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• Published: 25 August 2022

Age-related differences in the effect of chronic alcohol on cognition and the brain: a systematic review

• Lauren Kuhns   ORCID: orcid.org/0000-0002-3156-8905 1 , 2 ,
• Emese Kroon   ORCID: orcid.org/0000-0003-1803-9336 1 , 2 ,
• Heidi Lesscher 3 ,
• Gabry Mies 1 &
• Janna Cousijn 1 , 2 , 4  

Translational Psychiatry volume  12 , Article number:  345 ( 2022 ) Cite this article

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Adolescence is an important developmental period associated with increased risk for excessive alcohol use, but also high rates of recovery from alcohol use-related problems, suggesting potential resilience to long-term effects compared to adults. The aim of this systematic review is to evaluate the current evidence for a moderating role of age on the impact of chronic alcohol exposure on the brain and cognition. We searched Medline, PsycInfo, and Cochrane Library databases up to February 3, 2021. All human and animal studies that directly tested whether the relationship between chronic alcohol exposure and neurocognitive outcomes differs between adolescents and adults were included. Study characteristics and results of age-related analyses were extracted into reference tables and results were separately narratively synthesized for each cognitive and brain-related outcome. The evidence strength for age-related differences varies across outcomes. Human evidence is largely missing, but animal research provides limited but consistent evidence of heightened adolescent sensitivity to chronic alcohol’s effects on several outcomes, including conditioned aversion, dopaminergic transmission in reward-related regions, neurodegeneration, and neurogenesis. At the same time, there is limited evidence for adolescent resilience to chronic alcohol-induced impairments in the domain of cognitive flexibility, warranting future studies investigating the potential mechanisms underlying adolescent risk and resilience to the effects of alcohol. The available evidence from mostly animal studies indicates adolescents are both more vulnerable and potentially more resilient to chronic alcohol effects on specific brain and cognitive outcomes. More human research directly comparing adolescents and adults is needed despite the methodological constraints. Parallel translational animal models can aid in the causal interpretation of observed effects. To improve their translational value, future animal studies should aim to use voluntary self-administration paradigms and incorporate individual differences and environmental context to better model human drinking behavior.

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Introduction

Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide [ 1 ]. Most AUDs remain untreated [ 2 ] and for those seeking treatment, relapse rates are high [ 3 ]. Adolescence marks a rapid increase in AUD and an earlier onset of AUD is associated with worse long-term outcomes, including greater problem severity and more relapses [ 4 , 5 ]. Loss of control over alcohol use is a core aspect of AUD [ 6 ] and the developmentally normative difficulty to control motivational urges in tempting and arousing situations is thought to put adolescents at risk for developing addictive behaviors [ 7 ]. Moreover, neurotoxic consequences of alcohol use may be more severe for a developing brain [ 8 ]. Paradoxically, adolescence is also a period of remarkable behavioral flexibility and neural plasticity [ 9 , 10 , 11 ], allowing adolescents to adapt their goals and behavior to changing situations [ 12 ] and to recover from brain trauma more easily than adults [ 10 ]. In line with this, the transition from adolescence to adulthood is associated with high rates of AUD recovery without formal intervention [ 13 ]. While the adolescent brain may be a vulnerability for the development of addiction, it may also be more resilient to long-term effects compared to adults. Increased neural plasticity during this period could help protect adolescents from longer-term alcohol use-related cognitive impairments across multiple domains, from learning and memory to decision-making and cognitive flexibility. Therefore, the goal of this systematic review was to examine the evidence of age-related differences in the effect of alcohol on the brain and cognitive outcomes, evaluating evidence from both human and animal studies.

In humans, the salience and reinforcement learning network as well as the central executive network are involved in the development and maintenance of AUD [ 7 , 14 ]. The central executive network encompasses fronto-parietal regions and is the main network involved in cognitive control [ 15 ]. The salience network encompasses fronto-limbic regions crucial for emotion regulation, salience attribution, and integration of affective information into decision-making [ 15 , 16 ], which overlaps with fronto-limbic areas of the reinforcement learning network (Fig. 1 ). Relatively early maturation of salience and reinforcement learning networks compared to the central executive network is believed to put adolescents at heightened risk for escalation of alcohol use compared to adults [ 7 ]. Rodent models are regularly used for AUD research and allow in-depth neurobehavioral analyses of the effects of ethanol exposure during different developmental periods while controlling for experimental conditions such as cumulative ethanol exposure in a way that is not possible using human subjects because exposure is inherently confounded with age. For example, animal models allow for detailed neurobiological investigation of the effects of alcohol exposure in a specific age range on neural activation, protein expression, gene expression, epigenetic changes, and neurotransmission in brain regions that are homologous to those that have been implicated in AUD in humans.

A visual representation of the translational model of the executive control and salience networks in humans and rodents. The executive control and salience are key networks believed to play a part in adolescent vulnerability to alcohol-related problems.

While most of our knowledge on the effects of alcohol on the brain and cognitive outcomes is based on research in adults, several recent reviews have examined the effects of alcohol on the brain and cognition in adolescents and young adults specifically [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Heavy or binge drinking has been associated with reduced gray and white matter. Also, altered task-related brain activity [ 20 ], structural abnormalities [ 25 ], and overlapping behavioral impairment in executive functioning have been identified in adolescent and young adult alcohol users [ 19 ]. While some of the observed neurocognitive differences between drinkers and non-drinkers may be predisposing factors, they may be further exacerbated by heavy and binge drinking [ 21 , 23 ]. Furthermore, reviews of longitudinal studies concluded that adolescent alcohol use is associated with neural and cognitive alterations in a dose-dependent manner [ 17 , 22 ].

Although previous reviews underscore the potential negative consequences of heavy alcohol use on the brain and cognition in adolescence, they do not typically address the question of whether adolescents are differentially vulnerable compared to adults to the effects of alcohol on these outcomes. Explicit comparisons between adolescents and adults are crucial to identify potential risk and resilience factors. In the current review, we aimed to extend previous work by systematically examining this critical question: does the relationship between chronic alcohol use and neurocognitive outcomes differ between adolescents and adults? To address this question, we systematically reviewed human and animal studies that included both age groups and used a factorial design that would allow for the comparison of the effects of chronic alcohol use on cognitive and brain-related outcomes across age groups. We specifically highlight outcomes from voluntary self-administration paradigms when available and discuss the translational quality of the animal evidence base. We conclude with a discussion of prominent knowledge gaps, future research directions, and clinical implications.

Study inclusion criteria and search strategy

We followed the PRISMA guidelines for the current systematic review (The PRIMSA Group, 2009). An initial MedLine, Cochrane Library, and PsycInfo search was conducted during September of 2018 with terms related to alcohol, cognition, adolescence/adulthood, and study type (see Appendix for full search strategy and syntax). Two search updates using the same search strategy were conducted on 31 March 2020 and 3 February 2021. For all searches, the identified citations were split into batches and at least two of the following assessors (GM, LK, JC, or CG) conducted a blinded review to determine whether articles met the inclusion criteria. In the first phase of screening, only titles and abstracts were screened and articles that clearly did not meet the inclusion criteria were excluded. In the second phase, the remaining articles received a full-text review and those that did not meet all inclusion criteria were excluded. The first inclusion criterion that was not adhered to was recorded as the reason for excluding. If there was a discrepancy between authors after initial and full-text screening process, the reviewing authors discussed the article and a consensus was reached.

The inclusion criteria were: (1) Human samples including both adolescents younger than 18 and adults older than 18 and animal samples including adolescent (Post Natal Day (PND) 25–42 for rodents) and adult [ 8 ] animals (greater than PND 65 for rodents); (2) Exploration of alcohol as the independent variable and cognitive, reward-related, or brain outcomes as the dependent variables; (3) Alcohol and cognitive outcomes must meet our operationalization defined below; (4) Study design comparing adults and adolescents on outcome measures; (5) Administering or measuring alcohol use during adolescence or adulthood, not retrospectively (e.g., no age of onset work in humans using retrospective self-reports of alcohol consumption); (6) Primary quantitative data collection (no case studies, or review papers); (7) Solely looking at alcohol-related factors as the independent variables (e.g., cannot explore alcohol-related factors in individuals with psychosis); (8) Written in English; (9) Published in a peer-reviewed journal before February 3, 2021 (see Fig. 2 for a detailed screening process).

The definitions for adolescence are variable, hampering the direct comparison of human and rodent research. In rodents, the end of early-mid adolescence is considered to be approximately PND 42 when rats reach sexual puberty. By contrast, the boundaries for the onset of early adolescence are less clear. Based on the notion that most age-typical physiological changes that are characteristic of adolescence emerge from PND 28 [ 26 ], the conservative boundary for adolescence has been set at PND 28 (e.g., seminal review on adolescence [ 27 ]). The preceding week (PND 21-PND 28) has been described as the juvenile period (e.g., [ 28 , 29 ]) but these same reports consider PND 21-PND 23 as the lower boundary for early adolescence [ 28 , 29 ], further emphasizing that the boundary of PND28 may be too conservative. Indeed, multiple studies (e.g., [ 30 , 31 ]), have chosen to take PND25 as the boundary for early adolescence. Hence, we have decided to also follow this less conservative approach and include all studies where alcohol was administered between PND 25 and PND 42.

The exact boundaries of human adolescence are similarly nebulous. From a neurodevelopmental perspective, adolescence is now often thought of as continuing until approximately age 25 because of the continuing maturation of the brain [ 32 ]. However, the delineation of adolescence and adulthood is also dependent on societal norms, and is commonly defined as the transitional period between puberty and legal adulthood and independence which typically begins around age eighteen. In light of this, we chose a relatively liberal inclusion criteria for the human studies; studies needed to include at least some adolescents below eighteen, the age at which drinking typically begins, as well as ‘adult’ participants over the age of eighteen. We are careful to interpret the results of human studies within the neurodevelopmental framework of adolescence, such that 18–25-year-olds are considered late adolescents to young adults who are still undergoing cognitive and brain maturation.

Notably, we excluded studies that assessed alcohol exposure retrospectively (primarily early onset alcohol studies) because age of onset variables are often inaccurate, with reported age of alcohol onset increasing with both historical age [ 33 ] and current alcohol use patterns [ 34 ]. In addition, we excluded work that has not undergone peer-review to ensure high-quality papers.

In humans, we defined cognition as any construct that typically falls within the umbrella of neuropsychological testing, as well as brain-based studies. We also included more distal constructs of cognition, like craving and impulsivity, because they play a prominent role in addictive behaviors [ 35 , 36 ]. In rodents, we defined cognition as attention, learning, and memory in line with a seminal review paper [ 37 ]. Given the importance of social cognition in patterns of alcohol use particularly in adolescence [ 38 ] and its proposed role in adolescent risk and resilience to addiction [ 39 ], we included social behavior as an outcome. Furthermore, because many rodent studies assessed anxiety-related behaviors and the high degree of comorbidity between anxiety disorders and alcohol addiction [ 40 ], we also included anxiety as a secondary outcome. On the other hand, locomotor activity was excluded as an outcome because even though behavioral sensitization is considered to reflect neurobiological changes that may underlie certain aspects of addictive behavior [ 36 ], the translational relevance for addictive behavior and human addiction in particular remains unclear [ 41 , 42 ]. Across both rodents and humans, general alcohol metabolization and ethanol withdrawal studies were not included except if they included brain-related outcomes. The relevant reported findings (i.e., the results of an analysis of comparing age groups on the effect of alcohol on an included outcome) were extracted by a one reviewer and then confirmed by at least one other reviewer. In addition, the characteristics of the sample, details of alcohol exposure, and study design were extracted by a single reviewer and then confirmed by at least one other reviewer. No automation tools were used for extraction. Within the included studies, peripheral findings that did not relate to cognition were excluded from review and not extracted. The protocol for this systematic review was not registered and no review protocol can be accessed.

