We used data from the nationally representative 2021 Youth Risk Behavior Survey to examine associations between EVP use and prescription opioid misuse among high-school students in the United States. As our primary aim, we found that students who reported EVP use during the past 30 days were more likely to report current prescription opioid misuse compared to those who were not currently using EVPs. This association between EVP use and opioid misuse remained highly significant after controlling for multiple covariates, including sociodemographic factors and other substance use behaviors. Additionally, as our second aim, we examined the dose-dependent relationship between frequency of current EVP use and prescription opioid misuse. We found that an increased use of EVPs was strongly associated with an increased prevalence of prescription opioid misuse.

While previous research has investigated the association between EVP use and substance misuse among adults, the goal of this study was to understand this association in the adolescent population. Studying adolescents is critical, because this is the time of life when substance use behaviors start [11]. Moreover, our work is particularly relevant in the context of the current opioid epidemic, as opioid misuse in adolescents has been linked to increased risk for morbidity and mortality via opioid overdose [12]. This poses an important challenge for this vulnerable group and underscores the need for targeted public health interventions in adolescent EVP and opioid misuse. A strong body of research suggests a multi-pronged approach which entails early identification of at-risk adolescents as well as education on the potential harm of EVP use [13]. By identifying at-risk adolescents early, resources can be focused and appropriately distributed to maximize harm reduction.

Studies of adult populations have repeatedly found that individuals who engage in nicotine and cigarette use are at an elevated risk for misusing opioids [14]. A large meta-analysis published in 2019 with over 175,000 participants found that the pooled odds ratio of opioid misuse disorder was 8.23 (95% CI: 3.07–22.09) for adults who currently smoke compared to those who did not. Additionally, the meta-analysis investigated the relationship between age of smoking onset and opioid misuse and found that an early onset of smoking, defined as being under 14 years old at smoking onset, was positively associated with opioid misuse and opioid misuse disorder [14]. This finding adds evidence to the theory that exposure to nicotine at a younger age may increase vulnerability to the misuse of other substances, such as opioids. Other studies that have focused on individuals with opioid misuse disorders have shown an exceedingly high rate of nicotine use; for example, one study of patients with opioid misuse disorder enrolled in methadone treatment found that over 85% of the patients were smoking cigarettes [15]. One proposed mechanism that may contribute to the association between nicotine use and opioid misuse is an increased prevalence of chronic pain among those who use nicotine. Multiple studies investigating chronic pain have found that nicotine use and dependence were strong predictors of prescription opioid misuse [16,17]. One study investigating predictors for low back pain in adolescents found that one of the strongest factors associated with hospitalization due to low back pain was daily smoking [18]. However, previous studies investigating this relationship between EVP use and opioid misuse have mainly focused on adult populations, and the studies investigating adolescent populations have not been nationally representative.

Current biopsychosocial evidence points to an interplay of various factors during adolescents’ critical developmental stage that may influence social behaviors as well as nicotine’s effects on the brain. The endogenous opioid system is hypothesized as an important neurobiological pathway in the addictive properties of nicotine. Nicotine produces its effects through the activation of nicotinic acetylcholine receptors, with downstream upregulation of mu opioid receptors, which play a critical role in addiction [7,19]. As such, chronic and long-term use of nicotine leading to upregulation of mu-opioid receptor expression could provide a physiological basis for increased sensitivity to opioid misuse and addiction among people who use EVPs. The inverse of this relationship can be seen in the use of the opioid receptor antagonists, naltrexone and bupropion, decreasing nicotine withdrawal symptoms and nicotine cravings in some patients [19,20]. In addition to its effects on the endogenous system, nicotine from EVPs can also affect the brain’s reward pathways, thereby making adolescents more prone to using other substances like opioids that provide similar pleasurable effects [7,19]. Nicotine or EVP use in adolescent populations may be especially impactful, as biological and signaling pathway changes are occurring in a developing brain that does not have a fully formed frontal cortex with strong executive function to regulate decision-making and risk-assessment. These changes may affect adolescents’ vulnerable brain development, leading to behavioral impairment. Behavioral impairment can manifest as poor impulse control with a priming effect for subsequent increased adolescent participation in health-risk behaviors [21]. Social dynamics must also be considered in the context of adolescent decision making, as adolescents are particularly susceptible to peer pressure, which can be an external factor on the likelihood of engaging in risky behaviors, including substance use. Taken together, the confluence of these biological pathways, brain development changes, and social factors affecting adolescents all provide possible explanations underlying links between adolescents’ EVP use and prescription opioid misuse.

The findings of this study must be interpreted in context of several limitations. First, the cross-sectional survey captures data from a single point in time which does not allow us to draw conclusions about the causal relationship between EVP use and current opioid prescription misuse. However, our dose-dependent finding between EVP use and opioid misuse aligns with the results of studies conducted among adults which found a stronger relationship between opioid misuse among dependent adults who smoked heavily compared to those who smoked less heavily [16]. Finding a dose-dependent relationship between these variables is significant as it adds evidence to support a causal relationship between two variables by fulfilling one of Bradford Hill’s criteria for establishing causality in epidemiology. Importantly, this does not prove causation, however, as there may be additional confounding variables, and different research methodology would be needed to confirm this. One way to build upon this finding and add evidence to the possibility of this being a causal relationship would be to establish the temporal order between EVP use and opioid misuse, which this data set does not do. Longitudinal data captured over the course of students’ high school experiences would provide valuable insight into the directionality and temporality of this relationship. Another limitation to this study is that opioid misuse is measured by only one question that does not capture differences in potential routes of opioid misuse or extent of misuse. A more comprehensive measure of opioid misuse that captured frequency, quantity, and method of consumption, for example, would provide more data and allow for a more nuanced understanding of this relationship. The choice of which screening tool to use in evaluating opioid misuse in adolescents has been shown to have a significant effect on the reported rates of opioid misuse and should be considered carefully in any investigation into this topic [22]. The integration of validated pediatric screening tools, such as the CRAFFT Screening Tool, could improve opioid misuse data collection. Stigma surrounding opioid misuse may result in the reported YRBS rate being lower than the actual rate of opioid misuse. Similar limitations in the depth of questions and self-report status also apply to other variables measured such as marijuana use, alcohol use, and depressive symptoms. Despite these limitations, this study consists of a nationally representative sample of high school students and contributes valuable information to the field of adolescent addiction medicine. The large and diverse sample of adolescents allows for a generalizable understanding of the relationship between EVP use and prescription opioid misuse at a national level in the United States.

Recognizing the existence of a potential relationship between EVP use and adolescent opioid misuse could have significant public health implications by improving adolescent education, identifying adolescents at higher risk for opioid misuse, and improving resource allocation to more effectively prevent harm. While the popularity of cigarettes in adolescents has continued to fall, many adolescents still consider EVPs to be a safer alternative [23]. This problem is compounded by EVP marketing, which appeals to adolescents with sweet and tropical flavors, as well as the increased potential for peer pressure due to EVPs’ current popularity. Public health strategies to combat EVP misconceptions should be initiated through efforts to spread awareness of the health risks and potential sequelae of EVP use initiation. Similar public health measures targeting cigarette use have had immense success in reducing adolescent cigarette conception. Local efforts should include school and community-based programs with the active participation of teachers, parents, school counselors, healthcare providers, and other adolescents. On a larger scale, policy makers should advocate for public education through mass media or public health campaigns that highlight the potential harm of EVPs. Finally, consistently screening adolescents for EVP use during well-child visits could open the door for focused follow-up opioid screening and create an opportunity to provide education on the risks of EVPs.