The Healthy People 2020 initiative has set the goal to reduce the rate of adolescent marijuana use to six percent [25]. However, it only takes one look at the data from our sample (25% are regular users) to recognize that we are far from that goal. This widespread use should be alarming, since adolescence is a peak time for neurodevelopment, and subsequently a period of increased susceptibility to alterations in brain structure and function [2],[6]–[8],[26]–[29]. The present study specifically provides evidence that both initiation and regular use of marijuana predict changes in mature BDNF.

Although it is inherently difficult to establish causality in human studies, our methodological and design approaches provide a stronger basis for causal inference [30]. First, this study was longitudinal, which allowed for uniformity. Secondly, by including a sizable proportion of drug naïve subjects, and by performing drug screening tests, we were able to establish that drug use preceded the outcome. Our study took measures to exclude alternative explanations for our findings. Participants passed a rigorous health screening, including medical history, physical exam, and blood testing to assure the inclusion of adolescents without comorbid developmental or neurologic conditions. We also collected information on several covariates that potentially impact BDNF, such as diet, exercise, sociodemographics, and other drug use. Finally, animal models have long provided support that the observed relationship between marijuana and BDNF is more than a simple association [4]–[5],[12]–[13],[15],[28]–[29]. They have also provided the mechanisms of action by which these variables interact: a) activation of the extracellular signal-regulated kinase or b) through endocannabinoid transactivation of BDNF-TrkB receptors [16],[31].

While the increased levels of m-BDNF associated with cannabinoids have been previously reported, the functional relevance of these changes should be carefully interpreted [6],[13]. Though in the past they were viewed as beneficial, this is an erroneous deduction [6],[13]. This conclusion is derived from acute models where increases in m-BDNF protect the brain in the short-term [32]. Subsequent research has established that chronic exposure will lead to allostatic overload, maladaptive responses, and illness [33]. Additionally, a rise in BDNF, which is highly distributed in the hippocampus, increases the odds of hyperexcitability and/or excitotoxic damage by increasing long term potentiation [34]. Further confirming our postulates are human neuroimaging studies showing that marijuana use is associated with a volumetric reduction of the hippocampus [31].

By modifying BDNF, marijuana use could also induce alterations in “plasticity”, which reference neuronal changes associated with the acquisition of new skills or the ability to adapt [35]–[37]. Emerging data have demonstrated that synaptic plasticity may also be involved in the “learning” of addictive behaviors [16],[38]–[40]. In vertebrate model systems, exogenous BDNF promotes cocaine-taking behavior over a range of experimental conditions, and led to increased risk of relapse [41]. Moreover, BDNF infusions induced a switch in the γ-aminobutyric acid type A receptors from inhibitory to excitatory signaling, potentiating cue-induced drug seeking [39]. These findings from different fields let us conclude that sustained increases of m-BDNF are not beneficial. Translational studies are needed to confirm whether this interaction reflects a drug-induced, synaptic plasticity phenomenon similar to the one observed in animals [16],[39]–[41].

In addition, our data demonstrated that there are variations in BDNF responses between younger and older individuals. Since marijuana use among the younger teens in our study was generally “light”, it is possible to conclude that a dose-response should exist. The steep increases in BDNF associated with escalating marijuana use also suggested this trend. This phenomenon may result from BDNF-induced neuroplasticity changes that promote drug seeking [38]. Such activity-dependent remodeling has been proposed as part of the transition from casual drug use to drug addiction in other drug fields [39]–[40]. Supporting these posits are also data demonstrating that injection of a TrkB antagonist in the peripheral system significantly reduces drug-dependency behaviors in animals [40]–[42].

In summary, marijuana the most frequent drug used by these adolescents alter the production of BDNF. Alterations were both age and dose dependent and while past users improved their levels they did not return to basal levels. Analyses confirmed that they were not a pre-condition that leads to increase substance use. Our next goal is to analyze the consequences in neuropsychological performance to better understand the neurodevelopmental trajectories of users versus non-users.

These relevant findings come with some caveats. Our sample was limited to Hispanic adolescents in South Florida. Nevertheless, our study was longitudinal and had a good sample size for a single site study. BDNF levels were measured in plasma and not in the CNS. However, both in humans and in animals, peripheral levels highly correlated with changes observed in the brain [20],[43]–[44]. Though it is inherently difficult to establish causality in human studies, we ensured that conclusions were determined with a high level of confidence by using the correct design and laboratory methods. Animal models also provide strong support that the observed relationship between marijuana and BDNF is more than a simple association [5]–[6],[10]–[11],[16],[29]–[30]. They also provide support that such alterations could be deleterious during critical developmental periods, and could contribute to, and exacerbate, addictive behavior. Although, marijuana users exhibited lower BDNF levels raising a question about their potential predicting value, additional studies should be performed in order to confirm our findings. Finally, results indicated the importance of analyzing marijuana across the different phases of adolescence, as it can be more informative when determining long-term impact.

Now policy initiatives need to ensure that legalization of marijuana to protect the rights of ailing individuals does not harm the youth who will be the future of every country. It is clear from the data amassed herein that the adolescent body registers marijuana use as a stressor. Effects of chronic use remain pervasive via heightened m-BDNF, leading to alterations in brain function and structure [6],[26]–[29]. Such results caution against movements to broadly legalize marijuana.