In the ever-changing landscape of youth substance use, the co-use of nicotine and cannabis is a major concern. Nicotine tobacco products (NTPs), including cigarettes, smokeless tobacco, and vaping devices, play a significant role in this trend. Data from the 2022 US Monitoring the Future survey report past-year cannabis use at 31% and past-year nicotine vaping at 27% among 12th-grade students [1], while data for 19–22-year-olds shows past-year cannabis use at 41% and nicotine vaping rates of 26–30% [2]. While this study highlights individual prevalence rates for past-year cannabis and nicotine use, it does not provide information on potential overlap between users, underscoring the need for ongoing research in this area. Over the past two decades, cannabis users have been more likely to use tobacco and vice versa [3,4,5,6,7,8,9,10]. A study involving high school students in the U.S. revealed that 59% self-reported using both nicotine and cannabis in the past 30 days [11]. Another U.S.-focused study focused on 15–22-year-olds found that those who had used cigarettes were 3.2 times more likely to report past 30-day use of vaporized cannabis, and 5.5 times more likely to report combustible marijuana use in California [12]. These findings underscore the overlap between cannabis and tobacco use in adolescence and young adulthood.

The period of late adolescence into young adulthood is associated with dynamic brain development, including gray matter refinement, protracted white matter development, and reward system circuit changes [13,14,15,16,17,18,19,20]. As the brain’s reward, motivation, and decision-making areas continue evolving, young individuals become more susceptible to the impact of addictive substances such as nicotine and cannabis, likely driven by hyperactivation of reward systems, greater salience attribution, and habit formation [21,22]. Studies investigating the impact of cannabis use on the developing brain have suggested a range of structural and functional changes. Brain imaging studies, encompassing both cross-sectional and longitudinal designs, have reported alterations in cortical thickness estimates, reduced white matter integrity, and reduced cortical surface area among 16–22-year-olds who use cannabis, in comparison to non-users [23,24,25,26]. Similarly, investigations into the effects of nicotine on the developing brain suggest variations in gray and white matter integrity in comparison to non-users. For example, adolescent and young adult cigarette smokers, as opposed to non-smokers, have exhibited a reduction in frontal cortical thickness, an increase in subcortical striatal volume, thinner gray volume, and greater subcortical surface morphometry [27,28,29,30].

The concurrent use of cannabis and nicotine during the critical phase of adolescent brain development raises concerns regarding the potential additive or synergistic effects of the substances, which could amplify their individual impacts. Research has highlighted distinct neurobehavioral relationships in individuals using both substances. Notably, smaller hippocampal volumes have been linked to better memory performance among co-users, in contrast to a control group, where larger hippocampal volumes were correlated with improved memory scores [31]. Additionally, the interaction between cannabis and nicotine and tobacco product (NTP) use may also be compensatory, where one substance may offset or mitigate the effects of the other [28,32]. Interactive and compensatory relationships have been noted in cognitive functioning, including episodic and working memory [33,34,35], as well as white matter microstructure and cerebral blood flow [36,37], suggesting nicotine’s potential to mitigate cannabis-related impairment. Nonetheless, in a study comparing gray matter volumes, cannabis, tobacco, and co-users showed increased volume in the left putamen but decreased volumes in the left cerebellum and thalamus compared to healthy controls, with tobacco users resembling healthy controls in thalamic volume [38].

While preliminary evidence suggests a potential compensatory relationship between NTPs and cannabis on markers of brain tissue health (e.g., white matter integrity cerebral blood flow) [28,36,37,39], our current understanding of how co-use patterns specifically affect brain structure, neural circuits, and neurobiological development remains limited. Notably, there has been a paucity of prior research investigating the interactive effects of NTPs and cannabis on gray matter tissue integrity in adolescents and emerging adults, with only one study to the best of our knowledge [39]. Gray matter, a crucial component of the brain, undergoes intricate changes during this developmental period, encompassing processes like synaptic pruning, cortical thinning, and new synaptic formations [18,40]. Understanding the interplay between nicotine and cannabis and the development of gray matter is essential for assessing potential consequences on overall brain structure and function, including cognition and emotional regulation. This study aimed to examine the individual and combined effects of NTPs (with n = 136; without n = 87) and cannabis (with n = 156; without n = 67) on 11 bilateral independent frontal gray matter cortical regions among participants aged 16–22.

