Effect of Adolescent Cannabis Use on Brain Functions

Effect of Adolescent Cannabis Use on Brain Functions Cannabis Use During Adolescence: A Review of Impacts on Brain Functions and Associated Outcomes Recent years have seen a dramatic increase in the social acceptability of cannabis usage in the United States, with several states having already legalized recreational use of the substance and several more projected to do so within the next several years (Leyton, 2016).   Concurrently, there has been an increase in the amount of adolescents who report using cannabis, with recent data indicating that 39% of high school seniors report using cannabis within the past year and 6-7% reporting daily or near daily cannabis use (Johnston & O’Malley, 2015).   Despite increasing utilization of cannabis products for pain management and other ailments (Hwang & Clarke, 2016), some in the scientific community have expressed concern about the potential ramifications of recreational legalization of cannabis.   Chief amongst these concerns is the idea that adolescents will have very easy access to increasingly potent cannabis and synthetic cannabis products (Sobesky & Gorgens, 2016), as a great deal of research has indicated that the use of cannabis poses several risks specific to individuals in the adolescent age range (see Levine, Clemenza, Rynn, & Lieberman, 2017).   This paper will summarize the research examining the impact of cannabis use on the developing adolescent brain and potential associated outcomes, particularly in the areas of cognition/executive function, anxiety and depression, psychotic disorders, and future substance use/dependence.   The Adolescent Brain To understand the impact of cannabis use on the developing adolescent brain, it is first necessary to understand the changes taking place in the brain during this developmental period.   Not surprisingly, the period of adolescence is a time of tremendous change in the circuitry of the brain.   According to Arain et al. (2013), there is a significant amount of neuronal plasticity in the brain during adolescence, meaning the â€Å"wiring† of the brain is extremely adaptable to learning and experience.   Such plasticity, particularly in the prefrontal cortex, lends itself to difficulty thinking rationally and critically, often leading to the impulsive decision-making that is characteristic of the adolescent years.   In addition, the hypothalamic pituitary adrenal (HPA) axis, the system responsible for regulating human responses to stress, also undergoes significant development during the period of adolescence.   Within this system, the amount and duration of adrenocorti cotropic hormone (ACTH) and glucocorticoids released in response to stress increase significantly as compared to other life periods (Romeo, 2013).   Shortly before puberty, a â€Å"surge† of synaptogenesis and neuronal growth occurs in which grey matter in the brain thickens substantially.   From this point throughout the period of adolescence, the brain is continually rewired through dendritic pruning and increased myelination of synapses, particularly in the prefrontal cortex (Arain et al., 2013; Lubman, Bonomo, & Yucel, 2007).   In addition, white matter increases are seen in the corpus callosum (Arain et al., 2013).   Taken together, these changes increase the efficiency of communication within the brain, allowing for the eventual development of more complex cognitive functioning, including improved impulse control, operational thinking, and working memory (Hart, 2007; Lubman et al., 2007).   In addition to the constant rewiring of brain circuitry that occurs during adolescence, the levels of three neurotransmitters – dopamine, serotonin, and melatonin – change during the adolescent period (Arain et al., 2013).   According to Dahl (2003), dopamine and serotonin levels decrease during adolescence, resulting in emotional dysregulation, mood disruptions, and difficulties with impulse control.   Melatonin levels, on the other hand, increase, which in turn increases the amount of sleep that adolescents need to be fully â€Å"re-charged.†Ã‚     Given the massive changes that are occurring in the brain during the period of adolescence, it is a time in which the brain is especially susceptible to the use of substances, (Lubman et al., 2007) including cannabis.   Cannabis’ Action in the Brain Before discussing the specific impacts of cannabis use on the adolescent brain, it is important to understand how cannabis acts in the brain in general.   First, the brain has an endogenous cannabinoid system (endocannabinoid system) made up of the ligands anandamide and 2-arachidonoyl glycerol (2-AG) and cannabinoid receptors known as CB1 and CB2 receptors (Moreira & Lutz, 2008).   