Nicotine Gateway Effects on Adolescent Substance Use

Michelle Ren, MS; Shahrdad Lotfipour, PhD

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

Methods

Prior to drafting this manuscript, the two authors independently evaluated and summarized research articles that addressed adolescent substance use and nicotine's impact on the developing brain and behavior. We conducted a comprehensive review of the literature using a two- to three-word combination of the following keywords: adolescence, substance use, nicotinic acetylcholine receptors, gateway, reward, smoking, tobacco, nicotine, alcohol, psychostimulant, cocaine, amphetamine, cannabis, opioids. We utilized the electronic databases of PubMed and Google Scholar for research articles published in English between January 1968 and November 2018. Articles were included in the review if they discussed nicotine exposure during adolescence, drug sequence patterns, or adolescent substance use. The references from relevant articles and websites of relevant organizations were also examined for other potential sources of information. Out of 80,000 initial search results, approximately 5,000 were reviewed as relevant and non-duplicate articles. To retain focus on adolescent initiation of nicotine products, studies related to maternal tobacco or nicotine exposure were excluded. Studies evaluating other interventions (i.e., medication, sleep, exercise) were also excluded to maintain focus on nicotine's effects on brain function and behavior. We grouped studies together according to their methodological similarities, so findings without substantial support or reproducibility (i.e., fewer than 5 comparable studies) were excluded. Following exclusion and careful analysis of studies based on key results, limitations, suitability of the methods to test the initial hypothesis, and quality and interpretation of the results obtained, 174 references were selected. The use of two reviewers and two extensive electronic databases allows for a widespread range of research articles, which maximizes scientific credibility and minimizes potential bias.

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Table 1. Summary of epidemiological and clinical findings supporting the gateway hypothesis. Surveys of adolescents and/or young adults were conducted to assess gateway effects of nicotine on subsequent drug use. Details of these selected epidemiological and clinical surveys and findings are highlighted, including age, data source, data analysis, and main observation(s).
Age	Data source and analysis	Main observation(s)	Reference(s)
24–25 years (follow-up of former adolescents aged 15–16 years)	Longitudinal cohort of former New York State high school students, followed from grades 10 and 11 (ages 15.7–34.2). Detailed monthly drug use histories were obtained. The following sequence of progression was tested: alcohol, cigarettes, marijuana, other illicit drugs, and prescribed psychoactive drugs. In addition, months of use and non-use of cigarettes and cocaine were identified.	Sequence pattern: Cigarettes preceded marijuana use with or without initial alcohol use among women. However, in men, alcohol consistently preceded marijuana use even in the absence of initial cigarette use. Cigarettes preceded other illicit drugs among women, but not among men. Cigarette and cocaine use: Most cocaine users smoked cigarettes before they started using cocaine. In addition, most cocaine users started using cocaine while they were actively smoking cigarettes (i.e., within the same month).	3,5
11–16 years	Subjects were sampled from eight public schools in Milwaukee, Wisconsin. The subjects were interviewed twice, first during 1979-80 and again during 1981–82. Eighty-nine percent of those interviewed initially were re-interviewed two years later.	Cigarette use fell on a cumulative (Guttman) scale of use with other drugs (e.g., marijuana, beer, liquor, stimulants, depressants). Having tried substances lower on the Guttman scale made one significantly more likely to be using substances higher on the scale two years later. Use of cigarettes during middle or early high school significantly increased the likelihood that the subject would be using other drugs (e.g., beer, marijuana) two years later.	4
Years 12–15, 16-17, 18-25, 26–34, 35-49, 50 or over	1994 National Household Survey on Drug Abuse. Data were analyzed to clarify whether cigarette smoking has any effect on the initiation of illegal drug use.	Individuals who had smoked cigarettes were far more likely to use marijuana, cocaine, heroin, and/or crack. Those who smoked cigarettes before age 15 were up to 80 times more likely to use illegal drugs than those who did not. Cocaine was the drug most likely to be used among young cigarette smokers.	5
16–34 years	National Epidemiological Study of Alcohol Related Consequences, a cohort representative of the U.S. population. The rates of lifetime cocaine dependence were compared among three groups: 1) those who had started to use cocaine after they had started to smoke and before they had stopped smoking, 2) those who had started cocaine use before beginning to smoke; and 3) those who had ever smoked 0–100 cigarettes.	The rate of cocaine dependence was the highest among cocaine users who initiated cocaine after having smoked cigarettes. The rates of dependence were much lower among those who initiated cocaine before smoking or who had ever smoked 0–100 cigarettes.	8
11–20 years	National Longitudinal Study of Adolescent to Adult health data spanning a 14-year period. The relationship between gateway drugs during 11–20 years of age and drug use in adulthood was analyzed using generalized estimating equation regression models.	Exposure to marijuana and illegal substances during young adulthood was positively associated with illegal substance and cocaine use. Interactions between the gateway drugs and reporting high depressive symptoms in adolescence or adulthood were associated with increased use of marijuana, illegal drugs, and cocaine in early or young adulthood.	14
14–30 years	Systematic review and meta-analysis of longitudinal studies that assessed initial use of e-cigarettes and subsequent cigarette smoking. Study selection: longitudinal studies reporting odds ratios for cigarette smoking initiation associated with ever use of e-cigarettes or past 30-day cigarette smoking associated with past 30-day e-cigarette use.	E-cigarette use was associated with greater risk for subsequent initiation of cigarette smoking and past 30-day cigarette smoking.	17
14–16 years	Subjects were sampled from 10 public schools in Los Angeles, California. Students completed surveys at baseline (grade 9) and at a 24-month follow-up (grade 11). Associations of baseline e-cigarette, hookah, or combustible cigarette use with ever marijuana use (initiation), current marijuana use (past 30 days), and current dual use of marijuana and tobacco products were examined at the 24-month follow-up.	High schoolers who used e-cigarettes or hookah at baseline compared with those who did not were more likely to report initiation and current use of marijuana as well as dual use of tobacco and marijuana. E-cigarette and hookah use at age 14 years was associated with a 3.6- to 4-fold increase in the odds of initiating and currently using marijuana two years later. The use of e-cigarettes, hookah, and combustible cigarettes in early adolescence more than doubled the odds of currently using both tobacco and marijuana by mid-adolescence.	19

