Worldwide, cannabis use rates are known to vary across countries [1] and age of onset is typically between 18 to 19 years old [91]. Additionally, given the ongoing policy debate surrounding cannabis in the United States, its long-term effects in youth are of increasing scientific and clinical interest. To date, findings regarding the impact of regular use on brain morphometric outcomes have not been entirely consistent [12]. Reasons underlying these differential findings include demographic differences in samples, especially regarding gender, or other potential resilience or risk factors including extent of aerobic fitness [53,60,92]. Here, we attempt to clarify the confusion regarding cannabis effects by examining two potential moderators: aerobic fitness and gender. We found that after three weeks of monitored drug abstinence, cannabis users demonstrated greater SA in the cuneus. Notably, we also found significant interactions between gender, aerobic fitness, and cannabis use on SA and LGI outcomes in prefrontal and parietal cortical regions. Generally speaking, males appeared more sensitive to cannabis impacts following abstinence, and further, participants demonstrated a positive relationship between aerobic fitness and cortical surface structure more broadly.

After accounting for gender, alcohol, cotinine, and aerobic fitness level, the whole-group findings demonstrated increased SA in the cannabis users compared to controls in a region denoted as the cuneus in the left hemisphere. The cuneus is functionally connected with parietal and other occipital regions for the purposes of integrating visual information [93] and contains CB1 receptors [94]. This region has a non-linear trajectory of neuronal maturation [95] and thus larger SA in cannabis users may be evident of delayed development in this region compared to non-using counterparts. Further, cannabis users have previously demonstrated abnormal dose–response blood-oxygenated-level-dependent signaling in the cuneus [96] along with aberrant functional activation in the occipital region more broadly [13,97]. The present analysis builds on this literature by demonstrating SA in this region is structurally different between adolescent and young adult cannabis users and non-users. Yet, this is inconsistent with prior findings demonstrating either no differences between cannabis users and controls in cuneus SA [36,38,40], or research reporting decreased LGI in prefrontal and temporal lobes in cannabis users [36,37] and early onset cannabis use [38], and reduced SA in comorbid cannabis and alcohol-using adolescents [39]. These inconsistencies may be due to differences in gender distribution across the studies, all of which skewed male [55% (current study), 56% [39], 64% [37], 67% [40], 73% [38], and 77% [36] male], varying levels of aerobic fitness in the sample (current sample was balanced for recent physical activity levels), or accounting for aerobic fitness levels within the statistical design. In addition, these inconsistencies may be due to differing age of samples [36,38], with younger samples undergoing greater neurodevelopment; or, due to analysis design—e.g., whole-brain analyses compared to ROI analyses [37]. None of the prior studies examining these outcomes tested whether gender or aerobic fitness moderated these effects or controlled for aerobic fitness level. Although we found the relationship between cannabis use and cortical surface structure was moderated by two-way interactions which were observed between gender, cannabis and aerobic fitness in frontal, cingulate, and parietal regions; regions that have been found to be abnormal in previous studies [21,23,24,36,37,39]. Thus, we will focus on these novel interactions.