We hypothesized that: (1) there would be an independent and positive association between nicotine use and cortical thickness measurements, as indicated by previous research [27,29]; (2) there would be an independent and positive association between cannabis use and cortical thickness measurements [15,41,42]; and (3) given our preliminary research showing the potential for a compensatory effect of nicotine on cannabis-related neural outcomes [36,37], we also hypothesized that nicotine use over the past year would moderate the effect of cannabis on neural-related outcomes such that the effects of cannabis on cortical thickness estimates would be less robust among nicotine users than non-users.

In summary, our study investigated the neurobiological impact of NTPs and cannabis on cortical thickness in the frontal gray matter of individuals aged 16 to 22 with and without a history of regular (at least monthly) cannabis and nicotine use. We observed that NTP use is linked to thinner cortical estimates in specific regions, including the right precentral gyrus and left superior frontal gyrus. These regional effects suggest a targeted influence of NTP on cortical structures that underlie motor function and executive functions (e.g., right precentral gyrus, left superior frontal gyrus), which aligns with previous research demonstrating increased activation and connectivity in these regions [49,50]. Furthermore, a significant interaction between NTP and cannabis on cortical thickness estimates emerged in the rostral middle frontal gyrus, pars opercularis, and frontal pole. Within these regions, cannabis users exhibited thinner cortices if they did not have a history of NTP use. Conversely, among cannabis users with a history of NTP use, cannabis was linked to thicker cortices. These interactions suggest that the effects of cannabis use on cortical thickness in the left hemisphere may be modulated by a history of NTP use, such that nicotine may counteract possible deleterious effects related to cannabis use or influence the brain with different mechanisms (e.g., atrophy and inflammation). This finding indicates that the relationship between cannabis and brain structure may be influenced by previous exposure to nicotine, similar to other work in our laboratory looking at cannabis and nicotine interactions on metrics of brain integrity [36,37].

Cannabis, primarily through the psychoactive compound delta-9-tetrahydrocannabinol (THC), interacts with the developing endocannabinoid system (ECS) during adolescence, a period marked by ECS maturation and a higher density of CB1 receptors in the brain. Preclinical evidence suggests that the activation of CB1 receptors may play a crucial role in regulating structural brain development, influencing synaptic plasticity and impacting processes like synaptic pruning, dendritic arborization, and synaptogenesis, thereby shaping the brain’s structural organization [51,52]. Studies involving adolescents and emerging adults have reported varying findings regarding the impact of cannabis use [53]. We observed a significant cannabis effect in the left pars opercularis region (i.e., diminished cortical thickness estimates), which aligns with earlier research by Epstein and Kumra [47]. Broadly, observations suggest that there are minimal differences in cortical thickness estimates among cannabis users across various frontal regions of the brain, but cannabis user status is associated with thinner estimates. Yet, among cannabis users with a history of NTP use, we observe a contrasting pattern: thicker estimates, in contrast to thinner estimates for cannabis users who do not report using NTP. Furthermore, while some studies have reported thicker [15,54] and thinner [54,55] cortical thickness estimates among young adult cannabis users in frontal ROIs, many studies did not account for nicotine use. These differences highlight the complex and variable relationship between cannabis use and cortical thickness, particularly for regions rich in CB1 receptors. Consequently, this variability in findings may be influenced by factors related to study design, population characteristics, and methodological considerations.

Nicotine, a key component found in tobacco and electronic cigarettes, intricately engages with the developing brain primarily through its interaction with nicotinic acetylcholine receptors (nAChRs) crucial for regulating cognitive and neural functions, potentially resulting in changes at both structural and functional levels [56,57,58]. Prior research has shown that nicotine exposure during this adolescent and emerging adult developmental phase can influence neural plasticity and neurotransmitter systems, potentially leading to modifications in gray matter integrity, white matter development, and cortical thickness [27,29,59,60,61]. Our findings, showing thinner cortical estimates in regions such as the right precentral gyrus, left superior frontal gyrus, left pars opercularis, and left frontal pole among nicotine users, may reflect deleterious alterations in neuromaturation. Specifically, our results align with previous studies reporting cortical thinning in adolescents and young adults using nicotine, particularly in the left hemisphere regions like the superior frontal gyrus and pars opercularis; however, we did not observe significant differences in other regions [27].