Study search

Our searches identified 7229 studies once duplicates were removed. A total of 6791 studies were excluded after initial review of abstracts. Then, 434 studies received a full-text review and 371 were excluded for failing to meet all inclusion criteria. See Fig. 2 for a flow diagram of the full screening process. At the end of the inclusion process, 59 rodent studies and 4 human studies were included. The characteristics and findings of the final studies are detailed in Table 1 (rodents) and Table 2 (humans). Due to the heterogeneity of outcomes, meta-regression was not suitable for synthesizing results. Results are narratively synthesized and grouped based on forced or voluntary ethanol exposure and by outcome within the tables and by outcome only in text. Two authors independently rated the quality of evidence for human studies (Table 2 ) based on criteria used in a similar systematic review [ 43 ]: (1) strong level of causality: longitudinal design comparing adolescent and adults while adjusting for relevant covariates; (2) moderate level of causality: longitudinal design comparing adolescents and adults without adjusting for relevant covariates or cross-sectional designs with matched groups that considered relevant covariates; (3) weak level of causality: cross-sectional design without matched adolescent and adult groups and/or did not adjust for relevant covariates. A methodological quality assessment was not conducted for the animal studies due to a lack of empirically validated risk of bias tools and lack of standardized reporting requirements in the animal literature.

PRIMSA flow diagram detailing the screening process.

Animal studies

Cognitive outcomes, learning and memory.

Human evidence clearly suggests that alcohol is related to learning and memory impairments, both during intoxication [ 44 ] and after sustained heavy use and dependence [ 45 , 46 ]. Paradigms that assess learning and memory provide insight into the negative consequences of alcohol consumption on brain functioning, as well as the processes underlying the development and maintenance of learned addictive behaviors.

Conditioned alcohol aversion or preference: Lower sensitivity to alcohol’s aversive effects (e.g., nausea, drowsiness, motor incoordination) but higher sensitivity to alcohol’s rewarding effects has been hypothesized to underlie the higher levels of alcohol use, especially binge-like behavior, in adolescents compared to adults [ 47 ]. Several conditioning paradigms have been developed to assess the aversive and motivational effects of alcohol exposure.

The conditioned taste aversion (CTA) paradigm is widely used to measure perceived aversiveness of alcohol in animals. Repeated high-dose ethanol injections are paired with a conditioned stimulus (CS, e.g., a saccharin or NaCL solution). The reduction in CS consumption after conditioning is used as an index of alcohol aversion. Two studies examined CTA in mice [ 48 , 49 ] and two in rats [ 50 , 51 ]. Three of the four studies found age-related differences. In all three studies using a standard CTA paradigm, adolescents required a higher ethanol dosage to develop aversion compared to adults [ 48 , 49 , 50 ]. Using a similar second-order conditioning (SOC) paradigm pairing high doses of ethanol (3.0 g/kg) with sucrose (CS), both adolescent and adult rats developed equal aversion to the testing compartment paired with ethanol [ 51 ].

Overall, three studies found support for lower sensitivity to alcohol’s aversive effects in adolescents, whereas one observed no differences. Future research should employ intragastric as opposed intraperitoneal exposure to better mimic human binge-like drinking in order to increase the translational value of the findings.

To measure differences in alcohol’s motivational value, conditioned place preference (CPP) paradigms have been used. This involves repeated pairings of ethanol injections with one compartment and saline injections with another compartment of the testing apparatus. On test days, CPP is assessed by measuring how long the animal stays in the compartment paired with ethanol relative to saline injections. Four studies examined CPP, with two studies observing age-related differences [ 52 , 53 , 54 , 55 ]. In the only mouse study, history of chronic ethanol exposure during adolescence (2.0 g/kg for 15 days) but not adulthood [ 52 ] led to increased CPP after brief abstinence (5 days) before the conditioning procedure (2.0 g/kg, four doses over 8 days). This suggests that early ethanol exposure increases alcohol’s rewarding properties later on. However, two rat studies did not observe either preference or aversion in either age when using lower ethanol doses and a shorter exposure period (0.5 and 1.0 g/kg for 8 days) [ 53 ], nor when using higher doses and intermittent exposure (3.0 g/kg, 2 days on, 2 days off schedule) [ 55 ]. Next to species and exposure-specific factors, environmental factors also play a role [ 54 ], with adolescents raised in environmentally enriched conditions demonstrating CPP (2 g/kg) while adolescents raised in standard conditions did not. In contrast, CPP was insensitive to rearing conditions in adults with both enriched and standard-housed rats showing similar levels of CPP.

Overall, there is inconsistent evidence for age-related differences in the motivational value of ethanol. One study found support for increased sensitivity to the rewarding effects of ethanol in adolescents, whereas one found support for adults being more sensitive and two observed no differences.

Fear conditioning and retention: Pavlovian fear conditioning paradigms are used to investigate associative learning and memory in animals. These paradigms are relevant for addiction because fear and drug-seeking behavior are considered conditioned responses with overlapping neural mechanisms [ 56 ]. Rodents are administered an unconditioned stimulus (US; e.g., foot shock) in the presence of a conditioned stimulus (CS; unique context or cue). Conditioned responses (CR; e.g., freezing behavior) are then measured in the presence of the CS without the US as a measure of fear retention. Contextual fear conditioning is linked to hippocampus and amygdala functioning and discrete cue-based (e.g., tone) fear is linked to amygdala functioning. [ 57 , 58 , 59 ], and fear extinction involves medial PFC functioning [ 60 ]. Five studies investigated fear conditioning, four in rats [ 61 , 62 , 63 , 64 ] and one in mice [ 65 ].

Only one of the four studies observed age-related differences in tone fear conditioning. Bergstrom et al. [ 61 ] found evidence for impaired tone fear conditioning in male and female alcohol-exposed (18d) adolescent compared to adult rats after extended abstinence (30d). However, adolescent rats consumed more ethanol during the one-hour access period than adults, which may explain the observed age differences in fear tone conditioning. Small but significant sex differences in consumption also emerged in the adolescent group, with males showing more persistent impairment across the test sessions compared to females, despite adolescent females consuming more ethanol than males. In contrast, three studies found no evidence of impaired tone fear conditioning in either age group after chronic alcohol exposure (4 g/kg, every other day for 20d) and extended abstinence [ 62 , 63 ] (22d), [ 64 ].

Two of the three studies observed age-related differences in contextual fear conditioning [ 62 , 63 , 64 ]. In two studies with similar exposure paradigms, only adolescents exposed to chronic high dosages of ethanol (4 g/kg) showed disrupted contextual fear conditioning after extended abstinence (22d) [ 62 , 63 ]. Importantly, differences disappeared when the context was also paired with a tone, which is suggestive of a potential disruption in hippocampal-linked contextual fear conditioning specifically [ 64 ]. Furthermore, there may be distinct vulnerability periods during adolescence as contextual fear retention was disrupted after chronic alcohol exposure (4 g/kg, every other day for 20d) during early-mid adolescence but not late adolescence [ 62 ]. In the only study to combine chronic exposure and acute ethanol challenges, contextual conditioning was impaired by the acute challenge (1 g/kg) but there was no effect of pre-exposure history in either age group (4 g/kg, every other day for 20d) [ 63 ].

Only one study examined fear extinction, and found no effect of ethanol exposure (4/kg, every other day for 20d) on extinction after tone conditioning. However, adults had higher levels of contextual fear extinction compared to mid-adolescents while late adolescents performed similar to adults [ 62 ]. Moreover, looking at binge-like exposure in mice (three binges, 3d abstinence), Lacaille et al. [ 65 ] showed comparable impairments in long-term fear memory in adolescents and adults during a passive avoidance task in which one compartment of the testing apparatus was paired with a foot shock once and avoidance of this chamber after a 24 h delay was measured.

In sum, there is limited but fairly consistent evidence for adolescent-specific impairments in hippocampal-linked contextual fear conditioning across two rat studies, while no age differences emerged in context-based fear retention in one study of mice. In contrast, only one of the four studies found evidence of impaired tone fear conditioning in adolescents (that also consumed more alcohol), with most finding no effect of alcohol on tone fear conditioning regardless of age. With only one study examining medial PFC-linked fear extinction, no strong conclusions can be drawn, but initial evidence suggests context-based fear extinction may be diminished in mid-adolescents compared to adults and late adolescents. Research on age-related differences on the effect of alcohol on longer-term fear memory is largely missing.

Spatial learning and memory: The Morris Water Maze (MWM) is commonly used to test spatial learning and memory in rodents. Across trials, time to find the hidden platform in a round swimming pool is used as a measure of spatial learning. Spatial memory can be tested by removing the platform and measuring the time the animal spends in the quadrant where the escape used to be. The sand box maze (SBM) is a similar paradigm in which animals need to locate a buried appetitive reinforcer.

Six rat studies examined spatial learning and memory using these paradigms. Three of the six studies observed age-related differences. Four examined the effects of repeated ethanol challenges 30 minutes prior to MWM training, showing mixed results [ 30 , 66 , 67 , 68 ]. While one found ethanol-induced spatial learning impairments in adolescents only (1.0 and 2.0 g/kg doses) [ 66 ], another found no age-related differences, with both age groups showing impairments after moderate doses (2.5 g/kg) and enhancements in learning after very low doses (0.5 g/kg) [ 67 ]. Sircar and Sircar [ 68 ] also found evidence of ethanol-induced spatial learning and memory impairments in both ages (2.0 g/kg). However, memory impairments recovered after extended abstinence (25d) in adults only. Importantly, MWM findings could be related to thigmotaxis, an anxiety-related tendency to stay close to the walls of the maze. Developmental differences in stress sensitivity may potentially confound ethanol-related age effects in these paradigms. Using the less stress-inducing SBM, adults showed greater impairments in spatial learning compared to adolescents after 1.5 g/kg ethanol doses 30 min prior to training [ 30 ].

Two studies examined the effects of chronic ethanol exposure prior to training with or without acute challenges [ 69 , 70 ]. Matthews et al. [ 70 ] looked at the effect of 20 days binge-like (every other day) pre-exposure and found no effect on spatial learning in either age following an extended abstinence period (i.e., 6–8 weeks). Swartzwelder et al. [ 69 ] examined effects of 5-day ethanol pre-exposure with and without ethanol challenges before MWM training. Ethanol challenges (2.0 g/kg) impaired learning in both age groups regardless of pre-exposure history. Thigmotaxis was also increased in both age groups after acute challenges while pre-exposure increased it in adults only.

In sum, evidence for impaired spatial learning and memory after acute challenges is mixed across six studies. Two studies found support for ethanol having a larger impact in adolescents compared to adults, whereas one study found the opposite and three studies did not observe any differences. Differences in ethanol doses stress responses may partially explain the discrepancies across studies. Importantly, given the sparsity of studies addressing the effects of long-term and voluntary ethanol exposure, no conclusion can be drawn about the impact of age on the relation between chronic alcohol exposure and spatial learning and memory.

