Candice E. Van Skike1 , Shannon L. Zandy2 and Douglas B. Matthews3
Department of Pharmaceutical Sciences, University of Kentucky, 789 S. Limestone Street, BioPharm Complex 498, Lexington, KY 40536, USA
Department of Pharmacy, The University of Texas at Austin, 2409 University Ave, Stop A1915, Austin, TX 78712, USA
Department of Psychology, University of Wisconsin - Eau Claire, HHH 273, Eau Claire, WI 54701, USA
Candice E. Van Skike
Shannon L. Zandy
Douglas B. Matthews (Corresponding author)
Drug experimentation during adolescence is relatively common  and drug use during this time is increased, as the rate of past month illicit drug use in adolescents and young adults is nearly three times that of adults . The initiation and progression of substance use during adolescence is influenced by the distinctive behavioral and neurobiological alterations occurring during this developmental period. Various environmental and psychosocial factors also contribute to the initiation of drug use in adolescents. For instance, personality and psychological factors such as impulsivity, autonomy, depression, and anxiety are all associated with drug use. Additionally, a family history of substance abuse is a contributor to use and dependence , but that effect can be mediated by adolescent novelty seeking . This behavior, involving risk taking and sensation seeking, increases during adolescence, which is seen in humans [5, 6] and rodents . This parallels drug intake behavior, with adolescent humans  and rodents [9–11] consuming more of the substances per occasion than adults.
The progression of drug use is driven by drug responses that are unique to this developmental period. For most drugs of abuse , adolescents generally are more sensitive to the rewarding effects of drugs and also experience less aversive consequences than adults . Furthermore, exposure to drugs of abuse during adolescence permanently changes responses to drug use in the future even after a period of abstinence [13–16]. Perhaps because of these unique age-dependent effects, there is a clear association between an early age of onset and future substance use disorders [17, 18]. Therefore, adolescence can be thought of as a period of enhanced vulnerability to substance use and abuse .
The adolescent neurobiology is distinct from that of the adult. The adolescent brain is continuing to develop, with brain regions developing at different rates. For instance, activity in the nucleus accumbens, an area important in reward processing, peaks early during adolescence and correlates with increased laboratory risk-taking behavior . The prefrontal cortex , a region that governs cognitive control, develops later than reward-processing regions . It has been speculated that this offset in development of reward and control brain regions underlies the increased risk taking during adolescence, although recent data does not provide support for this theory on an individual basis . Additionally, the molecular targets of drugs of abuse, called receptors, have differential expression patterns and subunit composition that are differentially altered by brain region, age, and drug exposure. The unique neurobiology of the adolescent likely underlies the enhanced vulnerability of the adolescent to substance use and abuse.
With these generalizations in mind , this chapter will review the epidemiology of adolescent drug use, factors contributing to initiation, and the adolescent-specific neurobiological and behavioral consequences of several commonly used drugs during adolescence: nicotine, alcohol, and marijuana. While significant variability exists between all drugs during adolescence, we hope these three serve as hallmark drugs where the reader gains a valuable insight into how drugs impact this developmental window. We consider both human and animal studies to provide a thorough look at the effects of drug use during this time period. Human studies elucidate the epidemiology of drug use and provide data regarding the effects of individual patterns of intake. While reflective of the actual population, the research is limited by the wide variability of intake patterns and polysubstance use. Preclinical research allows for experimental control and manipulation of specific drugs of abuse and patterns of exposure. This permits the study of the behavioral, neurochemical, cellular, and molecular effects of these drugs under specific conditions. We cover both research approaches, as they complement each other when taking a comprehensive look at substance use during adolescence.
Smoking is a leading cause of preventable morbidity and mortality globally and continues to significantly impact public health in the United States. Smoking initiation occurs most often during adolescence and early use of cigarettes is associated with increased risk of dependence later in life . Conventional cigarette smoking is declining overall among American teenagers with 8 % of eighth, tenth and 12th grade students combined reporting smoking in the prior month . However, there has been a substantial rise in popularity of electronic cigarettes (e-cigarettes ) among adolescents. Specifically, the prevalence of e-cigarette use in the last 30 days is more than twice that of regular cigarettes in eighth and tenth grade students and fewer of these students associate significant risks with e-cigarettes compared to conventional cigarettes . This is a concern as e-cigarettes may be a more attractive nicotine delivery method for adolescents. Even low rates of nicotine use during adolescence increases the risk of dependence in adulthood, highlighting the need to understand the factors contributing to early use .
