Approximately 8% of those ages 12–17 meet criteria for substance abuse or dependence in the past year, but this peaks between ages 18–25, when 21% meet diagnostic criteria for a substance use disorder . Those with early substance use onset are more likely to continue use into adulthood; individuals who first used alcohol at age 14 or younger have a >5 time increased risk of lifetime alcohol use disorder as compared to those who first used alcohol after the U.S. legal limit of the 21st birthday . Adolescent alcohol and marijuana use has been linked to harmful effects on physiological, social, and psychological functioning . This includes increased delinquency , aggressivity, risky sexual behaviors, hazardous driving, and comorbid substance use .Given the extent of brain maturation occurring during this phase in life, adolescents who use substances appear to be vulnerable to alterations in brain functioning, cognition and behavior. Indication that alcohol and marijuana use may detrimentally influence the developing brain comes from studies showing diminutions in neurocognitive functioning, especially attention, visuospatial functioning, and learning and retrieval of verbal and nonverbal information ; morphological changes ; anisotropic differences in white matter ; and a more distributed functional network and recruitment of alternate brain regions . Heavy alcohol use is associated with a wide range of neural consequences in adults and similar sequelae are implicated in adolescent users. Alterations in anisotropy in the genu and isthmus of the corpus callosum in alcohol-using teens and in frontal, cerebellar, temporal,growing cannabis and parietal regions in adolescent binge-drinkers lends further support to atypical developmental trajectories.
White matter quality appears to relate to drinking in a dose dependent manner, where higher blood alcohol concentrations are associated with poorer tissue integrity in the corpus callosum, internal and external capsules, and superior corona radiata . Functional consequences of adolescent heavy drinking are seen in attenuated frontal cortex response during spatial working memory , and deficits on neuropsychological measures of attention , information retrieval , and visuospatial functioning , with some studies showing sustained effects into adulthood . Drinking so much that hangover or withdrawal symptoms are experienced is associated with decreased performance over time . Overall, these studies indicate that heavy drinking during adolescence may be associated with decrements in cognitive performance and brain health. However, longitudinal studies are critical to determine if substance use causes these abnormalities, or if these features predated the onset of regular substance use. One such study prospectively examined the influence of alcohol on neuropsychological functioning prior to initiation of drinking. For girls who transitioned into moderate or heavy drinking, more drinking days in the past year predicted a greater reduction in visuospatial task performance from baseline to 3-year follow-up. For boys, a tendency was seen for more past year hangover symptoms to predict poorer sustained attention . Gender differences are seen in prefrontal cortex volumes of adolescents with alcohol use disorders, where females show smaller, and males, larger volumes than controls. In addition, limited frontal response to a spatial working memory task and reduced grey matter volume in females with alcohol use disorders compared to males suggest that females may be more vulnerable to the impairing effects of alcohol . Marijuana use is also associated with atypical neural profiles. Adolescent marijuana users show a less efficient pattern of activation compared to non-users on working memory , verbal learning , and cognitive control tasks using fMRI. Brain response patterns in marijuana-using teens consistently indicate increased utilization of alternate brain networks .
In addition, users have demonstrated larger cerebellar volumes than non-users , and female marijuana users showed larger prefrontal cortex volumes than same-gender non-users , suggesting the possibility of attenuated synaptic pruning. White matter integrity is typically poorer in users than non-users, particularly in fronto-parietal circuitry and pathways connecting the frontal and temporal lobes . The functional implications of these differences appear disadvantageous, as marijuana-using teens show an increased susceptibility to depressive symptoms and poorer performance than non-users on neuropsychological tests of psychomotor speed, complex attention, verbal memory, planning, and sequencing ability, even after a month of sustained abstinence . The pharmacodynamics of alcohol and marijuana are the subject of study in several empirical works examining their physiological and behavioral effects. Chronic alcohol exposure is associated with cortical and white matter volume loss secondary to decreases in choline and Nacetyl aspartate, reduced GABAa receptor efficacy, and impaired neurogenesis . Similarly, the principal active component of marijuana, delta9-tetrahydrocannabinol , produces complex alterations in cognition and behavior that involve several neuronal substrates . Brain regions with high densities of CB-1 receptors, and thus susceptible to the effects of THC, include the frontal regions, hippocampus, basal ganglia, cerebellum, amygdala, and striatum . Human studies examining CNS sequelae of chronic marijuana use provide evidence for increased metabolism and activation of alternate neural pathways within these regions . Further adverse effects may result from the pharmacological interaction of alcohol and marijuana, where THC has been reported to markedly enhance apoptotic properties of ethanol. In infant rats, administration of THC alone did not result in neurodegeneration; however, the combination of THC and a mildly intoxicating dose of ethanol induced significant apoptotic neuronal cell death, similar to that observed at high doses of ethanol alone .