Non-spatial learning and memory: Non-spatial learning can also be assessed in the MWM and SBM by marking the target location with a pole and moving it across trials, measuring time and distances traveled to locate the target. By assessing non-spatial learning as well, studies can determine whether learning is more generally impaired by ethanol or whether it is specific to hippocampal-dependent spatial learning processes. A total of six studies assessed facets of non-spatial learning and memory. Two of the six studies observed age-related differences.

In the four studies that examined non-spatial memory using the MWM or SBM in rats, none found an effect of alcohol regardless of dose, duration, or abstinence period in either age group [ 30 , 66 , 67 , 70 ]. Two other studies examined other facets of non-spatial memory in rats [ 65 , 71 ]. Galaj et al. [ 71 ] used an incentive learning paradigm to examine conditioned reward responses and approach behavior towards alcohol after chronic intermittent ethanol (CIE; 4 g/kg; 3d on, 2d off) exposure to mimic binge drinking. To examine reward-related learning and approach behavior, a CS (light) was paired with food pellets and approach behavior to CS only presentation and responses to a lever producing the CS were measured. In both adolescents and adults, the ethanol-exposed rats showed impaired reward-related learning after both short (2d) and extended (21d) abstinence. No effect of alcohol on conditioned approach behavior was observed in either age group during acute (2d) or extended (21d) abstinence. Using a novel object recognition test in mice, Lacaille et al. [ 65 ] assessed non-spatial recognition memory by replacing a familiar object with a novel object in the testing environment. Explorative behavior of the new object was used as an index of recognition. After chronic binge-like exposure (three injections daily at 2 h intervals) and limited abstinence (4d), only adolescents showed reduced object recognition.

Across facets of non-spatial memory, there is little evidence for age-related differences in the effect of chronic alcohol, with four of the six studies finding no age differences. For memory of visually cued target locations in the MWM and SBM paradigms, alcohol does not alter performance in either age. Also, both adolescents and adults appear similarly vulnerable to alcohol-induced impairments in reward-related learning based on the one study. Only in the domain of object memory did any age-related differences emerge, with adolescents and not adults showing reduced novel object recognition after binge-like alcohol exposure in one study. However, more research into object recognition memory and reward-related learning and memory is needed to draw strong conclusions in these domains.

Executive function and higher-order cognition

Executive functions are a domain of cognitive processes underlying higher-order cognitive functions such as goal-directed behavior. Executive functions can include but are not limited to working memory, attentional processes, cognitive flexibility, and impulse control or inhibition [ 72 ]. A core feature of AUD is the transition from goal-directed alcohol use to habitual, uncontrolled alcohol use. Impaired executive functioning, linked to PFC dysfunction [ 73 ], is assumed to be both a risk factor and consequence of chronic alcohol use. A meta-analysis of 62 studies highlighted widespread impairments in executive functioning in individuals with AUD that persisted even after 1-year of abstinence [ 46 ]. Thirteen studies examined facets of executive functioning and higher-order cognition, specifically in the domains of working memory, attentional processes, cognitive flexibility, impulsivity in decision-making, and goal-directed behavior [ 65 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].

Working memory: Working memory refers to the limited capacity system for temporarily storing and manipulating information, which is necessary for reasoning and decision-making [ 84 ]. In the Radial Arm Maze test (RAM) [ 85 ], some of the equally spaced arms (typically eight) around a circular platform contain a food reward for animals to find. Spatial working memory is measured by recording the number of revisits to previously visited arms (i.e., working memory error) and first entries into unbaited arms (i.e., reference memory). Alternatively, the hippocampus mediated [ 86 ] spontaneous tendency to alternate arms can be used as a measure of spatial working memory. In this case, revisiting an arm in back-to-back trials in close temporal succession is interpreted as a working memory error. Five studies examined the effects of chronic ethanol exposure on spatial working memory [ 65 , 75 , 79 , 80 , 83 ]. One of the five studies observed age-related differences.

Chronic binge-like alcohol exposure had no effects on spontaneous alterations after prolonged abstinence (2d on, 2d off; 3 weeks abstinence) [ 79 , 80 ] in rats or limited abstinence (three injections daily at 2 h intervals; 24 h abstinence) [ 65 ] in mice, nor on RAM performance in rats (2d on, 2d off) [ 75 , 83 ]. However, acute ethanol challenges (1.5 g/kg) after chronic binge-like exposure (2d on, 2d off) resulted in RAM test impairments in both age groups in rats [ 75 , 83 ], with some evidence for increased working memory errors in adolescents [ 83 ].

In sum, there is little evidence for impairments in working memory function in rats after chronic ethanol exposure, with four of the five studies observing no difference between age groups. While acute intoxication impairs working memory function in both ages, there is evidence from only one study that adolescents may make more working memory errors.

Attentional processes: Attentional processing refers to the selection of information that gains access to working memory [ 87 ]. PPI is a pre-attentional cognitive function which provides an index of sensorimotor gating and measures the ability of a lower intensity sensory stimulus to reduce the magnitude of response to a more intense stimulus presented closely afterward. Reduced sensorimotor gating (reduced PPI) can disrupt information processing and thereby impair cognitive function, while enhanced sensorimotor gating (enhanced PPI) may reflect behavioral inflexibility [ 88 ]. For example, lesions in the medial PFC produce both behavioral inflexibility and enhancements in PPI in rats. Two studies assessed attentional processes by measuring prepulse inhibition (PPI) in rats [ 82 , 89 ]. One study observed age-related differences and one did not.

Slawecki and Ehlers [ 82 ] observed age-related differences in sensorimotor gating following ethanol vapor exposure (2w) and brief abstinence (6d), with adolescents showing enhanced PPI at some decibels reflective of behavioral inflexibility, while adults did not exhibit PPI at any of the intensities tested. Slawecki et al. [ 89 ] did not observe any age-related differences in PPI during the acute phase of ethanol withdrawal (7–10 h abstinence) during a period of chronic ethanol exposure (14d).

In sum, there is limited and mixed evidence from two studies of age-related differences in the pre-attentional process of sensorimotor gating. Only one study found support for adolescent sensitivity to ethanol effects.

Cognitive flexibility: Cognitive flexibility refers to the ability to update information based on environmental factors r changing goals in order to adaptively guide decision-making and is linked to the inability to reduce or abstain from drinking [ 90 ]. Three studies examined facets of cognitive and behavioral flexibility [ 79 , 80 , 81 ]. Two of the three studies observed age-related differences.

In two rat studies, cognitive flexibility was assessed using reversal learning paradigms [ 79 , 80 ]. In the reversal learning paradigm, rats were trained on simple (e.g., visual cue) and more complex discriminations (e.g., visual + scent cue) between rewarded and non-rewarded bowls. After learning the discriminants, the rewards were reversed. Ethanol exposure reduced flexibility in both adolescents and adults for simple discriminations in both studies. Age-related differences emerged for the more complex discriminations in one study, with only adults showing reduced flexibility after prolonged abstinence (21d) following binge-like exposure (5 g/kg, 2d on, 2d off) [ 79 ]. In contrast, both age groups showed reduced flexibility for complex discrimination in the other study after prolonged abstinence (21d) despite adolescents consuming more ethanol orally than adults during the 28 week exposure [ 80 ].

In another study, Labots et al. [ 81 ] used a conditioned suppression of alcohol-seeking task after two months of voluntary ethanol consumption (2 months) in rats to examine flexibility around alcohol-seeking behavior. After stratifying the age groups based on levels of ethanol consumption, medium- and high-consuming, adolescents showed higher levels of conditioned suppression compared to similarly drinking adults, indicating greater behavioral flexibility and control over alcohol-seeking in adolescents after chronic voluntary exposure.

Overall, there is limited evidence for adolescent resilience to the effects of chronic alcohol on cognitive flexibility. Two studies found support for adolescent resilience to ethanol’s effect on behavioral flexibility, whereas another study found no differences between adolescents and adults.

Impulsivity: Impulsivity is a multi-faceted behavioral trait that encompasses impaired response inhibition, preference for an immediate reward over a larger but delayed reward, and premature expression of behaviors which may be maladaptive or in conflict with conscious goals. Impulsivity is a risk-factor for the development of addiction and may also be a consequence of sustained substance use [ 35 ]. Pharmacological evidence points towards overlapping neuronal mechanisms in impulsivity and addictive behavior, particularly within the mesolimbic dopamine system [ 91 ]. Two studies examined impulsive decision-making behavior in rats [ 74 , 78 ]. Both studies observed age-related differences.

One study examined impulsive behavior using a delay-discounting task in which choices are made between immediate small rewards and larger delayed rewards [ 78 ]. Regardless of age, chronic intermittent exposure (2d on, 2d off) had no effect on choice behavior in non-intoxicated rats. Following acute challenges, adolescents but not adults demonstrated a reduced preference for the large reward regardless of ethanol exposure history, reflecting a general adolescent-specific heightened impulsivity during intoxication. Another study examined decision-making under risk conditions using an instrumental training and probability-discounting task [ 74 ]. After prolonged abstinence (20d), rats were trained to press two levers for sucrose rewards and were concurrently trained to choose between two levers with different associated probabilities of reward and reward size, creating a choice between a certain, small reward and an uncertain, large reward (i.e., riskier choice). Ethanol consumption was voluntary and while adolescents initially consumed more ethanol than adults at the beginning of the exposure period, the total amount of consumption was similar by the end of the exposure period. Only adolescents showed increased risky and sub-optimal decision-making compared to age-matched controls, while adults performed similarly to controls.

In sum, both studies found support for ethanol having a larger impact on adolescent compared to adults on impulsive behavior.

Goal-directed behavior: Goal-directed behavior refers to when actions are sensitive to both the outcome value (goal) and contingency between the behavior and the outcome [ 92 ]. Two studies used a sign-tracking and omission contingency learning paradigm to examine goal-directed versus habitual behavior [ 76 , 77 ]. One study observed age-related differences and the other did not. Sign tracking refers to tasks where a cue predicts a reward, but no response is needed for the reward to be delivered. Despite this, after repeated pairings of the cue and reward, animals and humans may respond (e.g., via a lever) when the cue is presented anyway, and even when no reward is known to be available. Sign-directed behavior is considered habitual and has been proposed to underlie the lack of control of alcohol use in addiction [ 93 ]. In humans, sign-tracking behavior is difficult to differentiate from goal-directed behavior based on only the observable behavior, i.e., seeing a cue such as a favorite drink or bar and then having a drink [ 94 ]. In the context of alcohol use, reflexively having a drink when seeing an item that is often associated with the rewarding effects of alcohol (e.g., wine glass, bar, smell of alcohol) despite not consciously desiring the alcohol ‘reward’ is an example of how habitual behavior (possibly driven by sign-tracking) can initiate the behavior as opposed to an intentional goal [ 93 ]. Omission contingency refers to a 2nd phase after sign-tracking when the response is punished and the behavior must be inhibited to avoid punishment. After both forced and voluntary ethanol exposure (6w), no alterations to sign-tracking behavior were observed in adolescent and adult rats [ 76 , 77 ]. One study did observe an age-related difference in omission contingency learning, with adolescents performing better than adults after chronic voluntary ethanol exposure [ 77 ]. This preliminarily suggests that adolescents may be more capable of adapting their behavior to avoid punishment compared to adults after chronic use. However, before behavioral testing began, adolescent rats were abstinent for 17 days, while adults were only abstinence for 10 days which may have influenced the results.

In summary, one study found support for adolescents being less sensitive to ethanol effects on goal-directed behavior compared to adults, whereas one study found no effect of ethanol in either age group.

