Eric R. Kandel, MD, who shared the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory, and Denise B. Kandel, PhD, professor of psychiatry at Columbia University Medical Center, write in the New England Journal of Medicine that electronic cigarettes (e-cigarettes) may function as a "gateway drug"—a drug that lowers the threshold for addiction to other substances, such as marijuana and cocaine— as part of the 120th Shattuck lecture and presented to the Massachusetts Medical Society.

In the lecture, the Kandels review Denise Kandel's earlier work on the gateway hypothesis and on the role of nicotine as a gateway drug, reported in a Science paper in l975. They also review subsequent studies in which they tested the gateway hypothesis experimentally in a mouse model. In those studies, conducted in collaboration with Amir Levine, Yan You Huang, Bettina Drisaldi, Edmund A Griffin, and others at CUMC, they found that when mice are exposed to nicotine, it alters their brain biochemically and induces activation of a reward-related gene.

As a result, nicotine primes the animals' subsequent response to cocaine, providing a molecular basis for nicotine as a gateway drug for cocaine.

"While e-cigarettes do eliminate some of the health effects associated with combustible tobacco, they are pure nicotine-delivery devices," said co-author Denise B. Kandel.

Dr. Denise Kandel's further analysis of 2004 epidemiological data from a large, longitudinal sample suggested that nicotine also primes human brains to respond to cocaine. She found that the rate of cocaine dependence was highest among users who started using cocaine after having smoked cigarettes.

"Our findings provided a biologic basis for the sequence of drug use observed in people," said Dr. Eric Kandel. "One drug alters the brain's circuitry in a way that enhances the effects of a subsequent drug."

E-cigarettes have been touted as a tool to curtail the use of conventional cigarettes and reduce the harmful health effects of combustible tobacco. But in light of the skyrocketing popularity of
e-cigarettes, particularly among adolescents and young adults, the researchers say that more effective prevention programs need to be developed for all products that contain nicotine.

"E-cigarettes have the same physiological effects on the brain and may pose the same risk of addiction to other drugs as regular cigarettes, especially in adolescence during a critical period of brain development. We don't yet know whether e-cigarettes will prove to be a gateway to the use of conventional cigarettes and illicit drugs, but that's certainly a possibility. Nicotine clearly acts as a gateway drug on the brain, and this effect is likely to occur whether the exposure comes from smoking cigarettes, passive tobacco smoke, or e-cigarettes."

Studies show that the typical e-cigarette user is a long-term smoker who has been unable to stop smoking. However, the researchers point out that e-cigarette use is increasing exponentially among adolescents and young adults. "The effects we saw in adult mice are probably even stronger in adolescent animals," said Dr. Eric Kandel.
"E-cigarettes may be a gateway to both combustible cigarettes and illicit drugs. Therefore, we should do all we can to protect young people from the harmful effects of nicotine and the risks of progressing to illicit drugs."

Jeffrey Lieberman, the Lawrence C. Kolb Professor of Psychiatry and chair of psychiatry at CUMC, said, "The emergence in our society of new recreational pharmaceuticals such as E-cigarettes and legalized marijuana, while justifiable on one level, may have adverse consequences of which we are not fully aware. The Kandels' research on 'gateway' drugs demonstrates such grave potential consequences."

"The recent legalization of marijuana in Colorado and Washington has rekindled the debate about whether marijuana is a gateway drug," said Dr. Denise Kandel. "Yet both proponents and opponents of legalization have overlooked the role of nicotine in leading to the use of illicit drugs and to addiction."