In sum, studies of adolescent alcohol and marijuana use indicate weaknesses in neuropsychological functioning in the areas of attention, speeded information processing, spatial skills, learning and memory, and complex behaviors such as planning and problem solving even after 28 days of sustained abstinence . There are also associated changes in brain structure and function that include altered prefrontal, cerebellar, and hippo campal volumes, reduced white matter micro-structural integrity, and atypical brain activation patterns . There may be potential reversibility of brain structural changes with long-term abstinence , though additional studies are needed to understand the extent to which abnormalities persist or remit with time. Further, the potential interaction of alcohol and marijuana are of concern considering that comorbid use is common .It is postulated that there is an asynchronous development of reward and control systems that enhance adolescents’ responsivity to incentives and risky behaviors . Bottom-up limbic systems involved in emotional and incentive processing purportedly develop earlier than top down prefrontal systems involved in behavioral control. In situations with high emotional salience, the more mature limbic regions will override prefrontal regions, resulting in poor decisions. The developmental imbalance is unique to adolescents, as children have equally immature limbic and prefrontal regions, while adults benefit from fully developed systems. Within this model,cannabis growing risky behaviors of adolescents is understood in light of limbic system driven choices to seek immediate gratification rather than long-term gains. Moreover, this relationship may be more pronounced in adolescents with increased emotional reactivity. Behavioral and fMRI studies show increased subcortical activation when making risky choices and less activation of prefrontal cortex, as well as immature connectivity between emotion processing and control systems overall . A more specific characterization of these patterns using comparisons of low- and high-risk gambles indicated that high-risk choices activate reward-related ventral striatum and medial prefrontal cortex, whereas low-risk choices activate control-related dorsolateral prefrontal cortex. Interestingly, activation of the ventral medial prefrontal cortex was positively associated with risk-taking propensity, whereas activation of the dorsal medial prefrontal cortex was negatively associated with risk-taking propensity , suggesting that distinct neural profiles may contribute to the inhibition or facilitation of risky behaviors.Development of effective treatments for alcohol use disorder remain a high priority area which involves screening compounds in the laboratory before proceeding to clinical trials . Within this process, there is a need to develop and understand relationships among human laboratory paradigms to assess the potential efficacy of novel AUD treatments in early-stage clinical trials. To date, reviews of the human laboratory literature in AUD pharmacotherapy development indicate significant outcome variability based on experimental paradigm parameters, population of interest, and sample size, and suggest that these myriad variables contribute to the disconnect between laboratory effect sizes and treatment outcomes . Amidst the efforts to develop translational experimental paradigms, neuroimaging tasks are increasingly used to explore potential pharmacotherapy effects on neural correlates of alcohol-induced craving . Alcohol consumption produces neuroadaptations in multiple circuits, including GABA-ergic regulation of traditional reward circuitry; alcohol craving is mediated by cortico-striatal-limbic activation, heightens relapse risk , and can be triggered through internal and external stimuli associated with alcohol consumption .
For this reason, neuroimaging techniques, such as functional magnetic resonance imaging , have been used to explore these circuits as potential medication targets. Recent qualitative reviews and meta-analyses suggested that while such fMRI tasks vary in sensory experiences and scan parameters, mesocorticolimbic areas consistently exhibit task-based neural activity and may be viable tools in understanding mechanisms of AUD pharmacotherapy . Based on this emerging literature, there is growing evidence that neural responses to alcohol cues and associated contexts are predictive of real-world consumption behavior and, potentially, clinical outcomes. For instance, among college students, alcohol cue-elicited blood oxygen level-dependent response in caudate, frontal cortex, and left insula predicted escalation to heavy drinking over a 1-year period . Further, insula and frontal gyrus activation in response to an emotion face recognition task similarly predicted alcoholrelated problems five years later in young adults . Regarding treatment outcomes, increased ventral striatum activation in response to alcohol cues was associated with a faster time to relapse in a sample of abstinent AUD individuals . Comparisons of AUD treatment completers and non-completers in a community sample indicated that non-completers showed stronger associations between reported alcohol craving intensity and resting state functional connectivity between striatum and insula, relative to completers . Of note, one study had contradicting results by reporting that relapsers, compared to successful alcohol abstainers and healthy controls, exhibited reduced alcohol cue-elicited activation in ventral striatum and midbrain . Several studies have examined whether AUD pharmacotherapies alter neural responses to contexts that elicit alcohol craving, including alcohol cues, exposure to reward and emotional faces, and stress exposure. While significant variability exists in sample populations, examined tasks, modified areas of activation, and molecular targets of treatments, there is some consistent evidence that AUD pharmacotherapies may reduce reward-related activation in regions such as the ventral striatum, precuneus, and anterior cingulate . Importantly, in one study of naltrexone, magnitude of reduction in alcohol cue-induced ventral striatum activation was associated with fewer instances of subsequent heavy drinking . In support, Mann and colleagues have found that individuals with high ventral striatum cue reactivity demonstrate lower relapse rates when treated with naltrexone than those with low VS reactivity. Bach and colleagues have also identified that individuals with high alcohol cue-reactivity in the left putamen exhibit longer time to relapse when treated with naltrexone, compared to those with low reactivity. Together, these studies underscore reward circuitry as a key area in the translation of neural responses to clinical outcomes in AUD medication development . Alcohol self-administration tasks in the laboratory are thought to capture alcohol use behavior in controlled settings that approximate consumption in real world settings. Studies have tested multiple variants of self-administration paradigms, including tasks that require participants to orally consume alcohol at the cost of monetary rewards per drink , and intravenous methods that can closely control breath alcohol concentration levels ; . Studies have used self-administration methods to test genetic, physiological, and psychological risk factors for heavy drinking . Self-administration tasks have also been used extensively in developing effective AUD pharmacotherapies . While both fMRI cue-reactivity tasks and alcohol self-administration tasks are widely used in alcohol research, the extent to which cue-reactivity predicts self-administration in the laboratory remains unknown. In light of the emerging role of functional neuroimaging in predicting drinking behavior and AUD treatment outcomes, a remaining question is the nature of the relationship between neuroimaging task-induced neural activation and widely utilized laboratory paradigms considered proximal to real-world consumption, including self-administration tasks. To date, several studies have examined relationships of response across different laboratory paradigms and have consistently identified that alcohol craving during intravenous alcohol administration mediates the relationship between alcohol induced stimulatory effects and subsequent oral alcohol consumption . While relationships across human laboratory paradigms are recently delineated, no studies have yet investigated whether alcohol cue-induced BOLD response is predictive of responses within laboratory self-administration paradigms.