While prior studies have explored how cannabis and NTPs can independently influence brain structure, the neurobiological impact of their combined use is even more intricate and multifaceted. This complexity arises from the interactions of both substances on neurotransmitters and receptors, which may lead to alterations in macrostructural development. For example, nicotine may stimulate the ECS, releasing anandamide and 2-AG and modulating the brain’s reward circuity, and thereby influencing dopamine levels and enhancing the rewarding effects of nicotine [26,62]. It appears that the relationship between cannabis and brain structure may be modulated by prior exposure to nicotine, as nicotine may potentially counteract some of the deleterious effects associated with cannabis use. This interaction suggests that the interplay between NTPs and cannabis extends beyond mere additive effects and involves intricate modulations within the brain’s neural networks. Prior research from our laboratory indicates the presence of a distinctive white matter structure among co-users, as compared to cannabis-only users, [37], which may be attributed to nicotine’s activation of nAChRs and its role in enhancing glial activity. Nicotine is recognized for its ability to stimulate the release of neurotransmitters such as dopamine and norepinephrine [63]. Additionally, it can elevate acetylcholine levels, which may enhance cognitive function [56,64,65]. These effects could potentially offset some of the adverse cognitive impacts of cannabis. The interplay between nicotine and cannabis may also exhibit individual variability, and such variability in findings may be attributed to factors such as the duration and frequency of cannabis use, age of onset, participant population studies, genetic and environmental factors, individual differences, and specific type of tobacco/cannabis product used [3,11,66].

While this study presents valuable insights into the relationship of NTP and cannabis co-use with cortical development among young adults, several limitations should be acknowledged. Importantly, the study’s cross-sectional design impedes the establishment of causal relationships, and the reliance on self-reported substance use could introduce recall bias or underreporting, potentially affecting the accuracy of substance use patterns reported. The focus solely on co-use within the past year may overlook lifelong cumulative effects, as compared to recency of use, and the study’s concentration on frontal cortical regions and cortical thickness does not provide comprehensive data on gray matter changes that may be related to co-use in other subcortical brain regions and brain metrics of health. Our study did not include cognitive tasks performed by cannabis and NTP users; future studies should consider incorporating cognitive tasks to further elucidate this relationship. While alcohol was not found to be a significant predictor of cortical thickness in our study, future research should expand this work to better understand the degree to which alcohol use influences nicotine and cannabis co-use-related brain imaging outcomes. Furthermore, a nuanced exploration of nicotine dose combined with objective markers of nicotine use via biological specimen assessment (e.g., hair and blood toxicology) could enhance our understanding of the intricate interplay between nicotine and cannabis across diverse brain regions and health metrics.

In summary, our study finds unique effects of NTPs and cannabis on frontal brain cortical thickness estimates. Furthermore, it highlights a nuanced and intricate interaction between cannabis and nicotine in the developing brain, and unique gray matter phenotypes related to single substance use as compared to co-use. Future studies that use comprehensive longitudinal designs will continue to probe the effects of cannabis and nicotine use on brain development.

Conceptualization, M.H.M., K.E.C. and J.J.; Data curation, R.E.B. and Q.S.; Formal analysis, M.HM.; Methodology, M.H.M., K.E.C., N.E.W., A.W. and J.J.; Supervision, J.J.; Writing—original draft, M.H.M.; Writing—review and editing, K.E.C., N.E.W., A.W., Q.S., J.P.H. and J.J. All authors have read and agreed to the published version of the manuscript.

Ethical review and approval were waived for this study due to the project being certified as Non-Human Subject Research according to the Code of Federal Regulations, Title 45, part 46, and UCSD Standard Operating Policies and Procedures.

Informed consent was obtained from all subjects involved in the study. For participants under 18 years of age, parental consent and participant assent were obtained.

Data are not publicly available due to restrictions (e.g., their containing information that could compromise the privacy of research participants) but are available upon request from the authors.

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

This project was supported by the National Institute of Health (PHS Grant No. T32 MH 122376 [to MHM; program director, Eric B. Hekler]), National Institute on Drug Abuse (Grant No. U01DA041089 [principal investigators, Susan F. Tapert and JJ] and Grant No. R21 DA 047953 [principal investigator, JJ]), California Tobacco-Related Disease Research Grants Program Office of the University of California (Grant No. 580264 [principal investigator, JJ], and National Institute on Alcohol Abuse and Alcoholism (NIAAA) grant T32 AA013525 [PI: Riley/Spadoni to AW] and R01 DA054106 [PI: JJ] and R01 DA054980 [PI: JJ]).