There are many environmental and psychosocial factors contributing to smoking initiation in adolescents. Environmental factors, such as exposure to smoking from family members and peers, influence initiation and escalation of smoking in adolescence. For example, parents and the number of friends who smoke is associated with a 30 and 44 % increase in likelihood of adolescent smoking, respectively . Autonomy also plays a significant role in contributing to nicotine use in the adolescent population. As parental involvement declines and decision-making autonomy increases, adolescents are more likely to become smokers, which is shown across ethnic, gender, and socioeconomic groups . In addition, psychological factors such as depression and anxiety are commonly associated with adolescent smoking. Depression and anxiety have been shown to predict initiation of smoking, nicotine dependence, and decreased success at smoking cessation. Young adults that reported elevated depression symptoms as adolescents were found to have significantly higher lifetime smoking rates .
Clinical reports suggest an enhanced sensitivity to the positive subjective effects of nicotine may contribute to initiation and continued tobacco use in adolescence. In particular, adult smokers that began smoking during adolescence describe more positive effects and fewer unpleasant side effects of their first smoking episode than smokers that initiated smoking in adulthood . In addition to enhanced positive effects, adolescents may be more resistant to negative effects of nicotine withdrawal, which is a significant predictor of relapse in adult smokers. However, in acute abstinence, adolescent smokers exhibited minimal withdrawal symptoms that were not associated with reports of dependence or biological measures of use . This might indicate that nicotine withdrawal symptoms may not influence maintenance of smoking behavior in adolescents as it does in the adult population. This has important implications for clinical identification and treatment of adolescent nicotine users, as the severity of nicotine withdrawal symptoms is prevalent in current diagnostic criteria and the focus of many available treatment options.
Given that 90 % of adult smokers were under 18 when they had their first cigarette , this suggests that there is something unique about the adolescent developmental period that confers increased rates of addiction. Consistent with this notion, preclinical studies indicate that nicotine exposure during the adolescent developmental period perpetuates nicotine use [10, 13], as well as other drugs of abuse . Specifically, voluntary nicotine intake is higher in adolescent rodents compared to adults [9, 10]. Although nicotine pharmacokinetics is altered in adolescent rats , studies suggest the age-dependent intake patterns are based on altered motivational properties of nicotine . Indeed, adolescent rodents are more sensitive than adults to the rewarding effects of nicotine . This increased reward during adolescence persists into adulthood even after a period of abstinence [13–15] and corresponds to increased nicotine self-administration later in adulthood compared to adults that were nicotine naïve during adolescence . Furthermore, nicotine exposure during adolescence, but not adulthood, sensitizes future behavioral responses to other drugs of abuse like cocaine [13, 28], THC , and alcohol .
The altered short- and long-term consequences of nicotine use during adolescence have a neurobiological basis: the adolescent brain is undergoing maturation , so the neurobiological response to nicotine is differentially modulated due to both development and drug exposure. Chronic nicotine exposure alters nicotinic acetylcholine receptor (nAChR) expression in the brain of humans  and rodents . Of particular interest due to their ubiquitous expression in mammalian brain  and role in nicotine dependence and reinforcement  are the α4β2-containing (α4β2*) nAChRs . The α4β2* receptors are differentially expressed throughout the brain based on age and brain region, with an average of 50 % greater radioligand binding to these receptors in adolescent rats . Additionally, adolescents have more α4β2* receptors on dopamine cell bodies and terminal regions than adults , and since nicotine-induced dopamine release is mediated by the α4β2* receptors , the overexpression of α4β2* receptors in these regions may contribute to the enhancement of the nicotine-induced reward seen during adolescence. Nicotine use upregulates α4β2* and α7 receptors, which are involved in acquisition and dependence . While the upregulation of these receptors is reduced in adolescents versus adults , these changes are more persistent and ubiquitous throughout different brain regions in adolescents . This distinct pattern of nAChR expression and nicotine-induced upregulation during adolescence may contribute to the initiation and persistence of nicotine use during adolescence.
