Is Nicotine a ‘Gateway’ to Cocaine Addiction (and Cancer)?

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Some have claimed that tobacco and alcohol are “gateway” drugs that people use before turning to illicit substances. While causal conclusions are hard to draw, at least one new study in mice shows that smoking may indeed increase the risk of cocaine addiction by changing gene activity in the brain. The findings also shed new light on how cigarettes cause cancer and why smoking can harm developing fetuses.

The study found that when mice received nicotine before and during exposure to cocaine, they were 78% more likely to prefer hanging out in the cage where they got the cocaine, compared with mice that were not similarly “pretreated” with nicotine. This so-called “place preference” is considered a reliable measure of how much animals like a drug, and can often predict a substance’s level of addictiveness in humans.

The nicotine-treated mice also showed greater changes in certain brain regions, compared with animals that received cocaine alone. However, giving the drugs in the reverse order, with cocaine first, did not increase the animal’s addiction to nicotine. Further, stopping nicotine delivery a week before giving cocaine eliminated the enhanced cocaine-related effects.

The authors also looked at data from a national survey on addictions and found that indeed being a smoker increased the risk of cocaine addiction. The majority of cocaine users in the group had smoked cigarettes before they started using cocaine, and started their cocaine use while they were active smokers.

Researchers have long noted that teens who later become addicted to drugs typically start by smoking cigarettes and drinking alcohol. But the order of events doesn’t necessarily mean that tobacco or alcohol use leads to other addictions. Rather, it may reflect the fact that these substances are a lot easier to acquire than illegal drugs. And since most smokers and drinkers do not become addicted to drugs, the significance of the order in which they are used remains unclear.

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“It’s hard to know what the most important implication of this study is because it has so many important implications,” says Nora Volkow, director of the National Institute on Drug Abuse, about the new mouse study appearing in Science Translational Medicine. Volkow wrote an editorial accompanying its publication.

The study shows at the basic science level that “nicotine has properties that we didn’t know about before,” Volkow says, explaining that the drug alters what are known as “epigenetic marks.” Unlike genetic mutations, which change DNA itself, epigenetic changes do not modify genes; instead, they influence the level of gene activity. In the brain such changes can affect learning and memory.

These epigenetic shifts could help explain why nicotine enhances certain aspects of mental performance and why it is addictive. Addiction is in many senses a form of learning: essentially, people who are addicted have learned to like drugs too well, and have difficulty unlearning this preference. That results in a diminished ability to resist using drugs in contexts that have become associated with drugs, or when under stress.

Indeed, rehabs have long tolerated cigarette smoking by patients for fear that asking people to make too many behavioral changes simultaneously would cause them to drop out. “That practice needs to be questioned,” says Volkow, noting that the new research suggests quitting cocaine might be easier in the absence of nicotine, whether it’s delivered through cigarettes or nicotine replacement therapy. She says other medications should be studied in this setting instead.

Epigenetic changes can also affect a person’s risk of cancer. “Nicotine itself is not carcinogenic,” says Volkow, but “nicotine can enhance the carcinogenic effect of other substances so that when [someone is] exposed to a certain carcinogen [along] with nicotine, it would have a worse effect. This could be potentially a mechanism by which nicotine could exacerbate the carcinogenicity of other chemicals.”

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Could this explain why marijuana smoking isn’t associated with the kind of cancer risk that is seen with tobacco? Volkow thinks the difference probably has more to do with quantity. “I would start with the dose effect,” she says, noting that people smoke a lot more tobacco than marijuana. But she doesn’t rule out the possibility of a qualitative difference. “[There] is definitely a much higher risk of cancer from smoking cigarettes than marijuana. It’s too premature to say that it’s just dose; it could be a difference between the combination of nicotine with other chemicals [in cigarettes] and the combinations seen in cannabis. We don’t know, but someone has to study it.”

The epigenetic changes that result from nicotine exposure may also explain why smoking during pregnancy can be harmful to the fetus. Indeed, research suggests it may be somewhat more harmful to developing fetuses than smoking crack, contrary to media claims made when that drug first appeared (though, obviously, taking any recreational drug during pregnancy is not advisable).

The study suggests that it may not be nicotine itself, but the changes in gene activity related to nicotine, that alters fetal development and causes harm during pregnancy, potentially resulting in problems like low birth weight and birth defects.

That suggests that nicotine replacement therapy may also be risky in the treatment of pregnant smokers. “I think that this is a very serious issue that needs to be properly addressed,” says Volkow.

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Maia Szalavitz is a health writer at Find her on Twitter at @maiasz. You can also continue the discussion on TIME Healthland’s Facebook page and on Twitter at @TIMEHealthland.