Across the domains of executive function, there is some evidence that adolescents may be more vulnerable to impairments in certain executive and higher-order cognitive functions following chronic alcohol exposure, with increased risky decision-making after prolonged abstinence [ 74 ], impulsivity during intoxication [ 78 ], and reduced working memory function during intoxication after chronic exposure. In contrast, animals exposed to alcohol during adolescence may better retain cognitive flexibility [ 77 , 79 ] and are better able to regain control over alcohol-seeking in adulthood [ 81 ].

Other behavioral outcomes

Anxiety : AUD is highly comorbid with anxiety disorders [ 95 ], especially in adolescence [ 96 ]. While anxiety is not strictly a cognitive outcome, it is related to altered cognitive functioning [ 97 , 98 ]. Many studies assessing the effects of ethanol on the rodent brain and cognition also include anxiety-related measures. Multiple paradigms have been developed to elicit behaviors thought to reflect anxiety in rodents (e.g., rearing, startle, avoidance, etc.). In the open field test (OFT), anxiety is indexed as the tendency to stay close to perimeter walls as animals have a natural aversion to brightly lit open spaces [ 99 ]. In the elevated plus maze paradigm, rodents are placed at the center of an elevated four-arm maze with two open arms two closed arms [ 100 ]. The open arms elicit unconditioned fear of heights/open spaces and the closed arms elicit the proclivity for enclosed, dark spaces. Anxiety is indexed as entries/duration of time in open vs. closed arms, as well as rearing, freezing, or other postural indices of anxiety. In startle paradigms, the startle response is a defensive mechanism reflecting anxiety which follows a sudden, unpredictable stimulus (e.g., tones, light) [ 101 ]. In light-dark box paradigms, anxiety is elicited using a testing apparatus with a light and dark compartment, relying on the conflict between natural aversions to well-lit spaces and the tendency to explore new areas. Percentage of time spent in the light compartment, latency to return to the dark compartment, movement between compartments (transitions), and rearing-behavior are measured as indices of anxiety [ 102 ]. Anxiety can also be assessed using a social interaction test with an unfamiliar partner, with approach and avoidance behaviors measured to index anxiety [ 103 ]. In the novel object test (NOT) [ 104 ], anxiety is elicited by the introduction of a new object in the rodent’s environment. The amount of contacts and time spent in contact with the object is used as an index of anxiety. Similarly, in the marble-burying test (MBT), novel marbles are placed in an environment and the amount of defensive burying of the objects is used as an index of anxiety [ 105 ].

Eleven studies examined anxiety-like behavior in rodents with mixed results across paradigms [ 70 , 78 , 82 , 83 , 89 , 106 , 107 , 108 , 109 , 110 , 111 ]. Overall, five of the eleven studies observed age-related differences.

Two studies used the OFT, finding no effects of voluntary (2w, 4 h/day access) or forced (12/day vapor) ethanol exposure on anxiety-like behavior in adolescents or adult rats during withdrawal (7–9 h) [ 110 ] or after a brief abstinence period (4 days) [ 107 ]. One study used both the MBT and NOT after voluntary ethanol consumption (2 h/d for 2 weeks; no abstinence) and observed higher anxiety in ethanol-exposed adults and reduced anxiety in ethanol-exposed adolescents compared to controls as indexed by marble burying [ 106 ]. However, no age effects were observed in response to a novel object, with reduced interaction with the novel object in both age groups after chronic exposure.

Four studies used the elevated maze paradigm with mixed results. Only one study observed age-related differences in mice after chronic exposure (8–10w vapor) [ 109 ]. Adolescents showed reduced anxiety compared to adults during the acute withdrawal period, but all mice were kept under chronic social isolation and unpredictable stress conditions, which may have affected the results. Two studies in rats found no effect of intermittent (1 g/kg) or binge-like (5 g/kg) exposure in either age group after short (24 h) [ 70 ] or sustained abstinence (20d) [ 83 ]. A third study observed heightened anxiety in both age groups after intermittent exposure (4 g/kg), with anxiety increasing with prolonged abstinence periods (24 h to 12d) [ 108 ].

Three rat studies used a startle paradigm to assess anxiety. Two observed reduced acoustic startle responses after ethanol exposure (12 h/d vapor) in both age groups during acute withdrawal periods (7–10 h) and following more sustained abstinence (6d) [ 82 , 89 ]. In the other study, light-potentiated startle was also reduced in both ages during days 1–10 of withdrawal after binge-like exposure (2d on, 2d off), but age-related differences emerged when the rats were re-exposed via a 4-day binge (1–4/kg). Then, only adults showed higher levels of light-potentiated startle compared to controls [ 78 ], suggesting that ethanol pre-exposure increases anxiety in adults but not adolescents when re-exposed to ethanol after withdrawal.

Two studies used the light-dark box paradigm with mixed results [ 89 , 111 ]. Only adult rats showed increased mild anxiety-like behaviors during early withdrawal (7–10 h) after chronic vapor exposure 12 h/d) [ 89 ]. In contrast, no age-related differences emerged after voluntary ethanol consumption (18 h/d access; 3d/w for 6 weeks), with male mice showing less anxiety-like behavior in both ages [ 111 ]. In contrast, the one study using the social interaction test observed reduced anxiety in adult mice compared to both adolescents and age-matched controls during early withdrawal (4–6 h) after chronic, unpredictable vapor exposure [ 109 ].

In summary, there is inconsistent evidence for age-related differences in the effect of chronic ethanol exposure on anxiety outcomes in rodents. The substantial differences across studies in how anxiety was elicited and measured make it challenging to draw strong conclusions. In the five studies that found age-related differences, adults tend to show higher levels of anxiety, particularly during early withdrawal; however, the opposite was found in the one study examining anxiety in social interactions. Six studies did not observe any age-related differences. Overall, adolescents may be less sensitive to the anxiety-inducing effects of chronic alcohol exposure.

Social behavior: Two studies were identified that examined the effects of chronic ethanol exposure on social behavior in rats [ 112 , 113 ], with both observing age-related differences. After chronic exposure (1 g/kg, 7d), followed by a brief abstinence period (24–48 h), one study found a decrease in social preference in adolescents only [ 112 ], while the other study found no ethanol-related effects on social behavior (2 g/kg, 10d) [ 113 ]. After acute challenges, age and treatment interactions emerged in both studies, but the directions of the results are inconsistent. In the first study, adolescents showed increased social preference, as indexed by the number of cross-overs between compartments toward and away from a peer, across multiple acute doses (0.5–1.0 g/kg) administered immediately before testing, while adults showed no changes in social preference [ 112 ]. In contrast, Morales et al. [ 113 ] found evidence for age-related temporal differences in social activity after acute challenge, with adults showing decreased social impairment five minutes post injection (1 g/kg) and adolescents (1.25 g/kg) after 25 min compared to age-matched controls.

The findings from these two studies paint a complicated and inconsistent picture of the effects of ethanol on social behavior in adults and adolescents warranting further research. One study found support for a larger effect of chronic ethanol on adolescent social behavior compared to adults, while the other did not observe effects of ethanol in either group. One study found support for a larger effect of chronic plus acute ethanol intoxication on social behavior, with the opposite observed in the other.

Brain outcomes

Neurotransmitter systems.

Glutamate is the brain’s main excitatory neurotransmitter and plays a crucial role in synaptic plasticity (i.e., experience-related strengthening or weakening of synaptic connections). Glutamatergic transmission plays an important role in the formation and maintenance of addictive behaviors and the nucleus accumbens (NAc) is considered an important hub in this, receiving glutamatergic input from cortical-limbic areas and dopaminergic input from the midbrain [ 114 ]. Seven studies investigated glutamate functioning in regions of the brain [ 106 , 107 , 108 , 109 , 115 , 116 , 117 , 118 ]. Four of the seven studies observed age-related differences.

Three studies investigated glutamate-related processes in the NAc [ 106 , 107 , 118 ]. Two weeks of voluntary binge drinking (4-h access, no abstinence) did not affect expression of calcium-dependent kinase II alpha (CaMKIIα) and the AMPA receptor GluA1 subunit in the NAc of mice [ 107 ]. In contrast, Lee et al. [ 106 ] showed that voluntary binge drinking (2-h access, no abstinence) increased mGlu1, mGlu5, and GluN2b expression in the shell of the NAc, as well as PKCε and CAMKII in the core of the NAc in adult mice only. In rats, Pascual et al. [ 118 ] showed reduced NR2B phosphorylation in the NAc of adolescents only after two weeks of chronic intermittent ethanol exposure; an effect that also lasted until 24 h after end of exposure. This indicates that adolescents might be less affected by the effects of ethanol on NAc-related glutamatergic neurotransmission than adults. This may in turn mediate decreased withdrawal symptoms and potentially facilitate increased drinking [ 106 ].

Two studies investigated glutamate-related processes in the (basolateral) amygdala [ 107 , 116 ]. In mice, Agoglia et al. [ 107 ] showed decreased CaMKIIα phosphorylation in adolescents, but increased GluA1 expression in adults after two weeks of voluntary binge drinking (4-h access, no abstinence). Also, drug-induced AMPAR activation resulted in increased binge drinking in adolescents but decreased binge drinking in adults, highlighting the potential importance of glutamatergic signaling in age-related differences in alcohol consumption. However, Falco et al. [ 116 ] reported no difference in NR2A mRNA levels in the basolateral amygdala for either age group after 60-day abstinence.

Alcohol’s effects on frontal cortex functioning is thought to be mediated by alterations in NMDA receptor subunit expression [ 119 , 120 ]. Two studies investigated glutamate-related processes in the frontal cortex of rats [ 115 , 118 ]. Pascual et al. [ 118 ] showed reduced NR2B phosphorylation after two weeks of forced intermittent ethanol exposure in adolescents only. Using a 2-week ethanol vapor paradigm, Pian et al. [ 115 ] found different patterns of NMDAR subunit expression. These patterns were highly dependent on abstinence duration (0 h, 24 h, 2w), however, they only statistically compared results within rather than between age groups. Ethanol exposure was associated with decreased NR1 receptor expression in both age groups, but only the adult group showed a decrease in NR2A and NR2B expression. The NR1 and NR2A expression returned to normal during withdrawal, but in adults NR2B expression increased after two weeks of abstinence.

Conrad and Winder [ 109 ] assessed long-term potentiation (LTP) in the bed nucleus stria terminalis (BNST), a major output pathway of the amygdala towards the hypothalamus and thalamus. Voluntary ethanol exposure resulted in blunted LTP responses in the dorsolateral BNST regardless of age. However, all mice were socially isolated during the experiments to induce anxiety, so it is unclear whether the effects were solely due to ethanol exposure.

Two studies looked at glutamate receptor subunit expression in the hippocampus [ 108 , 115 ]. Pian et al. [ 115 ] observed increased expression of NR1, NR2A, and NR2B in adults after 2 weeks of ethanol exposure. In adolescents, a reduction in NR2A expression was observed. After abstinence, adult levels returned to normal, while in adolescents, decreased NR1 and NR2A expression was seen after 24 h but an increased expression of these subunits was seen after 2 weeks of abstinence. These findings support regional specific effects of age group, with potentially increased sensitivity to the impact of alcohol on glutamatergic mediated hippocampal functioning in adolescents. Unlike expected, van Skike et al. [ 108 ] did not find effects of chronic intermittent ethanol exposure or withdrawal on NMDA receptor subunit expression in the hippocampus and cortex as a whole in adolescent and adult rats. The authors speculate that these null results might be associated with the exposure design (limited exposure and route of administration) and lack of withdrawal periods compared to Pian et al. [ 115 ].