Many factors contribute to smoking initiation; however, both human and preclinical research indicates that adolescents have an enhanced sensitivity to nicotine reward. Furthermore, nicotine exposure during adolescence alters future responses to other drugs of abuse, yielding a predisposition toward the development of a substance use disorder.
Alcohol is the most widely used drug by adolescents . Two-thirds of high school students have consumed alcohol by graduation and more than a quarter of students report drinking by eighth grade . Binge drinking (defined as consuming five or more drinks per drinking session for males and four or more per session for females) is the most common drinking pattern among adolescents, often drinking more on average in one session than adults . This is particularly concerning as binge drinking is associated with detrimental effects on brain development and cognition and increased rates of alcohol dependence. The rate of alcohol use dramatically increases between ages 12 and 20, which directly translates into an increase in alcohol use disorders. In fact, the highest prevalence of alcohol dependence occurs in ages 18–20, often referred to as “emerging adulthood,” the period immediately following adolescence . As with other drugs of abuse, age of onset for alcohol use is a significant predictor for future alcohol-related problems. Adolescents that began drinking prior to the age of 14 were shown to have a fourfold greater rate of alcohol dependence than individuals that did not begin drinking until after 20 years old .
Aside from rates of alcohol dependence , research has begun to show adolescents with a history of alcohol use differ significantly on cognitive and neural measures compared to those with little or no alcohol use. Studies show alterations in gray and white matter brain structure, poorer neurocognitive performance, and altered brain activation patterns . For example, adolescents with 2 years of heavy drinking history showed abnormalities in brain activation during a spatial working memory task, which was positively correlated to the amount of alcohol use and hangover symptoms reported . There also may be significant gender considerations to be made for consequences of adolescent alcohol use. Females are more vulnerable to alcohol-induced neurotoxicity [46, 47], an effect that begins to emerge during puberty.
In addition to neurocognitive abnormalities that result from alcohol use, it is also important to highlight neurobiological differences and genetic risks that can increase susceptibility to early initiation of alcohol drinking or heavy patterns of use during adolescence. Poorer performance on tests of inhibitory control in early adolescence prior to any alcohol or drug use was significantly related to heavy alcohol use in later adolescence. Additionally, lower baseline activation and structural differences predict future heavy alcohol use in adolescents . Interestingly, twin studies suggest that environmental influences such as access to alcohol have a large influence on the age that adolescents initiate alcohol use. However, a family history of alcohol misuse has a stronger influence than environmental factors on the amount of alcohol consumed in a session and escalation patterns . Together, these findings suggest that alcohol use in adolescence negatively impacts cognition, brain structure and function, and future health outcomes. Current and future research is leading toward unique opportunities to target prevention and treatment strategies specific to various risk factors within the adolescent population.
Preclinical models also indicate that there is a neurobiological predisposition to excessive binge-like alcohol consumption during adolescence. Indeed, much like adolescent humans , adolescent rodents will self-administer greater quantities of alcohol per unit weight than adults . This is likely underscored by age-dependent effects of ethanol on behavior and neurophysiology. Specifically, adolescents are less sensitive to ethanol-induced motor impairments , which serve as feedback cues to attenuate consumption within a single drinking session . Changes in cerebellar electrophysiology  suggest a neurological correlate for this behavioral difference. Furthermore, adolescents are more sensitive to the ethanol-induced reward and less sensitive to the adverse effects, like acute withdrawal or hangovers [51, 52]. These altered neurobiological responses create a predisposition toward excessive binge-like alcohol use in the adolescent.