CB1 receptors are located throughout the brain, but are particularly populous in the front region of the cerebral cortex, the basal ganglia, the cerebellum, the hypothalamus, the anterior cingulate cortex, and the hippocampus; CB2 receptors are generally found throughout the body’s immune system (Hill et al., 2010; Iversen, 2004).   The endocannabinoid system plays a role in a number of processes, including the regulation of the HPA axis stress response (Hill et al., 2010; Lee & Gorzalka, 2015), neural plasticity, and learning and memory (Lu et al., 2008).   According to Iversen (2004), the psychoactive component in cannabis is Δ9-tetrahydrocannabinol (THC).   THC, as well as increasingly popular synthetic cannabinoids, act as agonists on CB1 cannabinoid receptors in the brain.   Because CB1 receptors are generally presynaptic rather than postsynaptic, cannabinoids control the release of certain neurotransmitters, including acetylcholine, L-glutamate, ÃŽ ³-aminobutyric acid (GABA), noradrenaline (norepinephrine), dopamine, and 5-hydroxytryptamine (5-HT).   The use of exogenous cannabinoids, such as marijuana or synthetic marijuana products, leads to an unnaturally long-lasting activation of CB1 receptors, ultimately inhibiting the release of the aforementioned neurotransmitters in selected areas of the brain (Iversen, 2004).   In addition to its impact on CB1 receptors and associated neurotransmitters, THC also appears to trigger the firing of dopaminergic neurons in the ventral tegmental area of the brain and the nucleus accumbens – areas of the brain that are heavily implicated in the brain’s reward circuit associated with drug use.   This effect is also seen with heroin, cocaine, amphetamines, and nicotine, suggesting that THC may also act on the opioid receptor system within the brain (Iversen, 2004). Impact on Cognition and Executive Function Tasks The literature has focused on several larger areas of impact regarding cannabis use during adolescence, one of these being the potential impacts on cognition and tasks of executive function.   As previously mentioned, the brain undergoes a significant amount of change in the adolescent years, including the frequent re-wiring of neural connections through neural pruning processes, particularly in the prefrontal cortex.   According to Filbey, McQueeny, DeWitt, and Mishra (2015), cannabis use during adolescence disrupts this normal pruning process through its modulation of neurotransmitters and inhibition of microglial processes.   This results in abnormal connectivity within the brain, including a decrease in white matter volume and integrity (Gruber, Dahlgren, Sagar, Gonenc, & Lukas, 2014; Jacobus et al., 2009). Such changes result in a number of cognitive impacts, including increased impulsivity, poorer reaction times, and increased errors on executive function tasks (e.g., planning, organization, self-regulation, etc.) (Becker, Wagner, Gouzoulis-Mayfrank, Spuentrup, & Daumann, 2010; Gruber et al., 2014).   Indeed, studies have indicated that individuals who begin marijuana use in early adolescence are at an increased risk for developing deficits in attention (Ehrenreich et al., 1999) and visual processing (Tapert, Granholm, Leedy, & Brown, 2002), and exhibit a decreased full scale IQ and verbal IQ in adulthood (Meier et al., 2012).   Memory also appears to be affected by adolescent-onset cannabis use (Tait, Mackinnon, & Christensen, 2011), likely via its impact on the hippocampus – a part of the brain heavily implicated in memory functions.   Animal research has shown that the hippocampus is affected by cannabis use especially during the period of adolescence.   In rats, adolescent exposure to cannabis impacted the microstructure of the hippocampus as well as abnormalities in the way that proteins are expressed in the hippocampus (Quinn et al., 2008).   Specifically, it appears that exogenous cannabinoids bind to CB1 receptors and inhibit the release of glutamate, thus contributing to deficits in short-term memory (Hart, 2007) and negatively impacting performance on memory-related tasks (see Levine et al., 2017).   Some animal studies indicate that lower levels of cannabis use (those most reflective of the actual amount that adolescents use) are not predictive of long-lasting hippocampal changes.   However, because current cannabis products are continuing to increase in potency (Levine et al., 2017), hippocampal changes and subsequent memory problems are topics of concern, especially with regard to adolescent users of cannabis.   Working memory also appears to be impacted by cannabis use, particularly in individuals that began using cannabis before the age of sixteen.   Becker et al. (2010) used functional magnetic resonance imaging to examine performance on a working memory task in individuals who began using cannabis before age sixteen (early-onset) as compared to individuals who began using cannabis after the age of sixteen (later-onset).   