In sum, there is limited and inconsistent evidence for age-related differences in glutamate function across seven studies. The direction of the observed age-related differences varies across regions, with evidence of both increased and decreased sensitivity to ethanol effects in adolescents compared to adults in the four studies that observed age-related differences.

GABA is the brain’s main inhibitory neurotransmitter. GABA A receptors are a primary mediator of alcohol’s pharmacological effects [ 121 ]. A total of four studies looked at GABAergic functioning [ 108 , 116 , 122 , 123 ]. Three of the four studies observed age-related differences.

One study investigated GABA-related processes in the (basolateral) amygdala, showing reduced GABA A α1 and GAD67 (enzyme that converts Glutamate to GABA) mRNA expression in adult rats only, 60 days after 18-days ethanol exposure [ 116 ].

Two studies looked at the rat cortex as a whole [ 108 , 122 ]. Van Skike et al. did not find effects of chronic intermittent ethanol exposure on GABA A receptor expression [ 108 ]. Grobin et al. [ 122 ] showed that, while basal GABA A receptor functioning was not affected by 1 month of chronic intermittent ethanol exposure, GABA A receptors were less sensitive to the neurosteroid THDOC in adolescents. This neuromodulatory effect was not found in adults and did not persist after 33 days of abstinence. However, these results indicate that neurosteroids may play an indirect role in age differences in the GABAA receptor’s response to alcohol.

Two studies focused on the rat hippocampus [ 108 , 124 ]. Fleming et al. [ 124 ] found age-specific effects of chronic intermittent ethanol exposure on hippocampal (dentate gyrus) GABA A receptor functioning. Adolescent rats showed decreased tonic inhibitory current amplitudes after ethanol exposure, which was not the case for young adult and adult rats. Also, only the adolescents showed greater sensitivity to (ex vivo) acute ethanol exposure induced enhanced GABAergic tonic currents. The specificity of these effects to adolescent exposure might indicate adolescent vulnerability to ethanol-induced effects on the hippocampus; however, Van Skike et al. [ 108 ] did not find any effects of chronic intermittent ethanol exposure on GABA A receptor expression in the hippocampus.

In sum, given the limited number of studies and lack of replicated effects, no clear conclusions can be drawn about the role of age on the effects of alcohol on GABAergic neurotransmission. Age-specific effects appear to be regionally distinct. The only available study found support for heightened adult sensitivity to ethanol in the amygdala. In contrast, one study found support for greater adolescent sensitivity in the hippocampus and whole cortex, whereas the other found no age-related differences.

The mesocorticolimbic dopamine system, with dopaminergic neurons in the ventral tegmental area (VTA) projecting to the NAc and prefrontal cortex, plays a key role in AUD, particularly through reward and motivational processes [ 14 ]. Only two studies investigated dopaminergic processes, focusing on the frontal cortex, NAc, and broader striatum [ 118 , 125 ]. Both studies observed age-related differences in certain dopamine outcomes.

Carrara-Nascimento et al. [ 125 ] investigated acute effects of ethanol in adolescent and adult mice 5 days after a 15-day treatment with either ethanol or saline. In the PFC, ethanol pretreated adolescents showed reduced dopamine levels (DA) and related metabolites (DOPAC and HVA) in response to an acute ethanol challenge compared to ethanol pretreated adults and adolescent saline controls. In the NAc, there were no differences between pretreated adolescents and adults, but analyses within each age group revealed that ethanol-pretreatment with an acute challenge decreased DOPAC within the adolescent group. Results from the dorsal striatum also showed no differences between adolescents and adults. However, within the adolescent group, ethanol pre-treatment increased DOPAC and, within the adult group, it increased HVA. Pascual et al. [ 118 ] found similar results looking at the expression of DRD1 and DRD2 dopamine receptors after two weeks of chronic intermittent ethanol exposure in rats. In the NAc and dorsal striatum, DRD2 expression was reduced in adolescent compared to adult exposed rats, while both DRD1 and DRD2 expression were reduced in the frontal cortex.

These results suggest reduced alcohol-induced dopamine reactivity in adolescents in the PFC and NAc based on the two available studies, but more studies are warranted for a more detailed understanding of the relationship between age and dopamine receptor expression following chronic ethanol exposure.

Acetylcholine

Acetylcholine is a known neuromodulator of reward and cognition-related processes [ 126 ]. The composition and expression of nicotinic and muscarinic acetylcholine receptors have been implicated in various alcohol use-related behaviors [ 127 , 128 ]. Only one study investigated cholinergic processes and observed age-related differences. Vetreno et al. [ 129 ] showed global reductions in choline acetyltransferase (ChAT; cholinergic cell marker) expression after adolescent onset, but not adult onset of forced intermittent binge-like exposure (20 days – every other day, 25 days abstinence).

Neuromodulatory processes

Neurodegeneration and neurodevelopment.

Chronic alcohol consumption is thought to lead to brain damage by influencing processes involved in neurodegeneration and neurogenesis. The formation of addictive behaviors is paralleled by the formation of new axons and dendrites, strengthening specific neuronal pathways [ 130 ]. While brain morphology is commonly investigated in humans, it is a proxy of the impact of alcohol on the brain and therefore rarely studied in rodents. Five studies investigated facets of neurodegeneration or development in rodents [ 55 , 65 , 131 , 132 , 133 ]. All five studies observed age-related differences.

Huang et al. [ 131 ] showed reduced cerebral cortex mass in adolescent mice, but shortening of the corpus collosum in adults after 45 days of ethanol injections, suggesting some age-specific regional effects. Using an amino cupric silver staining, significant brain damage was revealed for both adolescent and adult rats after 4 days of binge-like ethanol exposure [ 132 ]. However, adolescents showed more damage in the olfactory-frontal cortex, perirhinal cortex, and piriform cortex.

Looking at hippocampal neurogenesis, ethanol exposure has been shown to initially reduce hippocampal neurogenesis in adult rodents, recovering after 1-month abstinence [ 134 ]. Compared to adults, neurogenesis in the dentate gyrus of the hippocampus was found to be reduced in adolescent exposed mice (Bromodeoxyuridine levels) [ 65 ] and rats (doublecortin levels) [ 133 ]. Lacaille et al. [ 65 ] also measured the expression level of genes involved in oxidative mechanisms after binge-like alcohol exposure. In whole brain samples, they found increased expression of genes involved in brain protection (i.e., gpx3, srxn1) in adults, but increased expression of genes involved in cell death (i.e., casp3) combined with decreased expression of genes involved in brain protection (i.e., gpx7, nudt15) in adolescents. Casp3 protein levels were also higher in the whole brain of adolescent exposed mice [ 65 ] and the adolescent dentate gyrus [ 133 ], suggesting more neurodegeneration and less neurogenesis in adolescents versus adults following ethanol consumption.

Cyclin-dependent kinase 5 (CDK5) is involved in axon, dendrite, and synapse formation and regulation. CDK5 is overexpressed in the prefrontal cortex and the NAc following exposure to substances of abuse including alcohol [ 135 ]. Moreover, CDK5 inhibition has been shown to reduce operant self-administration of alcohol in alcohol-dependent rats [ 136 ]. One study reported higher H4 acetylation of the CDK5 promoter in the PFC of adult versus adolescent ethanol-exposed rats during acute withdrawal, however, CDK5 mRNA expression was control-like after 2 weeks of abstinence [ 55 ].

In sum, strong conclusions cannot be drawn due to the limited number of studies and lack of replicated effects. However, preliminary evidence points to adolescent vulnerability to damage in the cortex, reduced neurogenesis, and increased neurodegeneration in the hippocampus and the cortex as a whole based on four of the five studies. In contrast, one study found support for adult vulnerability to ethanol’s effects axon, dendrite, and synapse formation and regulation.

Growth factors

Brain-derived neurotrophic factor (BNDF) and nerve growth factor (NGF) are involved in brain homeostasis and neural recovery [ 137 , 138 ]. While ethanol exposure initially increases BDNF and NGF, chronic ethanol exposure seems to reduce BDNF and NGF levels and can thereby result in long-term brain damage and related cognitive problems [ 139 , 140 ]. Four studies investigated growth factor expression in the frontal cortex [ 54 , 55 , 79 , 80 ] and two studies also investigated the hippocampus [ 79 , 80 ]. All four studies of the frontal cortex observed age-related differences. Neither study of the hippocampus observed age-related differences.

In rats, 30 weeks of chronic ethanol exposure reduced prefrontal mBDNF and β-NGF regardless of age, despite adolescents consuming more ethanol [ 80 ]. Moreover, the reduction of mBDNF was correlated with higher blood alcohol levels and was persistent up to 6–8 weeks abstinence. Interestingly, during acute withdrawal (48 h) adolescents but not adults temporarily showed control-like mBDNF levels. This might indicate an attempt to counteract neurodegeneration as a result of ethanol exposure in adolescents. These results were partially replicated using a shorter intermittent exposure paradigm (13 doses, 2 days on/off) [ 79 ]. While intoxication after chronic ethanol exposure reduced prefrontal BDNF, levels recovered after 3-weeks abstinence regardless of age. However, during acute withdrawal (24 h), BDNF was still reduced in early-adolescent onset rats, increased in adult-onset rats, but control-like in mid-adolescent onset-rats, suggesting slower recovery in younger animals. Looking at BDNF gene regulation, a similar study (8 doses, 2 days on/off) reported higher H3 demethylation but lower H4 acetylation of the BDNF promoter in the PFC of adult versus adolescent ethanol-exposed rats during acute withdrawal [ 55 ]. However, prefrontal BDNF mRNA expression returned to control levels after 2 weeks of abstinence. Interestingly, social housing may be protective, as reduced prefrontal BDNF was no longer observed in alcohol-exposed adolescent mice housed in environmentally enriched relative to standard conditions [ 54 ]. Two studies investigated hippocampal BDNF expression but reported no significant interactions between alcohol exposure and age group [ 79 , 80 ].

In sum, the results of the four available studies suggest lower prefrontal BDNF during chronic alcohol use that recovers after abstinence regardless of age. However, the rate of recovery may be influenced by age with slower recovery in adolescents. In the two available studies, no age-related differences were observed in BDNF expression in the hippocampus.

Transcription factors

The transcription factors cFos and FosB are transiently upregulated in response to substance use, and ΔFosB accumulates after chronic exposure, particularly in striatal and other reward-related areas [ 141 ]. Two studies investigated cFos and FosB [ 55 , 142 ] and one study ΔFosB related processes [ 111 ]. All three studies observed age-related differences.

After chronic ethanol exposure (8 doses, 2 days on/off), adolescent compared to adult rats showed increased prefrontal H3 and H4 acetylation of the cFos promotor region and increased H4 acetylation and H3 dimethylation of FosB promotor regions after acute abstinence [ 55 ]. Moreover, mRNA expression of FosB was elevated in adolescents but not adults after 2-weeks abstinence. The upregulating effects of an acute ethanol challenge on prefrontal cFos appears to reduce after chronic pre-treatment to a larger extent in adolescent than adult exposed mice [ 142 ]. This pattern of results was similar in the NAc, but desensitization to ethanol’s acute effects on cFos in the hippocampus was more pronounced in adults. Faria et al. [ 142 ] also looked at Egr-1 (transcription factor, indirect marker of neuronal activity and involved in neuroplasticity), showing a stronger reduction in Egr-1 expression in the PFC, NAc, and hippocampus of adolescent versus adults after repeated ethanol exposure. Regarding ∆FosB, Wille-Bille et al. [ 111 ] found increased ∆FosB in adolescent compared to adult rats in the prelimbic PFC, dorsomedial striatum, NAc core and shell, central amygdala nucleus capsular, and basolateral amygdala after 3 days per week 18 h ethanol exposure sessions for 6 weeks. In sum, the three available studies provide preliminary evidence for increased adolescent vulnerability to ethanol-induced long-term genetic (mRNA expression) and epigenetic (methylation) changes in mesocorticolimbic areas.