This susceptibility is particularly concerning because adolescents are especially vulnerable to ethanol-induced neurotoxicity, as well as age-specific long-lasting neuroadaptations. For example, after binge alcohol exposure, the adult brain has increased gene expression involved with mechanisms of repair and protection against oxidative damage, while adolescents have decreased expression of these genes and increased proapoptotic gene expression . Some of the ethanol-induced neuroadaptations extend into adulthood and are associated with persistent behavioral changes. For instance, adolescent chronic alcohol exposure yields persistent reductions of hippocampal volume , decreased neurogenesis , and increased cell death . This is correlated with an increase in disinhibitory behavior , suggestive of altered risk-taking behavior. In fact, chronic ethanol exposure increases risk preference in adolescent, but not adult, rats even after nearly 3 weeks of abstinence . Alcohol reward is also altered, as binge-exposed adolescents have reduced dopamine release in adulthood . These neuroadaptations likely underlie alterations in ethanol preference, as rats that were exposed to ethanol during adolescence, but not adulthood, had greater ethanol intake in the future , which mirrors the increased rate of future alcohol dependence seen in human adolescents . Overall, preclinical findings mirror the ethanol intake patterns of human adolescents and suggest that alcohol use during adolescence can yield persistent changes in brain and behavior despite long periods of abstinence.
Cannabis is one of the most commonly used illicit drugs among adolescents and adults. The use of marijuana has remained stable the last few years, with over 20 % of 12th grade students reporting use in the previous month . However, attitudes of greater acceptance and less perceived risk are becoming more prevalent among teenagers. In fact, only 36.1 % of high school seniors believe regular use puts them at great risk . While public acceptance increases and legalization of marijuana continues in the United States, it largely remains unclear how cannabis may cause potential alterations in neuromaturational processes during adolescence.
Chronic marijuana use in early adolescence is associated with deficits in cognitive function in humans due to structural changes and decreased connectivity in brain regions important to learning and memory . In fact, short-term memory impairments persist after 6 weeks of abstinence in cannabis-dependent adolescents . Additionally, adolescent marijuana users perform worse on tests of executive functioning, correlating with the number of days of cannabis use in the past 30 days . Although some studies suggest differences in learning and memory can recover to baseline levels following abstinence, attention deficits seem to be persistent .
Compelling evidence also suggests adolescent cannabis use is associated with the development of psychosis in adulthood. One prospective study showed an increased risk of psychotic disorders at age 26 associated with cannabis use in adolescence between ages 15–18 . Other studies report early use of cannabis predicts a significant younger age of onset of psychosis and poorer treatment prognoses. Overall, the role of genetics and brain white matter maturation have been hypothesized to contribute to determining whether cannabis use may influence the development of adult psychosis in predisposed individuals.
Functional imaging studies report significant differences in brain activation patterns between adolescent marijuana users and nonusers. Marijuana users show more activation in areas of the brain associated with executive control during an inhibitory processing task, suggesting additional recruitment may be needed to maintain inhibition in adolescents with a history of marijuana use . Additionally, initiation of cannabis use before age 16 is associated with increased brain activation during working memory tasks . A recent longitudinal study found adolescents that reported weekly cannabis use prior to the age of 18 showed greater neuropsychological decline into adulthood, even following prolonged abstinence .
The major psychoactive component of cannabis smoke is ∆9-tetrahydrocannabinol (THC) and exerts its effects through agonism of cannabinoid-1 receptors (CB1Rs). Cannabinoid receptors are expressed throughout the brain, increasing during adolescence and are thought to influence gene expression critical for neural development . Therefore, modulation of the endocannabinoid system during adolescence is likely to produce persistent neurological changes. Preclinical studies reveal baseline age-dependent differences in CB1R function that results in differential effects of THC at the CB1Rs. Adolescent CB1Rs are less sensitive to THC-induced desensitization, which corresponds with a lack of tolerance to the memory-impairing effects of THC . Adults also develop tolerance to THC-induced memory impairments, indicating that adolescents may have greater memory impairments due to altered THC-induced neuroadaptations. Indeed, adolescent rats are more sensitive than adults to chronic THC-induced spatial memory impairments , especially at high doses [69, 70]. These spatial learning deficits in THC-treated adolescents can be attributed to an impaired ability to organize working memory  and may arise from THC-suppressing transcription of learning-induced neuroplasticity in the adolescent hippocampus .