Table 2. Summary of preclinical studies supporting the gateway hypothesis. Rodent studies highlight nicotine pretreatment paradigms and subsequent observations, including nicotine treatment doses, duration of treatment, species used, age of exposure, behavior tests, and main observation(s).
Nicotine dose, route of administration, and duration	Species and age of nicotine exposure	Behavior test(s)	Main observation(s)	Reference
60 μg/kg, IV, 4 days	Sprague Dawley rats, PND 28–32 vs. PND 86–90	IV self-administration of cocaine (0.5 mg/kg/inj), methamphetamine (0.02 mg/kg/inj), or ethanol (1 mg/kg/inj), 1 day each	Adolescent rats pretreated with nicotine had increased initial acquisition of cocaine, methamphetamine, and ethanol compared to saline-treated adolescents and both saline- and nicotine-treated adults.	86
0.03 mg/kg/0.1 ml, IV, 2/daily for 4 days	Sprague Dawley rats, PND 28–32 vs. PND 86–90	IV self-administration of cocaine (200 or 500 μg/kg/inj), 5 days	Adolescent rats pretreated with nicotine had greater reinforced responding for cocaine compared to saline controls and adults.	87
0.4 mg/kg/day, IP, 10 days	Sprague Dawley rats, PND 34–43 vs. PND 60–69	IV self-administration of nicotine (0.04 mg/kg/inj), 15 days	Animals exposed to nicotine during periadolescence self-administered more nicotine than vehicle-exposed animals and animals exposed during postadolescence.	99
0.1, 0.5, or 1 mg/kg, SC, 2/daily for either 1 (acute) or 7 (repeated) days	ICR (CD-1) mice, PND 28–34 vs. PND 50–56	CPP for cocaine (1, 5, or 10 mg/kg, i.p.), morphine (5 mg/kg, s.c.), and amphetamine (0.2 mg/kg, s.c.,), 3 days conditioning	Adults exposed to nicotine during early but not late adolescence had increased CPP for cocaine, morphine, and amphetamine.	103
0.5 mg/kg, SC, 2/daily, 7 days	ICR mice, PND 24–30	Locomotor activity	Adults exposed to nicotine during early adolescence had enhanced cocaine-induced locomotor sensitization compared to saline-treated animals.	103
0.4 mg/kg, IP, 14 days	Long-Evans rats, PND 28–42	Operant ethanol self-administration: 8-day ethanol fading procedure (2-8% v/v)	Adults exposed to nicotine during adolescence had increased ethanol self-administration and altered GABA transmission and chloride homeostasis in the ventral tegmental area compared to adolescent and adult saline exposure and adult nicotine exposure.	104
0.1, 0.2, 0.4, 0.8 mg/kg, SC, 10 days	Wistar rats, 150 grams (age not specified)	Operant ethanol self-administration (12% v/v)	Nicotine pretreatment at a higher dose initially suppressed alcohol consumption but stimulated alcohol consumption on repeated treatment.	113
0.4 mg/kg, IP, 7 days	Sprague-Dawley rats, ~PND 30–37 vs. ~PND 60–67 (based on body weight)	Locomotor activity	Nicotine increased locomotor activity in all animals. Adolescent rats pretreated with nicotine had sensitization to nicotine-induced repetitive motion over the 7-day nicotine treatment period. Adolescent, but not adult, rats had increased amounts of cocaine-induced repetitive motion after nicotine pretreatment.	114
0.4 mg/kg, IP, 7 days	Sprague Dawley rats, ~PND 30–37 vs. ~PND 60–67 (based on body weight)	Locomotor activity, IV self-administration of cocaine (descending doses of 1.0, 0.5, 0.25, 0.125, 0.06 mg/kg/inj)	Adult rats exposed to nicotine during early adolescence were sensitized to the locomotor-activating effects of cocaine and self-administered a greater number of cocaine infusions than adolescent rats pretreated with vehicle.	116
0.4 mg/kg, IP, 10 days	Sprague Dawley rats, PND 35–44	CPP for cocaine (1 or 3 mg/kg, IP), 12 days alternating cocaine and vehicle	Adult rats that received nicotine treatment during adolescence had enhanced preference for cocaine.	117
0.16 or 0.64 mg/kg, SC, 16 days	Sprague Dawley rats, PND 35–50	IV self-administration of methamphetamine (0.05 mg/kg/inj); methamphetamine-primed reinstatement (1 mg/kg, IP)	Nicotine-exposed versus saline-exposed rats obtained more methamphetamine infusions. The high dose of nicotine had no effect on methamphetamine intake and neither nicotine dose altered methamphetamine-primed reinstatement.	118
0.1 or 0.5 mg/kg, SC, 2/daily, 7 days	ICR mice, PND 28-34 vs. PND 50–57 vs. PND 70–77	CPP for cocaine, morphine, or amphetamine	Mice treated with nicotine during early adolescence, but not late adolescence or adulthood, showed an increase in CPP for cocaine, morphine, and amphetamine later in adulthood.	151

PND, postnatal day; IP, intraperitoneal, IV, intravenous, SC, subcutaneous; Inj, injection, CPP, conditioned place preference; μg, microgram; kg, kilogram; ml, milligram.

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