Like conventional cigarettes, electronic cigarettes (or e-cigarettes) may function as a “gateway drug” - a drug that lowers the threshold for addiction to other substances, such as marijuana and cocaine - according to the 120th Shattuck lecture, presented to the Massachusetts Medical Society by Columbia researchers Denise and Eric Kandel and published today in the online edition of the New England Journal of Medicine.

“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, PhD, professor of sociomedical sciences (in psychiatry), Department of Psychiatry and Mailman School of Public Health, at Columbia University Medical Center (CUMC).

The other co-author of the Shattuck lecture is Eric R. Kandel, MD, University Professor and Kavli Professor of Brain Science, co-director of the Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator of the Howard Hughes Medical Institute at CUMC. Dr. Kandel shared the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.

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.

Dr. Denise Kandel’s further analysis of 2004 epidemiologic 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.”
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The article is titled, “A Molecular Basis for Nicotine as a Gateway Drug.” The study was supported by grants from the Howard Hughes Medical Institute and the National Institutes of Health (R01 DA024001) and the National Institute on Drug Abuse (K5 DA00081). The authors declare no financial or other conflicts of interest.

Columbia University Department of Psychiatry

Columbia Psychiatry is ranked among the best academic departments and psychiatric research facilities in the nation and has contributed greatly to the understanding and treatment of psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in northern Manhattan, the department enjoys a rich and productive collaborative relationship with physicians in various disciplines at Columbia University’s College of Physician’s and Surgeons. Columbia Psychiatry is home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders, eating disorders, and childhood psychiatric disorders. The 2000 Nobel Laureate Eric Kandel was recognized for research that helped elucidate the cellular processes that underlie learning and memory - contributions that have implications for treating conditions such as Alzheimer’s and age-related memory loss. Columbia Psychiatry’s extraordinary scientific base is supported by more federal grants than any other psychiatry department in the nation.

The Mortimer B. Zuckerman Mind Brain Behavior Institute

Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute is an interdisciplinary hub for scholars across the university, created on a scope and scale to explore the human brain and behavior at levels of inquiry from cells to society. The institute’s leadership, which includes two Nobel Prize-winning neuroscientists, and many of its principal investigators will be based at the 450,000-square-foot Jerome L. Greene Science Center, now rising on the university’s new Manhattanville campus. In combining Columbia’s preeminence in neuroscience with its strengths in the biological and physical sciences, social sciences, arts, and humanities, the institute provides a common intellectual forum for research communities from Columbia University Medical Center, the Faculty of Arts and Sciences, the School of Engineering and Applied Science, and professional schools on both the Morningside Heights and Washington Heights campuses. Their collective mission is to further our understanding of the human condition and to find cures for disease.

Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast.

Columbia University’s Mailman School of Public Health

Founded in 1922, Columbia University’s Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 450 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,300 graduate students from more than 40 nations pursuing a variety of master’s and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including ICAP (formerly the International Center for AIDS Care and Treatment Programs) and the Center for Infection and Immunity.

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Karin Eskenazi
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Columbia University Medical Center