Results of this study indicated that early-onset cannabis users exhibited increased cortical activity in the parietal lobe as compared to later-onset cannabis users.   The researchers concluded that this increased cortical activity indicated decreased cortical efficiency in response to challenging working memory-related tasks in early-onset, but not later-onset, cannabis users (Becker et al., 2010).   Such findings are consistent with a number of studies indicating that an earlier age of onset of cannabis use is associated with greater risk of negative impacts on cognitive functioning during adulthood (Ehrenreich et al., 1999; Fontes et al., 2011; Meier et al., 2012; Pope et al., 2003).   Impact on the Development of Anxiety and Depression Several studies indicate a connection between adolescent-onset cannabis use and the development of both anxiety and depressive disorders (e.g., Brook, Rosen, & Brook, 2001; Degenhardt et al., 2013; Fairman, 2015; Hayatbakhsh et al., 2007; Patton et al., 2002; van Laar, van Dorsselaer, Monshouwer, & de Graaf, 2007).   Though past researchers have speculated about the directionality of this relationship, studies have consistently indicated that adolescent-onset depression is not predictive of later cannabis use (e.g., Degenhardt, Hall, & Lynskey, 2003; Moore et al., 2007; Womack, Shaw, Weaver, & Forbes, 2016), negating the idea that depressive and/or anxiety symptoms lead to engagement in cannabis use as a method of symptom relief.   Instead, such findings promote the idea that cannabis use during adolescence, in combination with other potential risk factors, increase the risk for the development of anxiety and depressive symptoms in adulthood (Levine et al., 2017).   As with the cognitive changes discussed in the previous section of this paper, it is early-onset use of cannabis that appears to be riskiest with regard to the development of future anxiety and depressive symptoms (Hayatbakhsh et al., 2007; Patton et al., 2002).   In an interesting study by Spechler et al. (2015), fMRIs were used to examine activity in the amygdalas of adolescent users of cannabis.   The researchers showed participants images of both angry and neutral faces, a well-known test of amygdala activity and a well-regarded index of emotional processing.   Results of this study indicated that compared to the control group, adolescent cannabis users exhibited increased amygdala activity in response to the images of angry faces whereas the control group showed the same amount of amygdala activity when shown images of neutral faces.   Spechler et al. (2015) concluded that adolescent cannabis use is associated with increased hypersensitivity to negative affect.   However, in this case, the directionality of the relationship is unclear: it is possible that the sensitivity of the amygdala pre-dated the cannabis use and the cannabis use was engaged in due to its anxiolytic effect.   Conversely, it is possible that cannabis use led to increased sensitivity in the amygdala.   Either way, it appears that adolescent cannabis users are overly sensitive to negative affect and the potential threat that accompanies it, which may explain the increased incidence of depressive and anxious symptomatology in this population.    There are several potential neurobiological mechanisms explaining the relationship between adolescent cannabis use and the development of anxiety and depressive symptoms.   One possibility is the impact of exogenous cannabinoids on the HPA axis system.   The endocannabinoid system regulates the responsivity of the HPA axis, which, as previously mentioned, undergoes significant development during the adolescent years (Hill et al., 2010; Lee & Gorzalka, 2015; Romeo, 2013).   Studies with both human and rodent subjects have indicated that the use of exogenous cannabinoids during adolescence has the capacity to alter HPA axis stress responses, thus impacting emotionality and the development of anxiety-related symptoms (Lee & Gorzalka, 2015).   Lovelace et al. (2015) discuss another neurobiological mechanism that may underlie the relationship between adolescent cannabis use and the development of anxiety and depression.   In a rodent study, these researchers examined maladaptations in the prefrontal cortex due to cannabis use by looking at presynaptic plasticity at glutamatergic synapses in adolescent rats.   The results indicated that exposure to exogenous cannabinoids during adolescence led to over-activation of CB1 receptors, which led to permanent changes in synapses in the prefrontal cortex.   Overall, mice exposed to exogenous cannabinoids during adolescence showed a loss of presynaptic plasticity, which impacts the brain’s ability to adapt to changing environments and thus may contribute to an increased vulnerability of psychopathology during adulthood (Lovelace et al., 2015).   