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Addiction to Nicotine: The Science Behind Replacement Therapy

Smoking tobacco is by far the preferred choice for tobacco consumers. Approximately 25% of the U.S. population uses tobacco with 80% smoking cigarettes. There has been a general decline in smoking after its link to several adverse health problems, but only since the turn of the century have former smokers begun to outnumber current smokers. However, the problem of quitting is still a significant one. Over 2/3 of smokers want to quit, about half try to quit, but less than 7% are actually successful. Only 1/3 of smokers trying to quit used counseling and/or FDA approved smoking cessation products, and It is thought that rates of quitting might double or triple if used. Even then, success rates would be between 14-21%. So, the question is: why is quitting so difficult?

Part of the answer involves the route of administration. In his article about the pharmacology of nicotine, Dr. Benowitz states that smoking tobacco causes absorption of nicotine into the brain within seconds, which is comparable to intravenous (IV) administration. He goes on to say, “The more rapid the rate of absorption and entry of a drug into the brain, the greater the rush, and the more reinforcing the drug.”

Adapted from: Helena Digard et al. Nicotine Tob Res (2012).

In contrast, nicotine replacement therapies (NRT), like nicotine gum, the patch, or the inhaler are absorbed through the mucus membrane in the mouth and nose. These NRTs typically employ a number of advancements to increase the absorption rate, but still, from the figure, you can see the difference. Smoking cigarettes (red arrow/line) produces a sharp spike in nicotine plasma concentration, which means quicker transportation to the brain. Nicotine gum (green arrow/line) and other tobacco products (e.g., snus [black lines]) cause an increase in nicotine plasma on the order of minutes, and the peak from the gum doesn’t even reach that from a cigarette. This is seen as a problem by nicotine addiction researchers, essentially saying that the slower rate of absorption would limit the therapeutic value as a substitute for smoking.

Based on this information, it might seem that any drug administered rapidly would be more addicting. The quicker the rush, the stronger the reinforcement, but it’s more nuanced than that. A large part of this reinforcing effect has to do with underlying biological effects. Specifically conditioned learning. The average smoker who wants to quit will have a typical conditioned learning profile. Over time, the synaptic circuitry of the smoker’s brain has adapted to the smoking of cigarettes. Nicotine attaches to nicotinic achetocholine receptors (nAchR) at presynaptic neuronal terminals, stimulating the release of several neurotransmitters (e.g., serotonin, GABA, norepinephrine), including dopamine, which has been shown to play an important role in addiction. Importantly, nicotine over-stimulates dopamine in the reward center of the brain. As noted, smoking tobacco causes nicotine to reach the brain extremely quickly. The brain adapts to this type of nicotine consumption, and the reward system has a certain “expectation”, one that is met by smoking but not by chewing gum or using the patch. At least, not in the same way.

From U.S. Department of Health and Human Services (2008)

There are several approved medications for treating nicotine dependence. Most are NRTs, like the nicotine nasal spray, patch, and gum, but some are in pill form, like varenicline and bupropion. An analysis of 83 studies found that varenicline was the most effective (33%), with the nasal spray and high dose, long term patch use following behind at second and third (~26%). See the table for all investigated treatments.

What’s interesting is that these therapies are touted not as cures for nicotine addiction or even real replacements for smoking. Rather they’re used as smoking cessation tools to help reduce withdrawal symptoms and craving. If nicotine is the substance causing addiction, why doesn’t replacement nicotine counteract the addiction or at least replace the smoking addiction with a gum or inhaler addiction? After enough time, NRTs would replace the addiction, but the profile would look a little different.

Adapted rom Schultz 1998. Top panel shows dopamine activity (rows of black dots) in response to a novel reward. Middle panel shows dopamine activity in response to a cue that has been paired with the same reward from the top column. Notice the lack of increase in dopamine activity at the reward. Bottom panel shows dopamine activity in response to the same cue as in middle panel but no reward. Notice the decreased dopamine activity in response to no reward (gap in rows of black dots).

Moving from one type of nicotine consumption to another – each with different routes of administration – slowly changes an “expectation” at the neural level. Wolfram Schultz was one of the first to discover the interesting ways in which dopamine neurons “expect” certain cues and rewards, acting accordingly. He found that by pairing a cue with a reward, initially dopamine neurons increased activity at the reward. This increased dopamine signal essentially says, “This is good.” After several cue-reward pairings, the dopamine neurons increased activity at the cue but remained stable at the reward. The signal at the cue essentially says, “This leads to something good.” Importantly, after presentation of the cue but not the reward, dopamine neurons still had increased activity at the cue but actually decreased activity at the time when the reward usually was given (but wasn’t). The signal essentially says, “This used to be good.” This “depression” of dopamine neurons at the time when the reward should have been present is like disappointment when the “expectation” isn’t met and is thought to be partially attributable to withdrawal symptoms.

One more thing to consider is the many cues associated with nicotine addiction. People smoke everywhere; before work, after meals, while having a drink, after sex, etc. The many cues associated with smoking make it so dopamine neurons are constantly “expecting” the nicotine reward. It takes time for the neurons to reset and not expect the nicotine reward after all of these cues.

Applying this to smoking and NRTs, imagine a smoker that tries to quit while using the gum. Smokers are instructed to use the gum any time they have a craving to smoke. The problem is that the time course of nicotine from gum entering into the brain differs from smoking. When someone is cued to smoke and the dopamine’s expectation is not met, there is a “depression” of dopamine neurons, only partially offset by the delayed and gradual increase of nicotine from the gum.

One of the reasons the long term, high nicotine patch and varenicline are better treatment options – or if used in combination with gum, even more effective – is that they work chronically. The patch slowly releases nicotine for many hours, and varenicline acts as a partial agonist (stimulates) of nAchRs. Therefore, when the smoker is cued to light up, there’s already nicotine in the brain, partially meeting that dopamine “expectation”. Over enough time, not smoking but chewing gum would change the brain to “expect” the gum, forming a new addiction. That’s why it’s recommended smokers trying to quit reduce the nicotine content of the gum or patch over a number of weeks.

Thus, NRTs haven’t greatly alleviated the nicotine addiction problem, because they merely serve as another vehicle for an addicting substance, and a poor one at that. But, used in combination with counseling and a desire to quit, they can be effective in reducing addiction withdrawal, helping people kick the smoking habit.


Paul S. Regier has a PhD in neuroscience and is an addiction researcher at UPenn.

For resources on quitting, go here.

Reduce the stigma:  Until recently, smoking was socially acceptable. The discovery of disastrous health effects associated with smoking changed that, as well as social perception, leading to stigma. The irony is that those who were able to quit in the face of this new information probably hadn’t progressed as far along in addiction or weren’t as susceptible to addiction in the first place. This meant that those unable to stop were among the most vulnerable population, and yet they received – and continue to receive – the brunt of society’s judgment.