Unraveling the Mysteries of Nicotine Addiction

The Surgeon General’s landmark report directly linked cigarette smoking to lung cancer 50 years ago but, yet, nearly 40 million adults in the U.S. still smoke cigarettes, and new ones start every day. What is drawing them in, and why can’t they stop?

“Tobacco dependence is a complicated behavior,” said Robert Schnoll, PhD, director of Penn’s Center for Interdisciplinary Research on Nicotine Addiction (CIRNA). “It requires researchers to come at it from a variety of different perspectives and angles.”

And that’s what CIRNA’s multidisciplinary team does: tackle nicotine addiction on every level, from how a person’s genes might control the ability to quit to the impact cigarette packaging has on smoking behavior.

The Basics of Nicotine Addiction

Nearly 70 percent of smokers who try to kick the habit relapse within one week. Indeed, it can take smokers eight tries – or more – to break the habit for good. Yet, for some people, it’s basically one and done.

Research at Penn led by Caryn Lerman, PhD, the vice dean for Strategic Initiatives in the Perelman School of Medicine, and James Loughead, PhD, of Psychiatry, have studied how brain processes link to ease of quitting. Their studies show that smokers who exhibit increased activity in the brain’s executive cognitive network – which governs working memory, attention and cognitive function – are more likely to succeed at quitting smoking.

“This brain network is important for self-control, which smokers require to overcome strong urges to smoke that emerge during nicotine withdrawal,” said Lerman, who created CIRNA in 2001. Their work was the first was the first study to show that “withdrawal-related alternations in working memory and brain function can accurately predict relapse in smokers.”

They are now translating this research into clinical neuroscience-based interventions, studying the effects of different forms of noninvasive brain stimulation -- transcranial direct current electrical stimulation and transcranial magnetic stimulation – on brain function and behavior. Early results show that even a single session can reduce smoking “although we expect that repeated sessions will have stronger and more sustained benefits. We envision these forms of brain stimulation as an adjunct to medication for smoking cessation treatment, to improve clinical outcomes,” Lerman said.

Stopping Addiction Before it Starts

Every day, more than 3,800 young people – some as young as in middle school – smoke their first cigarette (or, possibly, electronic cigarette). For some, it’s just part of teenage “experimentation,” but for others, it leads to a lifelong addiction.

Janet Audrain McGovern, PhD, of CIRNA’s Adolescents and Young Adults Program, is examining the reasons why and how to prevent them from starting.

Studies show having peers – or family members – who smoke is a major factor, as is depression. But, even more interesting, studies show that adolescents who don’t engage in sports or school clubs are more likely to seek out smoking or alcohol. Audrain-McGovern’s 2003 study showed that “higher levels of physical activity across mid-to-late adolescence have been shown to reduce the odds of smoking initiation and progression by almost 50%.”

Electronic cigarettes – as opposed to combustible tobacco products such as cigarettes, cigars, or hookahs – have become quite popular among adolescents, but Audrain-McGovern cautions, “They may contain less known toxins compared to combustible cigarettes, but we don’t know the long-term impact of inhaling a heated vapor with flavorants. These flavorings were approved for consumption, not inhalation.”

An even more worrisome connection: are e-cigs a stepping stone to using combustible tobacco? A 2015 JAMA study that Audrain-McGovern coauthored showed that students who had used e-cigarettes by the time they reached ninth grade “were significantly more likely to report initiation of combustible tobacco use over the next year.

“Do adolescents begin vaping flavor and then transition to nicotine and flavor? Is the delivery of nicotine more rewarding in combustible tobacco products? Who are the adolescents that end up regularly using both e-cigarettes and combustible cigarettes?” Audrain-McGovern said. “This is what we’re investigating.”

Repurposed Meds: Can They Prevent Relapse?

Nicotine withdrawal often brings on many unpleasant symptoms, including depression, difficulty sleeping and concentrating, fatigue, and irritability, any of which can lead to a relapse. CIRNA researchers are investigating medications that, originally approved for one reason, could help prevent these symptoms and the accompanying return to smoking.

“With FDA-approved meds, we know they’re safe, we know the side effects, and we know their mechanism of action,” said Rebecca Ashare, PhD, who leads these investigations at CIRNA.

One study examined the use of galantamine – approved for cognitive decline in Alzheimer’s patients – for smokers who had trouble concentrating during nicotine withdrawal. “Early data shows that people who took the medication -- before they quit smoking – smoked fewer cigarettes than the people on a placebo,” Ashare said.

“This is consistent with the pharmacology of nicotine,” Schnoll added. “Studies show that nicotine has cognitive-enhancing effects. That’s one reason people become addicted.”

Ashare said that symptom-based medications would be paired with nicotine replacement therapy. “The hypothesis is that the two medications will boost quit rates.” The ultimate goal is to “characterize smokers based on a particular withdrawal pattern, for a precision medicine approach” to help them quit.

Schnoll is also tackling another type of challenge: connecting patients who smoke with resources to help them quit. This collaboration with Frank Leone, MD, director of Penn Stop: Penn’s Comprehensive Smoking Treatment Program, uses electronic medical records to flag cancer patients who are still smoking and then send an automated referral to Penn’s Tobacco Use Treatment Service (a component of Penn Stop).

“It makes tobacco cessation treatment part of a patient’s treatment plan,” Leone said.

Manipulating Perceptions

Over the decades, tobacco companies have used many strategies to keep people smoking, for example, endorsements by doctors, dentists and athletes. With the passing of the Family Smoking Prevention and Tobacco Control Act of 2009, the U.S. Food and Drug Administration finally had the authority to regulate the industry, including the ability to take over control of cigarette packaging and graphic warning labels.

Andrew Strasser, PhD, director of Penn’s Biobehavioral Smoking Lab, has shown that packaging does matter. In one of his studies, smokers received the same cigarettes in randomized, different colored packages and were asked to rate the cigarettes. Although it’s still early, “we can already see differences in how the smokers rate the cigarettes – how much they smoke, the quality... It’s all about manipulating perceptions.”

Strasser has also studied the impact of combining both graphic warning images with text as opposed to text alone. While 83 other countries already have these images on cigarette packages, warnings on U.S. packages remain on the side of the pack – in small print. 

“Studies show that people can’t even tell you what the text says,” he said.

Early results from another study, published in Tobacco Control, showed that when the image and text convey the same information – for example, a diseased lung along with the text ‘cigarettes cause lung cancer’ – “people do recall the information more than just text alone. This could be an important public health intervention in terms of better informing people about the risks.”

Penn is also one of 10 sites funded by the National Institutes of Health and the FDA studying the impact of modifying the nicotine level in cigarettes. Lowering the nicotine levels to 5.2 milligrams (vs 10-12 milligrams in regular cigarettes) – or even .4 milligrams – did not lead to smoking additional cigarettes or “oversmoking,” i.e. puffing more vigorously. Strasser said this strategy is not new; it was first proposed in 1995. “Many people long before me did a yeoman’s work to get to this point,” he said. “All along, we’ve been getting interesting findings but, before the 2009 ruling, it couldn’t be used to change anything.”

Now, though, it’s a different story – “We can also use science to better inform and drive policy.”