Immune factors

Ethanol is known to trigger immune responses in the brain (e.g., increase production of hemokines and cytokines), causing inflammation and oxidative stress [ 143 , 144 , 145 ]. Three studies examined immune factors [ 146 , 147 , 148 ]. Two of the three studies observed age-related differences.

Microglia remove damaged brain tissue and infectious agents and are key to the brain’s immune defense. Only one study investigated microglia levels [ 146 ]. Although direct comparisons between age groups were missing, both adolescent and adult rats showed less microglia in the hippocampus (CA and DG) and peri-entorhinal cortex, and more dysmorphic microglia in the hippocampus after 2 and 4 days of binge-like ethanol exposure [ 146 ]. Notably, age groups were matched on intoxication scores, with adolescents needing more ethanol to reach the same level of intoxication. An in silico transcriptome analysis of brain samples from mice after 4 days of 4 h/day drinking in the dark, suggest overexpression of neuroimmune pathways related to microglia action (toll-like receptor signaling, MAPK signaling, Jak-STAT signaling, T-cell signaling, and chemokine signaling) in adults that was not observed in adolescents, while adolescents consumed more ethanol [ 147 ]. Similarly, ethanol-exposed adult mice showed higher chemokine expression (CCL2/MCP-1) in the hippocampus, cerebral cortex, and cerebellum and higher cytokine expression (IL-6, but not TNF-α) in the cerebellum, while no chemokine or cytokine changes were observed in ethanol exposed adolescent mice [ 148 ]. Both adolescents and adults showed increased astrocyte levels in the hippocampus (CA1) and the cerebellum after ethanol exposure, but changes in astrocyte morphology were only observed in the adult hippocampus.

In sum, two of the studies found support for increased immune responses after ethanol exposure in adults compared to adolescents, whereas the one other study found no difference between the age groups.

HPA-axis functionality

Chronic stress and HPA-axis functionality have been associated with the maintenance of AUD (e.g., reinstatement drug seeking, withdrawal) [ 149 ]. Two studies investigated corticotropin-release factor (CRF) expression in rats [ 116 , 150 ]. One study observed age-related differences and the other did not.

Falco et al. [ 116 ] found decreased CRF mRNA expression in the adult but not adolescent basolateral amygdala 2 months after 18-day restricted ethanol exposure. In contrast, Slawecki et al. did not find any interaction between age and treatment on CRF levels in the amygdala, as well as the frontal lobe, hippocampus, hypothalamus, and caudate 7 weeks after 10-days of ethanol vapor exposure.

No conclusions can be drawn. One study observed found support for reduced effects of ethanol on HPA-axis functionality compared to adults, whereas the other observed no difference between the age groups. Future studies using different (voluntary) exposure paradigms are needed to further investigate the effects of alcohol on HPA activity in relation to age of alcohol exposure.

Neuropeptides

Neuropeptides are a diverse class of proteins that have a modulatory function in many different processes, including but not limited to neurotransmission, stress, immune responses, homeostasis, and pain [ 151 , 152 , 153 ]. Only one study investigated neuropeptides in rats and observed age-related differences [ 150 ].

Slawecki et al. [ 150 ] specifically investigated neuropeptide-Y, substance-P, and interleukine expression in the frontal lobe, hippocampus, hypothalamus, dorsal striatum, and amygdala 7 weeks after 10-days of ethanol vapor exposure in rats [ 150 ]. Interactions between age and treatment were found for the hippocampus and caudate only. Ethanol-induced reductions in hippocampal neuropeptide-Y and increases in caudate neurokinine were more pronounced in adults compared to adolescents suggesting long-lasting effects of ethanol in adults but not adolescents.

Ethanol metabolism

The first metabolite of ethanol is acetaldehyde, which has been theorized to mediate the effects of ethanol on both brain and behavior [ 154 ]. Only one study investigated ethanol metabolism in the brain and did not observe age-related differences [ 155 ].

Rhoads et al. showed that despite the fact that adolescent rats consumed more alcohol brain catalase levels after 3-weeks of ethanol exposure (no abstinence) did not differ between adolescents and adults [ 155 ]. Although the general role of catalase in ethanol metabolism is small, catalase can oxidize ethanol to acetaldehyde in the brain, affecting elimination of ethanol after consumption [ 156 , 157 ]. These findings may therefore imply that ethanol metabolism may not differ between adolescent and adult animals, which should be studied in a more direct manner.

Full proteome analysis

While the previously described studies focused on specific factors involved in neurotransmission, brain health, and plasticity, proteomics allows for the study of the full proteome in a specific region or tissue type. One study investigated the impact of age on ethanol-induced changes in the hippocampal proteome, observing age-related differences [ 158 ]. In this study, rats intermittently and voluntarily consumed beer for 1 month and the hippocampal proteome was analyzed after 2 weeks of abstinence. The results point to the involvement of many of the factors described above and imply age-specific effects of alcohol. Adult beer exposure increased citrate synthase (part of the citric acid, or Krebs, cycle) and fatty acid binding proteins (involved in membrane transport) compared to controls. Adolescent beer exposure increased cytoskeletal protein T-complex protein 1 subunit epsilon (TCP-1), involved in ATP-dependent protein folding, and reduced expression of a variety of other proteins involved in glycolysis, glutamate expression, aldehyde detoxification, protein degradation, and synaptogenesis, as well as neurotransmitter release. These more extensive changes suggest that the adolescent hippocampus might be more vulnerable to the effects of ethanol exposure, but more studies are needed to clarify and replicate these findings and extend the focus to different brain areas.

Neuronal activity and functioning

Ethanol-induced molecular changes may eventually change neuronal activity. Three studies investigated neuronal activity and functioning [ 89 , 159 , 160 ] using electrophysiological methods. All three studies observed age-related differences.

Galaj et al. [ 159 ] assessed firing patterns and the structure of pyramidal neurons in the L2 and L5 layers of the prelimbic cortex of the rat brain using ex vivo electrophysiological recordings and morphological staining. Following chronic intermittent ethanol exposure and brief abstinence (2 days), adolescents, but not adults, showed reduced amplitudes of spontaneous excitatory post-synaptic currents (sEPSCs) in L5 neurons compared to controls, indicating reductions in intrinsic excitability. In line with this, Dil staining showed increased thin spine ratios in the L5 layer in adolescents only. Age differences were more pronounced after prolonged abstinence (21 days), with adolescents showing reduced amplitude and frequency of sEPSCs in L5 neurons while adult’s L5 neurons showed augmented firing patterns (i.e., amplitude and frequency). Furthermore, adolescent rats showed decreased total spine density and non-thin spines, indicating less excitatory postsynaptic receptors in the L5 layer. In contrast, adults showed increases in spine density and non-thin spines.

Li et al. [ 160 ] examined the functioning of CA1 interneurons, which are important for learning and memory processes [ 161 ], in the rat hippocampus using ex vivo whole-cell recordings. After prolonged abstinence (20 days), voltage-gated A-type potassium channel ( I A ) conductance was measured. Differences emerged between age groups (although no statistical interaction effect was directly assessed): EtOH-exposed adolescents and adults both showed lower I A mean peak amplitude compared to the respective control groups. However, adolescents also showed reduced I A density and increased mean decay time, which decreased in adults. Furthermore, only adolescents showed increased depolarization required for activation compared to controls, which can result in higher interneuron firing rates in the CA1 region that could affect learning processes. Additional research is needed to connect these findings to behavioral measures of learning and memory.

Slawecki et al. [ 89 ] was the only study to use in vivo electroencephalogram (EEG) recordings with rats to examine function in the frontal and parietal cortex at different times during a 14-day vapor exposure period. During acute withdrawal (7–10 h abstinence period), following daily exposure no effects emerged in frontal cortical regions throughout the exposure period. In parietal regions, only adolescents showed increased high frequency (16–32 Hz and 32–50 Hz) power on days 8 and 12 compared to controls. Adolescent hyperexcitability during withdrawal may indicate increased arousal in adolescents compared to adults during withdrawal, but more studies linking brain activity to behavioral indices of withdrawal will allow for clearer interpretations.

Overall, strong conclusions cannot be drawn given the disparate paradigms and outcomes utilized. While adolescents and adults appear to differ in the effect of ethanol on neuronal firing, the meaning of these differences is not clear given the lack of connection between these findings and behavioral outcomes.

Human studies

Four studies examined age-related differences of the effect of alcohol on brain or cognition in humans [ 162 , 163 , 164 , 165 ].

Müller-Oehring et al. [ 162 ] examined the moderating role of age on resting state functional connectivity and synchrony in the default mode, central executive, salience, emotion, and reward networks of the brain in a sample of no/low and heavier drinkers aged 12–21 years old. While the study did not compare discrete groups of adolescents and adults, analyses investigating the interaction between continuous age and alcohol exposure history were conducted which provide insight into the effect of alcohol use on functional brain networks from early adolescence to emerging adulthood. Regardless of age, no differences were observed between matched subgroups of no/low drinkers and moderate/heavy drinkers in the default mode, salience, or reward networks. However, in the central executive network, connectivity between the superior frontal gyrus (SFG) and insula increased with age in the no/low drinkers but not in heavier drinkers. Age-related strengthening of this fronto-limbic connection correlated with better performance on a delay discounting task in boys, suggesting that adolescent alcohol use may interfere with typical development of higher-level cognitive functions. In the emotion network, amygdala-medial parietal functional synchrony was reduced in the heavier drinkers compared to the no/low drinkers and exploratory analyses suggested that weaker amygdala-precuneus/posterior cingulate connectivity related to later stages of pubertal development in the no/low drinking group only. Interestingly, in the default mode (posterior cingulate-right hippocampus/amygdala) and emotional networks (amygdala, cerebellum), connectivity in regions that exhibited age-related desynchronization was negatively correlated with episodic memory performance in the heavy drinkers. These results give preliminary evidence that alcohol might have age-dependent effects on resting state connectivity and synchronization in the central executive, emotion, and default mode networks that could potentially interfere with normative maturation of these networks during adolescence.

Three studies examined age effects in alcohol-related implicit cognitions, specifically attentional bias [ 163 , 165 ], alcohol approach bias [ 165 ], and implicit memory associations and explicit outcome expectancies [ 164 ]. Attentional bias refers to the preferential automatic allocation or maintenance of attention to alcohol-related cues compared to neutral cues which is correlated with alcohol use severity and craving [ 166 ]. McAteer et al. [ 163 ] measured attentional bias with eye tracking during presentation of alcohol and neutral stimuli in heavy and light drinkers in early adolescents (12–13 yrs), late adolescents (16–17 yrs), and young adults (18–21 yrs). Regardless of age, heavy drinkers spent longer fixating on alcohol cues compared to light drinkers. Cousijn et al. [ 165 ] measured attentional bias with an Alcohol Stroop task [ 167 ], comparing the speed of naming the print color of alcohol-related and control words. Consistent with the findings of McAteer et al. [ 163 ], adults and adolescents matched on monthly alcohol consumption showed similar levels of alcohol attentional bias. In the same study, Cousijn et al. [ 165 ] did not find any evidence for an approach bias towards alcohol cues in any age group.

