Michelle Ren, MS; Shahrdad Lotfipour, PhD


Western J Emerg Med. 2019;20(5):696-709. 

In This Article

Abstract and Introduction


Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine's impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.


The growing use of tobacco and electronic nicotine delivery systems ("vaping") among teenagers represents a major public health concern. Smoking is not only the leading cause of preventable death worldwide, but epidemiological, clinical, and preclinical data have also shown that adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances.[1–19] This phenomenon is known as the gateway hypothesis.[10,20,21] Furthermore, adolescents are more likely to first experiment with combustible cigarettes and/or e-cigarettes than they are marijuana.[22,23] Sequence patterns of drug initiation were examined in a recent study (2015), which reported that 38.8 percent of adolescents initiate nicotine before alcohol and/or marijuana, while 21.3 percent use alcohol prior to nicotine and/or marijuana, and 8.6 percent use marijuana before nicotine and/or alcohol.[23]

Although previous reports highlight that the rates of cigarette smoking are decreasing in the United States (U.S.), from 20.9 percent in 2005 to 15.5 percent in 2016, current trends in teen use of electronic nicotine delivery systems (e.g., e-cigarettes, vaporizers, hookah pens) are rapidly increasing.[24–26] In particular, the rate of current e-cigarette use in high school students jumped from 1.5 percent in 2011 to 11.7 percent in 2017, then alarmingly to 20.8 percent in 2018.[24,27] Among middle school students, a rise of 48 percent in e-cigarette use has also been reported from 2017 to 2018. This translates to a massive surge of an additional 1.5 million youth having been exposed to e-cigarettes in the last year alone in the U.S. The youth are often attracted to e-cigarettes due to their flavoring, easy availability, and a lack of awareness of their harmful effects.[28,29] While e-cigarettes are marketed to aid in smoking cessation for adults, they have had inconsistent effects on cessation in adults and have been shown to promote smoking progression in the youth, with increased cigarette smoking in adolescents who had previously used e-cigarettes (19.1 percent) compared to those who had not (4.6 percent).[30,31] In this review, we present studies that support a causal role of adolescent nicotine exposure in maladaptive alterations in reward processing during and beyond adolescence, with molecular, neurochemical, and cognitive impacts on the brain that ultimately encourage subsequent drug use.

Adolescence is a period of transition characterized by significant hormonal, psychosocial, and neural changes in rodents (postnatal day (PND) 28–42) and humans (12-18 years of age).[32] Adolescence is a time of increased exploration and the development of social, emotional, and cognitive skills to prepare for independence of adulthood. However, adolescence is also associated with increased vulnerability to stress and risk-taking behaviors, such as sensation seeking and experimentation with recreational drugs.[33–35] These age-specific behaviors are largely due to maturational changes in the brain.

During this sensitive maturational period, the brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products. Nicotine is the primary psychoactive constituent in tobacco products and binds to nicotinic acetylcholine receptors (nAChRs), which are pentameric ligand-gated ion channels composed of α and β subunits (α1-7, 9–10; β1-4). nAChRs are widely distributed throughout the human and rodent brain and periphery, and are critical in the processes of the neuromuscular junction, neurotransmitter release, brain maturation, reward processing, and cognition.[36–45] nAChRs are activated endogenously by acetylcholine or exogenously by nicotine, and are expressed by the majority of neuronal subtypes, including dopaminergic neurons, which facilitate drug intake and abuse.[46–49] Nicotine exposure during adolescence, in particular, disrupts the normal development and expression of neuronal nAChRs, ultimately altering the function and pharmacology of the receptor subunits and changing the release of dopamine, serotonin, GABA, glutamate, and other reward-related neurotransmitters.[50–52]

Many factors are recognized to contribute to the onset of teenage substance abuse, such as genetics, stress, and socioeconomic status.[53,54] While various mechanisms may impact substance abuse and addiction, this review focuses on the influence of developmental nicotine exposure on long-term changes in reward neural circuitry and subsequent drug use. We highlight findings from both human and rodent studies, as animal models provide insight into human brain maturation, physiology, and behavior.[32,55,56] We argue that the effects of nicotine are highly dependent on timing of exposure, and that nAChRs interact with other drug receptor systems to directly mediate reward and reinforcement.

Clinical Implications. The escalation in teenage use of nicotine products prompts the need to raise awareness of the detrimental effects of developmental nicotine exposure. A more complete understanding of nicotine's gateway effects during adolescence is critical due to the extremely high and rising economic and societal costs, as well as deaths, associated with substance use. Estimates suggest that drug dependence in the U.S. is associated with over $700 billion in annual costs and more than 64,000 drug overdose deaths in 2016, which is nearly double what was observed the prior decade and continues to climb.[57–59] We provide evidence for the gateway hypothesis in an effort to build knowledge for Emergency Department clinicians and other healthcare professionals to exhaustively advise their patients and patients' caretakers. The depth of this understanding, specifically the molecular consequences of adolescent nicotine use, allows for individualized treatment plans with a greater emphasis on medication interactions, care coordination, community resources, education, and advocacy. These clinical adjustments may contribute to decreases in addiction and drug-related emergencies.