tobacco—addictive because tobacco contains nicotine, but tobacco also contains more than 19 carcinogens as well as more than 4,000 other chemicals. According the CDC, smoking is the leading preventable cause of death in the United States. Smokers are more likely than nonsmokers to develop heart disease, stroke, and lung cancer. In fact, smoking can cause cancer almost anywhere in the body.

Many smokers know all this, yet continue to smoke. For smoker John, whose name has been changed for this piece, quitting is anything but a simple cost-benefit analysis.

“I think I started [at 13 years old] because the kids I was hanging around with smoked,” he says. While that sublime sense of “calmness” he used to get is long gone, he understands that he needs to smoke. “I don’t think I recognize the high, but I get it physically.”

Biology of nicotine addiction

Nicotine is a compound found in the nightshade family of plants (Solanaceae) and a stimulant drug. It is a nicotinic acetylcholine receptor agonist, which means it can bind as well as acetylcholine to the acetylcholine receptor.

Acetylcholine is the oldest neurotransmitter and acts throughout the body and brain on the autonomic nervous system. The autonomic nervous system is essentially the hardware of our bodies, running unbeknownst to us in the background and maintaining essential bodily functions, controlling our GI system, and stimulating the fight-or-flight response when needed. It’s possible that the difficulty in quitting smoking is directly related to that fact that acetylcholine’s effect on our bodies is so varied and ubiquitous.

There are two main types of acetylcholine receptors: the nicotinic acetylcholine receptor (nAChR), which is so named so because it is responsive to nicotine; and the muscarinic acetylcholine receptor (mAChR), which responds particularly well to muscarine. There are many receptor sub-types of the nAChR, but nicotine has a high affinity for the one in which the β2 subunit is coupled with α4 or another subunit. Chronic exposure to nicotine “up-regulates” these specific receptors, which enhances craving and worsens withdrawal in smokers.

The effects of ingesting nicotine are widespread. About 20 seconds after smoking a cigarette, nicotine binds to the nAChRs in the brain and increases the level of several neurotransmitters, including dopamine, norepinephrine, and serotonin. Because nicotine activates the autonomous nervous system, prompting the release of adrenaline, this causes an increase in heart rate, blood pressure, and respiration, among other things.

In fact, nicotine can act as both—or alternately—a stimulant and a relaxant. Increased acetylcholine improves concentration and memory; more norepinephrine enhances alertness and arousal. Increased beta-endorphin reduces pain and anxiety. More dopamine works to give pleasure and increase the sensitivity of the brain’s reward system to nicotine.

In moderation, nicotine’s effects are generally good. In small, therapeutic doses—an entire area of scientific study—nicotine can be used to promote well-being. However, from the standpoint of nicotine addiction, one cigarette is too many for some people.

Withdrawal sucks

Craving is a “physical tic,” John says. He gets irritable, anxious, and automatically goes for a smoke. “It’s hard to say what’s a physical urge and what’s just going about the routine. I don’t think about it, I do it.”

Withdrawal is what keeps nicotine users addicted, whether they are conscious of this process or not. The symptoms of nicotine withdrawal usually appear approximately two hours after the last dose. Common symptoms include an intense craving for nicotine, anxiety, depression, drowsiness, bad dreams or trouble sleeping, feeling restless or frustrated, headaches, increase in appetite, weight gain, and difficulty concentrating.

“I think about quitting, but I talk myself out of it,” John says. “I make up one reason or another and say, ‘I’m not prepared to go through this.’ I’m not thinking about how it’s going to feel to not have a cigarette for the next hour, I’m thinking about, I don’t want to go through the next month.” Cravings last for a long time, he says. He once quit for two years, but the cravings never went away completely. “Two years later, I had a craving and a cigarette and then three days later, I was smoking a pack a day again.”

Addicted from the first cigarette?

In the 1960s and 1970s, researchers started exploring the idea of tobacco addiction, but it wasn’t until the 1980s that the mechanism behind this addiction—that nicotine acted on a well-studied receptor and improved mood and memory—began to be elucidated. The 1990s saw the first drugs to treat the withdrawal associated with nicotine abuse.

In 2008, Dr. Joseph DiFranza, professor of family medicine and community health at the University of Massachusetts Medical School, wrote a piece for Scientific American magazine about the effects of just one cigarette. His novel theory at the time says that one cigarette is all it takes to become addicted—by definition, this means experience withdrawal symptoms.

“It is now clear that the brain reacts rapidly to the first exposure to nicotine in ways that alter its structure and function,” DiFranza says. “We do not know exactly what these alterations are doing to the brain to cause addiction, but our best hypothesis is that the brain reacts quickly to counter the effects of nicotine. As a result of these countermeasures, the brain is no longer in balance when nicotine is absent. Anytime the brain has gone too long without nicotine it generates a craving for the drug.”

Laura Bierut disagrees. “I do not believe that we become addicted from the first cigarette,” she says. “There is very strong data that some individuals smoke lightly for long periods of time.” Bierut, who is a professor of psychiatry at Washington University School of Medicine and who has led the Collaborative Genetic Study of Nicotine Dependence (COGEND) study for nine years, believes that our increasing knowledge of genetic susceptibility to becoming addicted to nicotine will lend more nuance to the question, Why do some people become addicted?

Genetics plays a role in addiction, as we know from twin studies that show that in general, addiction is half genes, half environment. In nicotine addiction, receptor subtypes are important to understanding the severity. In other words, the nicotinic receptors of the person who becomes addicted are not the same as those of the person who does not. Variants within a cluster of nicotinic receptors on chromosome 8, CHRNB3-A6, have been associated with cigarette consumption in several genome-wide association studies (GWAS)—specifically that a variation in the cholinergic nicotinic receptor subunit α5 (CHRNA5) increases the risk for developing a dependence on nicotine. Nicotine addiction has been found to frequently co-occur with bipolar disorder and alcoholism, adding another layer of complexity to the problem. Finally, there are both genetic- and environmentally-influenced differences between individuals and ethnic groups in how nicotine is metabolized.