Rooke and Hine [ 164 ] found evidence for age-related differences in implicit and explicit alcohol cognitions and their relationship with binge drinking. Using a teen-parent dyad design, adolescents (13–19 yrs) showed stronger memory associations in an associative phrase completion task and more positive explicit alcohol expectancies than adults. Interestingly, both explicit positive alcohol expectancies and implicit memory associations were a stronger predictor of binge drinking in adolescents compared to adults. It is important to note that adolescents also had higher levels of binge drinking than adults in the study.

Cousijn et al. [ 165 ] also investigated impulsivity, drinking motives, risky decision-making, interference control, and working memory. No age differences emerged in the cognitive functioning measures including risky decision-making (Columbia Card Task – “hot” version), interference control (Classical Stroop Task), or working memory (Self-Ordered Pointing Task). However, adolescents were more impulsive (Barrett Impulsiveness Scale) than adults and reported more enhancement motives. Importantly, impulsivity as well as social, coping, and enhancement motives of alcohol use correlated with alcohol use in both ages. However, age only moderated the relationship between social drinking motives and alcohol use-related problems (as measured by the Alcohol Use Disorder Identification Test), with a stronger positive association in adolescents compared to adults. Importantly, the adolescent group had a different pattern of drinking, with less drinking days per month but more drinks per episode than the adult group.

In summary, human evidence is largely missing, with no studies comparing more severe and dependent levels of alcohol use between adolescents and adults. The preliminary evidence is too weak and heterogeneous to draw conclusions, warranting future studies investigating the impact of age.

The current systematic review assessed the evidence for the moderating role of age in the effects of chronic alcohol use on the brain and cognition. The identified 59 rodent studies (Table 1 ) and 4 human studies (Table 2 ) provide initial evidence for the presence of age-related differences. Rodents exposed to ethanol during adolescence show both increased risk and resilience to the effects of ethanol depending on the outcome parameter. However, due to the high variability in the outcomes studied and the limited number of studies per outcome, conclusions should be considered preliminary. Moreover, brain and behavioral outcomes were mostly studied separately, with studies focusing on either brain or behavioral outcomes. The behavioral consequences of changes in certain brain outcomes still need to be investigated. Table 3 provides a comprehensive overview of the strength of the evidence for age-related differences for all outcomes. Below, we will discuss the most consistent patterns of results, make connections between the behavioral and neurobiological findings when possible, highlight strengths and limitations of the evidence base, and identify the most prominent research gaps.

Patterns of results

Age-related differences in learning and memory-related processes appear to be highly domain specific. There is limited but fairly consistent evidence for adolescent-specific impairments in contextual fear conditioning, which could be related to hippocampal dysfunction. Results for other hippocampus-related memory processes such as spatial memory are mixed and largely based on forced exposure with acute challenge studies rather than voluntary long-term exposure to alcohol. The evidence base is currently insufficient to draw conclusions about the role of age in alcohol’s effects on non-spatial types of learning and memory. Alcohol generally did not impact performance in the non-spatial variants of the MWM and SBM paradigms or in reward-learning, but the results of the limited studies in the object-learning domain highlight potential impairments and the importance of age therein. For example, adolescents but not adults demonstrated impaired object memory in the only study using the novel object recognition task [ 65 ]. Acute challenges after chronic pre-exposure to alcohol also appear to impair performance in the working memory domain, with one study suggesting heightened adolescent sensitivity to working memory impairment [ 83 ]. Thus, although the domain-specific evidence is limited by the relative lack of research, overall patterns suggest that learning and memory functions that are primarily hippocampus-dependent may be differentially affected by adolescent compared to adult alcohol use. Studies focusing on neural hippocampal processes corroborate these findings, reporting more extensive changes in protein expression [ 158 ], less desensitization of cFos upregulation [ 142 ], larger changes in GABAa receptor subunit expression [ 124 ], longer lasting changes in NMDA receptor expression [ 115 ], and larger reductions in neurogenesis [ 65 , 133 ] in the hippocampus of adolescent compared to adult ethanol-exposed rodents. On the other hand, ethanol-induced changes in the hippocampus recovered more quickly in younger animals after abstinence [ 150 ] and adolescent mice showed less signs of ethanol-induced neuroinflammation compared to adults [ 148 ].

Higher rates of adolescent alcohol use, especially binge drinking, may be facilitated by a heightened sensitivity to the rewarding properties of alcohol in combination with a reduced sensitivity to the negative effects of high doses [ 47 ]. In line with this, there is limited but consistent evidence that adolescents show less CTA in response to chronic ethanol and consequently voluntarily consume more ethanol [ 50 ]. Importantly, distinct vulnerability periods within adolescence for altered CTA may exist [ 168 , 169 ], with early adolescents potentially being least sensitive to aversive effects. Future studies using chronic exposure paradigms comparing different stages of adolescence to adults are needed. In contrast to CTA, there is insufficient evidence of age-related differences in the motivational value of alcohol based on CPP paradigms, with only one of five studies reporting stronger CPP in adolescents than adults [ 52 ]. Adolescents may be more sensitive to the effects of environmental factors on the motivational value of alcohol than adults, as adolescents housed in enriched environments acquired CPP while those in standard housing did not, an effect that was not found in adults [ 54 ]. Evidence for environmentally enriched housing being protective against these changes in adolescents provides an important indication that environmental factors matter and are important factors to consider in future research on the motivational value of ethanol on both the behavioral and neural level. Complementary studies on the functioning of brain regions within the mesolimbic dopamine pathway and PFC, which play an important role in motivated behavior, indicate limited but consistent evidence for age-related differences. Adolescents showed less dopamine reactivity in the PFC and NAc compared to adults after chronic ethanol exposure. Furthermore, there is limited but consistent evidence that adolescents are more vulnerable to epigenetic changes in the frontal cortex and reward-related areas after chronic ethanol exposure. For instance, adolescents may be more sensitive to histone acetylation of transcription factors in motivational circuits underlying the rewarding effects of alcohol [ 55 ], which may contribute to addictive behaviors [ 170 , 171 ]. Chronic alcohol use is also associated with lower BDNF levels in the PFC and subsequent increases in alcohol consumption, implicating BDNF as an important regulator of alcohol intake [ 172 ]. While evidence is limited, chronic alcohol use consistently reduced prefrontal BDNF in both age groups. However, the rate of recovery of BDNF levels after abstinence appears to be slower in adolescents.

Regarding executive functioning, there is limited but fairly consistent evidence from animal studies that adolescents are more vulnerable to long-term effects of chronic exposure on decision-making and are more impulsive than adults during acute intoxication and after prolonged abstinence following chronic exposure. Impulsivity is associated with functional alterations of the limbic cortico-striatal systems [ 91 ], with involvement of both the dopaminergic and serotonergic neurotransmitter systems [ 173 ]. While no studies investigating serotonergic activity were identified, the consistent reduction in dopamine reactivity observed in the PFC and NAc in adolescents compared to adults parallel the behavioral findings. There is also limited but fairly consistent evidence that adolescents are more resilient to impairments in cognitive flexibility than adults following chronic exposure to alcohol, and that adolescents may more easily regain control over their alcohol-seeking behavior than adults. These behavioral findings provide preliminary support for the paradox of adolescent risk and resilience in which adolescents are at once more at risk to develop harmful patterns of drinking, but are also more resilient in that they may be more equipped to flexibly change behavior and with time regain control over alcohol consumption. However, studies assessing processes that might be related to brain recovery provide little conclusive evidence for potential underlying mechanisms of these behavioral findings. While adolescents appear more vulnerable to ethanol-induced brain damage [ 131 , 132 ], show reduced neurogenesis [ 65 , 133 ], and show less changes in gene expression associated with brain recovery [ 65 , 133 ], adults show relatively higher immune responses after repeated ethanol exposure [ 147 , 148 ]. The limited evidence for adolescent resilience to alcohol’s effects on cognitive flexibility diverge from the conclusions of recent reviews that focused mostly on adolescent-specific research. Spear et al. [ 18 ] concluded that adolescents are more sensitive to impairments in cognitive flexibility; however, this was based on adolescent-only animal studies. Similarly, the systematic review of Carbia et al. [ 19 ] on the neuropsychological effects of binge drinking in adolescents and young adults also revealed impairments in executive functions, particularly inhibitory control. However, as pointed out by the authors, the lack of consideration of confounding variables (e.g., other drug use, psychiatric comorbidities, etc.) in the individual studies and the lack of prospective longitudinal studies limit our ability to causally interpret these results. This further highlights the difficulty of conducting human studies which elucidate causal associations of the effects of alcohol, and the need for animal research that directly compares adolescents to adults to bolster interpretation of findings from human research.

Only a few studies have investigated age-related differences in cognitive functioning in humans. These studies focused on mostly non-dependent users and studied different outcomes, including cognitive biases and implicit and explicit alcohol-related cognitions. Overall, there was limited but consistent evidence that age does not affect alcohol attentional or approach biases, with heavy drinkers in both age groups allocating more attention to alcohol cues compared to controls [ 163 , 165 ]. In contrast, in line with a recent meta-analysis of the neurocognitive profile of binge-drinkers aged 10–24 [ 23 ], there is limited evidence that age affects alcohol associations. One study found age effects on implicit (memory associations) and explicit (expectancies) cognition in relation to alcohol use. Adolescents showed stronger memory associations and more positive expectancies than adults [ 164 ]. These expectancies were also predictive of higher binge drinking in adolescents but not adults, highlighting the importance of future research into age differences in alcohol-related cognitions and their consequences on alcohol consumption. However, the quality of the evidence was rated as weak based on the methodological design of the included studies.

Regarding anxiety-related outcomes, results are inconsistent across studies and paradigms. When age-differences are observed, adolescents often show reduced anxiety compared to adults during both acute withdrawal and sustained abstinence following chronic ethanol exposure. However, the direction of age-related effects of alcohol may also be anxiety-domain specific. In social settings, adults show reduced anxiety compared to adolescents. Research on the neurocircuitry of anxiety processes implicates the extended amygdala, especially the BNST, in anxiety behaviors with an emphasis on the role of GABAergic projections to the limbic, hindbrain, and cortical structures in rodents [ 174 ]. Despite adolescents showing less non-social anxiety than adults after ethanol exposure, no age-differences were observed for LTP in the BNST [ 109 ]. Also, GABA receptor expression in the hippocampus and whole cortex was not altered by ethanol exposure in either age group [ 108 ]. However, the anxiolytic effects of NMDA antagonists [ 175 ] also highlight the importance of glutamatergic activity in anxiety processes [ 176 ]. In line with behavioral findings, adolescents were less sensitive to changes in glutamate expression: adults showed heightened expression in the NAc, which has been suggested to underlie the higher levels of anxiety observed in adults compared to adolescents [ 106 ]. Importantly, across the various studies, different paradigms were used to assess anxiety, potentially contributing to the inconsistent results. Furthermore, most of the identified studies used a forced ethanol exposure paradigm. As alcohol-induced anxiety is likely also dependent on individual trait anxiety, voluntary consumption studies in high and low trait anxiety animals are important to further our understanding of the interaction between alcohol use and anxiety. Of note, the observed pattern suggestive of reduced anxiety in adolescents compared to adults diverges from conclusions of previous reviews such as Spear et al. [ 18 ] which concluded that adolescents are more likely to show augmented anxiety after alcohol exposure based on animal studies with adolescent animals only. Importantly, anxiety was included as a secondary outcome in this review because of the high comorbidity between anxiety disorders and alcohol addiction, warranting the inclusion of age-related differences in the relation between alcohol and anxiety. However, the search strategy was not specifically tailored to capturing all studies assessing age-related differences in the effect of alcohol on anxiety.