Male cannabis users had lower SA in left precuneus, rostral middle frontal, and right superior frontal and lower LGI in left precentral, lateral orbitofrontal, and right supramarginal regions compared to non-using males—after accounting for alcohol use, cotinine level, and aerobic fitness level. Of note, our sample underwent three-weeks of monitored abstinence from cannabis and other drugs of abuse before structural scans were conducted; thus, THC and other exogenous cannabinoids were metabolized out of the system [98], representing chronic rather than residual associations. These fronto-parietal cortical findings are consistent with several studies reporting abnormal brain morphometry in cannabis users, including reduced volume [21,23,24,99] and lesser cortical gyrification [36,37] in samples that were primarily male. These overall interactions did uncover SA abnormalities in the male cannabis users, which is inconsistent with prior null or marginal SA findings [37,40,100], however, future gender-stratified analyses are needed to ascertain gender-specific mechanisms in the relationship between cortical surface structure and cannabis. In females, cannabis use was linked with greater SA in left precuneus, rostral middle frontal, and right superior frontal and greater LGI in left precentral and supramarginal regions compared to non-using females. Interestingly, female cannabis users also exhibited slightly reduced SA in another right superior frontal region and within left lateral orbitofrontal LGI. The increased SA and LGI findings could suggest that cannabis use in adolescent and young adult females is either advantageous, or potentially represents delayed pruning, as the female trajectory of pruning has an earlier rate compared to males [101]. Of note, our groups did not differ in age and we are capturing a cross-sectional snapshot potentially depicting a delay due to cannabis use specifically in females, whereas, smaller volumes in male cannabis users could be interpreted as detrimental effects associated with use. Interpretation of the present female findings are consistent with prior studies reporting greater brain volumes in female adolescent cannabis users [17,19]. More pronounced differences in males is consistent with prior findings that male cannabis users were more vulnerable to neurocognitive deficits in sequencing ability compared to females [66]. Interestingly, across genders, LGI differences were equally apparent compared to SA differences; indicating that LGI, an understudied structural index in addiction literature, is potentially susceptible to environmental influences [30,31,32,33] and is a viable avenue for further investigation. It is notable that our prior work has found cognitive deficits in psychomotor speed, working memory, sustained attention, and inhibitory control in an overlapping sample of both male and female young adult cannabis users [53,66,76], findings that are consistent with recent meta-analysis [102] and longitudinal [103] studies. Thus, structural deviancies may represent a mechanism for downstream cognitive functioning, although future studies are needed to assess whether structural changes directly impact function.

These differential gender patterns in cannabis findings may be due to multiple reasons. One potential underlying cause is differential substance use patterns. While male or female cannabis-using groups did not statistically differ from one another in their use patterns, our male users had more cannabis use on average compared to female users. This is consistent with previous literature indicating males have more severe use patterns compared to females [63]. Moreover, male users may also be more prone to using greater individual doses or more potent THC products [104], although the current study cannot address that possibility. Male sensitivity may also be due to differences in CB1 receptor density, as greater density in males is observed in animal models [105,106]. These gender differences may also be influenced in part by inherent sexual dimorphism in neurodevelopment [107,108] and the introduction of cannabis into these staggered developmental trajectories. Another possibility is that there was less power to detect differences in females, as their sample size was smaller overall (female: n = 33 vs. male: n = 41) and within cannabis users (female: n = 13 vs. male: n = 23); thus, additional research utilizing larger samples specifically examining the relationship between gender and cannabis use on these morphometric outcomes is needed.

Regarding aerobic fitness, results demonstrated several main effects of VO₂ max across both cortical surface structure indices in both the cannabis users and non-users. Greater VO₂ max was associated with increased SA in left superior and inferior parietal, and right inferior parietal and inferior temporal regions; and, increased LGI in left superior temporal, and right lateral orbitofrontal and inferior parietal regions. These findings indicate that in both cannabis users and non-users, VO₂ max has a strong positive relationship with cortical surface structural indices. This is consistent with previous analyses in our lab showcasing a positive link between AE and neurocognitive outcomes [53], and recent reviews of brain morphological outcomes in aerobic fitness literature [109]. Further, these findings suggest that, similar to non-users, cannabis users appear to have a positive link between aerobic fitness and brain structure in several regions of interest. When examining the interaction between cannabis and aerobic fitness, an interaction was observed in left cuneus SA and left lateral occipital LGI, with non-using controls exhibiting positive associations between increased indices with greater VO₂ max compared to cannabis users who demonstrated either a flat or negative relationship. This finding suggests that the impact of aerobic fitness may be less pronounced in regular cannabis users in these particular regions. Albeit, main effects of VO₂ max suggest that both groups generally had a positive relationship between aerobic fitness and brain morphometry; which is consistent with prior studies in adolescents, young adults, and older adults [51,110,111]. On balance, we previously reported that aerobic fitness was linked with superior visual memory, verbal fluency, and sequencing ability and highly fit cannabis users performed better on psychomotor speed, visual memory and sequencing ability compared to low-fit users [53]. It is important to note that our participants had no comorbid metabolic conditions (e.g., hyperlipidemia, hypertension, diabetes) suggesting benefits of aerobic fitness even in physically healthy youth. Possible mechanisms supporting positive effects of aerobic fitness and brain structure are likely multi-factorial. As aforementioned, engaging in AE releases BDNF [42], vascular growth factors [112], insulin-like growth factor-1 (IGF-1) [113], neurogenesis [114], improved catecholaminergic signaling [115], increased c-FOS expression [41], is linked with increased hippocampal volume [116], and reduces inflammation and oxidative stress [44,45]. Future studies are needed to tease apart these potential underlying mechanisms.

