To our knowledge this is the first large-scale study to simultaneously integrate the effects of alcohol and marijuana use on college GPA using a longitudinal statistical model. Given the challenges presented by comorbid and collinear use of both alcohol and marijuana in college students, we performed a data-driven categorization of cumulative substance use and then used a LMM approach to evaluate the longitudinal effects of both alcohol and marijuana use on individual college GPA in a cohort of 1000+ college students. However, it is important to note that our study design or analysis was not geared to examine causation. Given the analysis presented in the paper, all we can infer is that academic performance and substance use was significantly associated. Our data-driven analysis revealed that roughly 40% of the students did not use, or consumed very light amounts of alcohol and MJ. Students who consumed moderate-to-large amounts of alcohol but only small-no MJ comprised another 40%, and the rest of the sample was heavy users of both substances. We also found almost no individuals with minimal alcohol and heavy MJ use. This is interesting given the popular belief that MJ-only users are much more common than individuals who use both substances together. However, the data driven patterns of substance use clusters we found was largely consistent with past reported data in college students [22].

The substance-use clusters identified across individuals in our study were relatively stable across semesters. Thus, heavy substance users during freshman year were more likely to maintain the same use pattern throughout the 2 study years. As hypothesized, even after controlling for a variety of demographic and clinical characteristics, cluster 3 students (who were moderate-heavy users of both substances) had poorer grades (from study outset to completion) than their peers who consumed little or no alcohol/marijuana. Overall, cluster 2 students (moderate-high alcohol + low-or-no marijuana) had lower GPA’s compared to their non/low substance use peers. However, contrary to our hypothesis we found no cluster by semester interaction, which suggests that the overall relationship between cluster and GPA is the same across each semester (as seen in Fig 2). Despite a non-significant interaction term, we looked at post-hoc simple effects to better interpret the data. These analyses revealed that the difference in GPA between cluster 1 and 2 diminished to trend-level significance during semester 2 and was non-significant for semesters 3 and 4. One possible explanation is that students consuming moderate-to-high levels of alcohol and only low levels or no marijuana (cluster 2), adapt over time, develop tolerance to substance effects and/or regulate their behavior to eventually catch up academically with their sober peers. Alternatively, it is possible that cluster 2 students chose to switch to less academically challenging courses. We were not able to distinguish among these possibilities.

The above was however not true for students who heavily used both MJ and alcohol (cluster 3). Despite the fact that cluster 3 students had similar SAT scores of academic achievement coming into college, compared to cluster 1 and 2, we noted that by the end of semester 1, they had significantly reduced GPAs. Our results therefore suggest that consuming moderate-to-high levels of both substances were associated with significantly lower GPA, which seemed to follow across subsequent semesters (see Fig 2). However, this level of consumption was not associated with a decline in GPA from semester 1, i.e. when we tracked cluster 3 academic performance over time, there was no significant change in GPA over the two-year period. Although partly consistent with our initial hypothesis, this particular finding was not entirely expected, as we had initially predicted that engaging in heavy substance use of both substances would also result in a faster decline in academic achievement over time (i.e. we would see a significant cluster by semester interaction). One simple possibility is that we had too few time points in the study in later semesters to detect a significant GPA decline over time. Also, larger attrition of subjects across substance use clusters over time could have resulted in a non-significant decline of GPA as well. Finally, it could be possible that heavy substance users are able to tolerate deleterious effects of those substances, due to perhaps a combination of genetic predisposition and adaptive cellular or systemic tolerance, thus preventing them from a continuing decline in academic performance. This hypothesis is supported in-part by evidence from both the animal and human literature. A rodent study demonstrated that exposures to large quantities of alcohol led to functional tolerance independent of environmental influences [44]. In humans, a study investigating alcohol tolerance in offspring of alcoholics and non-alcoholics, found that the former experience alcohol’s pleasurable effects at the start of drinking and are less affected by its subsequent impairing effects during the drinking session, that in turn might contribute to increased drinking behaviors [45, 46]. Similar animal-based evidence for tolerance effects at both the observational and neuronal levels has been noted for heavy marijuana use [47]. It is possible that a large number of students belonging to cluster 3 fit the above pattern and were thus able to maintain their grades over time due to adaptive tolerance to heavy substance use.