In an interesting rodent study conducted by Rubino et al. (2008), researchers found that exposure to THC during adolescence was associated with decreased density and function of CB1 receptors in the ventral tegmental area, the nucleus accumbens, and the amygdala.   These areas of the brain are implicated in emotional processing and reward and are thus implicated in the development of depressive symptomatology.   The behavior of the rats in this study also mirrored depressive symptomatology.   Specifically, rats exposed to THC during adolescence exhibited both â€Å"behavioral despair† (which the researchers defined as time the rats were immobile) and anhedonia (as measured through decreased consumption of sucrose).   Taken together, it appears that several neurobiological mechanisms are at play in the connection between adolescent cannabis use and the development of anxiety and depressive symptoms.   Impact on the Development of Psychotic Disorders A substantial body of literature has indicated a connection between the use of cannabis during adolescence and the later development of psychotic disorders (e.g., van Os et al., 2002; Henquet et al., 2005; Stefanis et al., 2004).   This is especially true for individuals who are already genetically predisposed to develop psychotic disorders (Henquet et al., 2005) though the connection has also been found in individuals that do not have this genetic predisposition (van Os et al., 2002).   As with the impact on cognition and on anxiety/depressive symptoms, it appears that early-onset cannabis use (Arseneault et al., 2002; Moore et al., 2007) as well as heavier (i.e. daily or near-daily) use pose the greatest risk for the later development of a psychotic disorder (Moore et al., 2007; van Os et al., 2002). Rubino and Parolaro (2014) discuss the possible neurobiological mechanisms behind the connection between adolescent cannabis use and the development of psychotic disorders.   In general, it appears that the use of exogenous cannabinoids during adolescence disrupts the maturational processes occurring in the brain during this time, especially in the hippocampus and the prefrontal cortex – two areas of the brain that are implicated in the psychotic disorder schizophrenia, in particular.   The endocannabinoid system itself undergoes a significant amount of change during the adolescent years; thus, exogenous cannabinoid exposure during this time period has the potential to alter the long-term functionality of CB1 receptors, which then impacts the activity of several neurotransmitters implicated in psychotic symptomatology, especially dopamine (Rubino & Parolaro, 2014). Additionally, being exposed to cannabis during the adolescent period has been shown to disrupt prepulse inhib ition (the ability to accurately perceive and process stimuli) and down-regulate GABAergic activity in the prefrontal cortex – both symptoms commonly seen in individuals with schizophrenia (Morales-Muà ±oz et al., 2014; Zamberletti et al., 2014).  Ã‚   As previously mentioned, individuals who have a genetically predisposed vulnerability to develop psychotic disorders are at an especially high risk to do so if they engage in cannabis use during adolescence (Henquet et al., 2005).   For example, individuals who have a specific variant of the gene for catechol-O-methyltransferase (COMT), which breaks down dopamine – the neurotransmitter implicated in schizophrenia – are at a much higher risk for developing the disorder if they used cannabis during adolescence as compared to individuals who do not have that specific variant of the gene for COMT (Caspi et al., 2005).   Another gene that influences the relationship between adolescent cannabis use and psychosis is the ATK1 gene, which affects dopamine breakdown in the striatum.   According to DiForti et al. (2012), cannabis users with a certain variant of the ATK1 gene were seven times more likely to develop psychosis as compared to individuals with this gene variant w ho did not use cannabis.   Clearly, in individuals that already possess these specific genetic variants, cannabis use during adolescence can be the trigger that leads to the expression of these genes and the development of psychotic symptoms and/or disorders.   In addition, adults with psychotic disorders who used cannabis during adolescence are at a greater risk for relapse of psychotic symptoms, poorer adherence to treatment, and increased rates of hospitalization related to their diagnosis (Hunt, Bergen, & Bashir, 2002; Lewis, Tarrier, & Drake, 2005; Wade et al., 2006).   Impact on the Future Development of Substance Use Disorders   Several studies have indicated a link between adolescent cannabis use and the later development of a substance use disorder.   Again, this relationship is especially strong for individuals that engage in cannabis use in early adolescence and who engage in heavy (i.e., daily or near-daily) use (Fergusson, Boden, & Horwood, 2006; Hall & Lynskey, 2005; Stuart & Green, 2008).  