THC exposure during adolescence has long-term consequences as well. Chronic exposure to THC during adolescence produces residual impairments in spatial working memory, changes in hippocampal morphology, and reduced markers of neuroplasticity that extend into adulthood even after 30 days of abstinence . Additionally, adolescent females appear to be particularly vulnerable to both the short- and long-term consequences of THC exposure, as they are more sensitive to immediate memory disruptions  and exhibit depressive symptomology during adulthood . These effects are associated with persistent sex-specific cognitive impairment and neuroplastic alterations of the prefrontal cortex [75, 76] and are mediated by ovarian hormones .
Adolescent THC exposure can also change responsiveness to future illicit drug intake. Subchronic cannabinoid treatment in adolescents and adults suppressed dopamine neuron firing; however, cross-tolerance to cocaine, amphetamine, and morphine was observed for only the adolescent rats exposed to cannabinoids . Furthermore, THC enhances the effects of cocaine in adolescent, but not adult, rats . There is some evidence that THC exposure during adolescence increases responding for heroin in adulthood  and subsequently increases heroin relapse rates . This mirrors illicit drug use in surveys of human 'font-size:13.5pt;font-family:"Times New Roman",serif;color:blue'>2].
Together, human and preclinical research suggests marijuana use in adolescence can significantly impact both short- and long-term cognitive performance despite periods of abstinence. Additionally, adolescent marijuana use is associated with altered responses to other drugs of abuse, which likely contribute to the increased rates of illicit drug dependence in adults who began using marijuan a during adolescence .
Adolescent drug experimentation is rather common , and after reviewing the effects of the three most commonly used drugs during adolescence , it is clear that this experimentation is not benign. Drug use during this time period is associated with excessive intake patterns [8–11], increased rates of future dependence [17, 18], and altered cognitive outcomes [44, 59, 60, 69, 70] compared to drug use during adulthood. While not all adolescents that experiment with drugs become dependent, adolescence represents a unique time period where the vulnerability to addiction is increased . Adolescent drug use permanently changes future responses to substance use even after a period of abstinence, making drug use more likely to progress [13–16, 28, 31, 32].
Adolescents have a unique neurobiological composition, partly due to age-related changes in brain structure, function, and neurochemistry. It is likely that because of these innate differences, the effects of drug use during adolescence are different when compared to adulthood. While this has been appreciated in terms of research efforts for several years, it is also necessary to begin to alter therapy and/or treatment options to reflect the inherent differences that exist between adolescents and adults.
Initial onset of drug use during this developmental period is influenced by several factors, including changes in personality, mental health, parental supervision, autonomy, and impulsivity. Maturational changes are rampant during adolescence, with hormonal changes playing a primary role in development. For example, pubertal onset, especially early puberty in males, is associated with increases in substance use . Indeed, the emergence of hormones can produce sex-dependent patterns of intake and escalation of drug use (for an excellent review, see ). For instance, unlike the majority of illicit drug use among teens , slightly more than half (52 %) of all adolescent prescription drug exposures requiring medical treatment involved females . It is also worthwhile to mention that a significant proportion (38 %) of these prescription drug exposures were suspected suicide attempts , perhaps indicative of motivational differences in prescription drug use as compared to other drugs among a specific subset of youth.
Briefly, it is important to consider that other substances like anabolic androgenic steroids (AAS ) may also be used during adolescence and emerging adulthood. Preclinical models of AAS use indicate that AAS administration during adolescence produces increased aggression, whereas no such change is observed in adulthood . In humans, AAS use is associated with impaired attention and impulsivity in both ages, with adolescent-onset users displaying a greater sensitivity to these impairments . Further, AAS use is associated with prescription drug misuse and illicit drug use . This substance is relatively new compared to other drugs of abuse, so population usage data are scarce and its abuse potential has yet to be fully recognized at both the research and clinician levels .
Importantly, single substance use is hardly ever found in those who struggle with addiction. The vast majority of the current work, including the much of the current work reviewed here, does not consider the effects of polydrug use. This void of understanding needs to be addressed for research to more accurately address the needs of society.
In conclusion, substance use during adolescence continues to be a societal concern . While decreasing usage rates and further understanding of the neurobiological impact is in progress, additional resources, efforts, and new questions need to be acknowledged to better address the issue. Only through the continued collaboration between research and practitioners will the impact of drug use during adolescence be understood.
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