A key strength of the current study is its focus on a critical age group, college-attending late adolescents to early adults, when substance use and initiation is prevalent. Animal studies suggest that compared to adults, adolescents may be particularly sensitive and vulnerable to neurotoxic effects of substances including alcohol and marijuana [48–50]. Preclinical studies also report increased cellular changes in adolescents compared to adults associated with exposure to THC (delta-9- tetrahydrocannabinol), a major psychoactive compound in marijuana [48, 49]. Human studies indicate that regular marijuana use starting before age 18 is associated with deficits in attention, visual search, executive functioning and IQ [7, 9, 16–18]. Newer research seems to indicate that persistent cannabis use across four years of high school is associated with lower GPA, SAT scores and higher externalizing symptoms [51]. A recently-published large longitudinal cohort study that utilized trajectory analyses, seems to indicate that students who smoked cannabis (irrespective of use being infrequent, frequent, increasing or decreasing) during college had significantly lower college GPA and other related academic outcomes (even at study onset) [52]. Another study used structural equation modeling to conclude that MJ use during the first semester was directly related to lower GPA in college students. The study also found similar indirect effects of alcohol and other substances on academic outcomes such as GPA and graduation time [53]. Our results both confirm and extend previous reports by suggesting that students who consume moderate-large quantities of both alcohol and marijuana show significantly lowered college academic performance that is seen consistently over a two-year period. It was also encouraging to observe that students who in general were able to moderate or lower substance use patterns while in college over time performed significantly better academically compared to students who remained in the same substance use cluster. Our pseudo-trajectory analysis might therefore provide important clues in terms of how regulating, curtailing and modifying substance use behavior while in college could have a significant impact on academic GPA.

Our results suggest that early intervention to substance abuse in college students might be vital in shaping their academic success over time. Students who use alcohol and MJ (especially MJ) minimally during their incoming semester seem to do better academically over time. This might in-turn lead to significantly better life outcomes upon graduation. It was interesting to note that despite no differences in SAT scores between clusters, we begin to see a dramatic difference in GPA associated with heavy substance use by the end of the first semester. First-year students typically have exaggerated ideas about how much college students drink. Wanting to fit in and being free of parental control for the first time, these students can be led by this misperception into a pattern of heavy drinking that increases their risk of academic failure, serious injury, sexual assault, and even death. As stated by Moos et al 1976, “College health and academic counseling services may benefit from knowledge of individuals at high risk for poor physical health, academic dropout, and alcohol abuse.” This could translate into identification of heavy student alcohol and substance users through improved substance use education and readily available counseling programs, with the aim of reducing substance-associated morbidity. It is typical for freshman students to be subjected to peer pressure of drinking given the somewhat false sense of excessive drinking and substance use culture in colleges. One way to counteract this would be to roll out social norms marketing campaigns that try to convey accurate survey data about student drinking norms. The idea is that once students learn that far fewer students are drinking heavily than they once thought, they will feel less social pressure to drink and, therefore, moderate their alcohol use. In addition to enforcing strict rules and disseminating knowledge on alcohol and substance abuse during social events especially during the freshman year, schools could also take a more proactive role in creating a substance-free environment by promoting alcohol-free events for students and supporting student clubs and organizations that are substance-free and create and promote service learning and volunteer opportunities that are an integral part of the academic curriculum.

As mentioned previously mental illness is an important piece of the picture, given that psychiatric disorders and substance abuse are often co-morbid; we tried to control for these important factors. However, these measures were only collected at study onset, future studies might therefore benefit by collecting history of tobacco use, depression and anxiety measures longitudinally to better account for variability in these potentially important mediating factors. In the current study however, exploratory analyses performed within the LMM framework found no interaction between depression or anxiety scores with cluster definition.

Other strengths of the current study included being among the first to assess simultaneous longitudinal influences of both alcohol and marijuana on academic performance. Further, we controlled for a variety of demographic and clinical variables that might otherwise be comorbid with substance use. The study also had several limitations. We were not able to detect a meaningful group of individuals with low alcohol and moderate-high marijuana use, which would have allowed us to better parse effects of substance use on academic performance. Unfortunately we did not capture a variety of other interesting mediating factors such as “pre-college” drinking or marijuana use patterns, high school GPA, skipping classes, course difficulty or degree of college engagement which could have enabled us to draw better inferences. There was a significant degree of non-reporting of marijuana use in later semesters, in subjects who volunteered other types of data; we do not have a ready explanation for the specific failure to report these substance data. However, given that missingness seemed to increase from cluster 1 to cluster 3 in a step-wise manner, one might speculate that participants who frequently abused substances were less motivated to provide survey data as time progressed. The above missing data was also significantly different across substance use clusters which could have possibly impacted our findings.