Ã‚   Past researchers have speculated upon various explanations for this trend, including the so-called ‘gateway hypothesis.’   In general, the ‘gateway hypothesis’ assumes that individuals who use â€Å"harder† drugs such as heroin and cocaine almost always started their use of substances with using cannabis, and that this link is explicitly causal (Van Gundy & Rebellon, 2010).  Ã‚   This hypothesis is based on research findings indicating that the use of cannabis during adolescence often predates the use of other illicit substances, including heroin, methamphetamines, and cocaine (Fergusson et al., 2006).   Though the causality of this link has been repeatedly questioned in the literature (e.g., Morral, McCaffrey, & Paddock, 2002; Van Gundy & Rebellon, 2010), many researchers have attempted to explain the mechanisms behind the early use of cannabis and the later use of other substances and/or development of a substance use disorder.   There are countless potential psychosocial explanations for this connection (e.g., peer pressure, propensity toward risk-taking behaviors, availability of substances, etc.); however, for the purposes of this paper, the potential neurobiological mechanisms behind the connection will be discussed. The major possible neurobiological mechanism behind the connection between early cannabis use and the later development of a substance use disorder has to do with the effect of cannabis on the brain’s opioidergic system.   A great deal of animal research has indicated that the endocannabinoid system and the opioidergic system are intricately linked.   For example, Pickel, Chan, Kash, Rodriguez, and Mackie (2004) and Rodriguez, Mackie, and Pickel (2001) found that CB1 receptors and  µ opioid receptors are found on the same neurons in both the striatum and the ventral tegmental area, and Cossu et al. (2001) and Ledent et al. (1999) found that animals without CB1 receptor genes do not self-administer opioids. Drawing upon this clear connection between the endocannabinoid and opioidergic brain systems, Ellgren, Spano, and Hurd (2007) investigated the hypothesis that cannabis exposure during adolescence changes opioid-related neural functions and leads to increased likelihood of later opioid use.   Findings of this research confirmed that rats exposed to THC during the adolescent period self-administered greater amounts of heroin compared to the control group.   Moreover, findings indicated that rats exposed to THC in adolescence showed a persistent disturbance in the activity of enkephalin, which is the endogenous opioid neuropeptide associated with reward behaviors and hedonic states.   Findings also indicated that THC exposure led to changes in the functions of  µ opioid receptors such that heroin use was more reinforcing (via dopamine release) for rats exposed to THC during adolescence as compared to the control group.   Taken together, these results indicate that cannabis use during adolescence leads to a greater vulnerability to the reinforcing effects of opioids during adulthood, potentially leading to a greater risk for dependence and likelihood of relapse of substance use disorders.   Conclusion Despite the increasing popularity of cannabis use, both for medicinal and recreational purposes (Hwang & Clarke, 2016; Leyton, 2016), it is important to consider the resulting increased availability of cannabis to individuals during the sensitive period of adolescence.   Given the profound changes occurring in the brain during adolescence (Arain et al., 2013; Dahl, 2003; Hart, 2007; Lubman et al., 2007), teenagers are particularly susceptible to the influence of substances, which may lead to lasting changes in the brain’s functioning.   Such changes are associated with poor outcomes in several areas, including deficits in performance on executive function tasks (Becker et al., 2010; Ehrenreich et al., 1999; Fontes et al., 2011; Gruber et al., 2014; Meier et al., 2012; Pope et al., 2003; Tapert et al., 2002), an increased risk for the development of anxiety and/or depressive symptoms (Brook et al., 2001; Degenhardt et al., 2013; Fairman, 2015; Hayatbakhsh et al., 2007; Patt on et al., 2002; van Laar, van Dorsselaer, Monshouwer, & de Graaf, 2007), an increased risk for the development of a psychotic disorder (Arseneault et al., 2002; Caspi et al., 2005; DiForti et al., 2012; Henquet et al., 2005; Moore et al., 2007; Rubino & Parolaro, 2014; Stefanis et al., 2004; van Os et al., 2002), and an increased risk for future substance use/dependence (Fergusson et al., 2006; Hall & Lynskey, 2005; Stuart & Green, 2008).   Such considerations may have important implications for policy development related to the legalization of cannabis.   References Arain, M., Haque, M., Johal, L., Mathur, P., Nel, W., Rais, A., Sandu, R., & Sharma, S. 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