As we have postulated previously [53,60], AE intervention may be a plausible avenue to explore in further studies aiming to reduce or ameliorate neurocognitive deviances associated with repeated and chronic cannabis use [92]. Indeed, other groups have reported that aerobically-fit cannabis users reported reduced craving and fewer symptoms of cannabis use disorder compared to unfit users [61,117]. One potential explanation of the interactive association between cannabis use and AE could be more aerobically-fit users are metabolizing exogenous cannabinoids out of the body faster, thus, mechanistically dampening the impact on cortical surface structure integrity and neurocognition more broadly. Previous literature has shown mixed findings in acute AE increasing cannabinoid metabolites (i.e., THCCOOH) [118,119]. Further, AE releases endocannabinoids [120,121,122], which may help mitigate the negative impact of repeated exogenous cannabis exposure. Notable for future studies, it is hypothesized this relationship may be gender-specific; thus, research examining the potential use of aerobic interventions in cannabis users should prioritize investigation of potential gender differences.

There are potential weaknesses to note. First, causality cannot be determined from the present sample, sMRI scans were obtained after regular cannabis use was established. Second, the sample size for female cannabis users was relatively small compared to male cannabis users; still, findings support gender-specific cannabis and aerobic fitness associations through the interactions uncovered. This lends additional evidence for the need to examine sex as a potential moderator of cannabis effects, which has largely been understudied in cortical surface structure indices. Findings may not generalize to other samples of cannabis users with substantially different use patterns, e.g., length of abstinence, age of regular use onset, or other substance use. Third, concerns have been raised within the literature regarding divergent findings based on different brain morphometry detection algorithms and software [123]. While several validation studies of Freesurfer’s surface indices have been published [89,124,125], future work should examine how differing surface-based analyses may produce slightly different regions of interest from cannabis use in adolescents and young adults. Fourth, the relationship between cannabis use and cortical surface structure has other potential moderators of interest; two important ones are genetic factors [126,127,128] and psychiatric comorbidities [129,130,131]. The ability to simultaneously examine several potential moderators of cannabis effects on neurocognitive outcomes will soon be available with the large-scale, prospective, longitudinal Adolescent Brain Cognitive Development (ABCD) Study [132] (www.abcdstudy.org/), which has enrolled over 11,800 youth. Lastly, our average VO₂ max was lower than age-based norms [79], so assessing a more aerobically fit group may demonstrate even stronger associations with cortical surface structure.

The current study found that cannabis users had larger cuneus SA and male cannabis users exhibited smaller SA and less complex LGI in frontal, cingulate and parietal regions, even after three weeks of monitored abstinence, compared to male non-users. In contrast, female cannabis users generally demonstrated increased SA and LGI in the aforementioned regions. Prospective, longitudinal studies, such as the ABCD Study, are needed to address whether abnormalities in LGI were caused by cannabis or due to premorbid factors, and identifying the potentially gender-specific developmental trajectories in the impact of cannabis use on the brain. We also found that both cannabis users and non-using controls had a significant link between increased aerobic fitness and more complex LGI and larger SA in frontal, parietal, and temporal regions. These findings, combined with our prior report of superior cognitive functioning in aerobically-fit cannabis users [53], support the notion that it is viable to investigate whether enhancing aerobic fitness, through AE, may be a feasible prevention or ameliorative tool aimed at reducing the impact of chronic cannabis on neurocognitive outcomes in adolescents and young adults.