Translational considerations, limitations, and future directions

The reviewed studies revealed a high degree of variability in study designs and outcomes, hindering integration and evaluation of research findings. We were unable to differentiate our conclusions based on drinking patterns (i.e., comparing binge drinking, heavy prolonged use, AUD). The prevalence of binge-drinking in adolescence is very high and is associated with neurocognitive alterations [ 177 ]. Studies investigating the potential differential impact of binge-drinking compared to non-binge-like heavy alcohol use in adolescence and adulthood are critical for understanding the risks of chronic binge-like exposure in adolescence, even if it does not progress to AUD.

It is also important to acknowledge the limitations of the choice of adolescent and adult age ranges in our inclusion criteria. Rodent studies had to include an adolescent group exposed to alcohol between the ages of PND 25–42 and an adult group exposed after age PND 65. Ontogenetic changes may still be occurring between PND 42–55, and this period may more closely correspond to late adolescence and emerging adulthood in humans (e.g., 18–25 years). Studies that compared animals in this post-pubertal but pre-adulthood age range were not reviewed. Studies investigating age-related differences in the effects of ethanol on brain and cognitive outcomes in emerging adulthood are also translationally valuable given the high rates and risky patterns of drinking observed during this developmental period [ 178 ]. Indeed, an important future direction is to examine whether there are distinct vulnerability periods within adolescence itself for the effects of ethanol on brain and cognitive outcomes. Given that emerging adulthood is a period of continued neurocognitive maturation and heightened neural plasticity, studies comparing this age range to older adults (e.g., over 30) are also necessary for a more thorough understanding of periods of risk and resilience to the effects of alcohol.

Furthermore, we did not conduct a risk of bias assessment to examine the methodological quality of the animal studies. The applicability and validity of the risk of bias tools for general animal intervention studies, such as the SYRCLE risk of bias tool [ 179 ], remain in question at the moment. The lack of standardized reporting in the literature for many of the criteria (e.g., process of randomizing animals into intervention groups) would lead to many studies being labeled with an ‘unclear risk of bias’. Furthermore, there is still a lack of empirical evidence regarding the impact of the criteria in these tools on bias [ 179 , 180 ]. This is a significant limitation in evaluating the strength of the evidence for age-related differences based on the animal studies, which highlights the importance of more rigorous reporting standards in animal studies.

Moreover, most work is done in male rodents and is based on forced ethanol exposure regimes. In a recent opinion article, Field and Kersbergen [ 181 ] question the usefulness of these types of animal models to further our understanding of human substance use disorders (SUD). They argue that animal research has failed to deliver effective SUD treatment and that social, cultural, and other environmental factors crucial to human SUD are difficult, if not impossible, to model in animals. While it is clear that more sophisticated multi-symptom models incorporating social factors are needed to further our understanding of SUD and AUD specifically, a translational approach is still crucial in the context of investigating the more fundamental impact of alcohol use on brain and cognition. In humans, comparing the impact of alcohol use on brain and cognition between adolescents and adults is complicated by associations between age and cumulative exposure to alcohol; i.e., the older the individual, the longer and higher the overall exposure to alcohol. Although animal models may be limited in their ability to model every symptom of AUD, they can still provide critical insights into causal mechanisms underlying AUD by allowing direct control over alcohol exposure and in-depth investigation of brain mechanisms.

The intermittent voluntary access protocol resembles the patterns of alcohol use observed in humans, and also result in physiologically relevant levels of alcohol intake [ 182 , 183 , 184 ]. Only a minority of the studies included in this review employed a voluntary access protocol, with one study using beer instead of ethanol in water [ 158 ], which better accounts for the involvement of additional factors (e.g., sugar, taste) in the appeal of human alcohol consumption. Voluntary access protocols can also model behavioral aspects of addictive behavior such as loss of control over substance use and relapse [ 185 , 186 , 187 ], an important area in which little is known about the role of age. Ideally, one would also investigate choices between ethanol and alternative reinforcers, such as food or social interaction, that better mimic human decision-making processes [ 188 ]. However, studies on the effects of ethanol on social behavior are limited and show inconsistent results and studies assessing reward processes often lack a social reward component as an alternative reinforcer.

On a practical level, rodents mature quickly and choice-based exposure paradigms are more complex and time-consuming than most forced exposure paradigms. Consequently, by the time final behavioral measurements are recorded, both the adolescent and adult exposure groups have reached adulthood. To combat this, many of the included studies use forced ethanol exposure, such as ethanol vapor, to quickly expose rodents to very high doses of ethanol. Although the means and degrees of alcohol exposure may not directly translate to human patterns of alcohol use, such studies do allow for the assessment of the impact of high cumulative doses of ethanol within a relatively short period of time which allows for more time in the developmental window to test age-related differences in the outcomes. When considering the translational value of a study, it is therefore important to evaluate studies based on the goal, while not ignoring the practical constraints.

While human research is challenging due to the lack of experimental control and the inherent confounds in observational studies between age and alcohol exposure history, large-scale prospective longitudinal studies offer a gateway towards a better understanding. Comparisons of different trajectories of drinking from adolescence to adulthood (i.e., heavy drinking to light drinking, light drinking to heavy drinking, continuously heavy drinking, and continuously light drinking) could offer insight into the associated effects on cognitive and brain-related outcomes. Of course, different drinking trajectories are likely confounded with potentially relevant covariates which limits causal inference. Direct comparisons of low and heavy adolescent and adult drinkers, supported by a parallel animal model can help to bolster the causality of observed age-related differences in human studies. In addition, changes in legislation around the minimum age for alcohol consumption in some countries provide a unique opportunity to investigate how delaying alcohol use to later in adolescence or even young adulthood impacts cognitive functioning over time. Importantly, future studies investigating the moderating role of age in humans should carefully consider the impact of psychiatric comorbidities. While adolescence into young adulthood is the period in which mental health issues often emerge [ 189 , 190 ], there is some evidence that the prevalence of comorbidities is higher in adults with AUD [ 95 ]. This is an important to control for when considering age-related differences on cognition and the brain given the evidence of altered cognitive functioning in other common mental illnesses [ 191 , 192 ].

Concluding remarks

The aim of this systematic review was to extend our understanding of adolescent risk and resilience to the effects of alcohol on brain and cognitive outcomes compared to adults. In comparison to recent existing reviews on the impact of alcohol on the adolescent brain and cognition [ 17 , 18 , 19 , 22 , 23 ], a strength of the current review is the direct comparison of the effects of chronic alcohol exposure during adolescence versus adulthood. This approach allows us to uncover both similarities and differences in the processes underlying alcohol use and dependence between adolescents and adults. However, due to the large degree of heterogeneity in the studies included in sample, designs, and outcomes, we were unable to perform meta-analytic synthesis techniques.

In conclusion, while the identified studies used varying paradigms and outcomes, key patterns of results emerged indicating a complex role of age, with evidence pointing towards both adolescent vulnerability and resilience. The evidence suggests adolescents may be more vulnerable than adults in domains that may promote heavy and binge drinking, including reduced sensitivity to aversive effects of high alcohol dosages, reduced dopaminergic neurotransmission in the NAc and PFC, greater neurodegeneration and impaired neurogenesis, and other neuromodulatory processes. At the same time, adolescents may be more resilient than adults to alcohol-induced impairments in domains which may promote recovery from heavy drinking, such as cognitive flexibility. However, in most domains, the evidence was too limited or inconsistent to draw clear conclusions. Importantly, human studies directly comparing adolescents and adults are largely missing. Recent reviews of longitudinal human research in adolescents, however, revealed consistent evidence of alterations to gray matter, and to a lesser extent white matter, structure in drinkers [ 17 , 18 ], but also highlight the limited evidence available in the domains of neural and cognitive functioning in humans [ 17 ]. Future results from ongoing large-scale longitudinal neuroimaging studies like the ABCD study [ 193 ] will likely shed valuable light on the impact of alcohol use on the adolescent brain. However, our results also stress the need for direct comparisons with adult populations. Moreover, while the lack of experimental control and methodological constraints limit interpretations and causal attributions in human research, translational work aimed at connecting findings from animal models to humans is necessary to build upon the current knowledge base. Furthermore, the use of voluntary self-administration paradigms and incorporation of individual differences and environmental contexts are important steps forward in improving the validity of animal models of alcohol use and related problems. A more informed understanding of the effects of alcohol on adolescents compared to adults can further prevention efforts and better inform policy efforts aimed at minimizing harm during a crucial period for both social and cognitive development.

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This work was supported by grant 1RO1 DA042490-01A1 awarded to Janna Cousijn and Francesca Filbey from the National Institute on Drug Abuse/National Institutes of Health. The grant supported the salaries of authors Lauren Kuhns, Emese Kroon, and Janna Cousijn. Thank you to Claire Gorey (CG) for running the initial search and aiding in the screening process.

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Kuhns, L., Kroon, E., Lesscher, H. et al. Age-related differences in the effect of chronic alcohol on cognition and the brain: a systematic review. Transl Psychiatry 12 , 345 (2022). https://doi.org/10.1038/s41398-022-02100-y

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Research on alcohol suggests a sobering conclusion: Drinking alcohol in any amount carries a health risk. While the risk is low for moderate intake, the risk goes up as the amount you drink goes up.

Many people drink alcohol as a personal preference, during social activities, or as a part of cultural and religious practices. People who choose not to drink make that choice for the same reasons. Knowing your personal risk based on your habits can help you make the best decision for you.

The evidence for moderate alcohol use in healthy adults is still being studied. But good evidence shows that drinking high amounts of alcohol are clearly linked to health problems.

Here's a closer look at alcohol and health.

Defining moderate alcohol use

Moderate alcohol use may not mean the same thing in research studies or among health agencies.

In the United States, moderate drinking for healthy adults is different for men and women. It means on days when a person does drink, women do not have more than one drink and men do not have more than two drinks.

Examples of one drink include:

• 12 fluid ounces (355 milliliters) of regular beer
• 5 fluid ounces (148 milliliters) of wine
• 1.5 fluid ounces (44 milliliters) of hard liquor or distilled spirits

Health agencies outside the U.S. may define one drink differently.

The term "moderate" also may be used differently. For example, it may be used to define the risk of illness or injury based on the number of drinks a person has in a week.

Risks of moderate alcohol use

The bottom line is that alcohol is potentially addictive, can cause intoxication, and contributes to health problems and preventable deaths. If you already drink at low levels and continue to drink, risks for these issues appear to be low. But the risk is not zero.

For example, any amount of drinking increases the risk of breast cancer and colorectal cancer. As consumption goes up, the risk goes up for these cancers. It is a tiny, but real, increased risk.

Drinking also adds calories that can contribute to weight gain. And drinking raises the risk of problems in the digestive system.

In the past, moderate drinking was thought to be linked with a lower risk of dying from heart disease and possibly diabetes. After more analysis of the research, that doesn't seem to be the case. In general, a healthy diet and physical activity have much greater health benefits than alcohol and have been more extensively studied.

Risks of heavy alcohol use

Heavy drinking, including binge drinking, is a high-risk activity.

The definition of heavy drinking is based on a person's sex. For women, more than three drinks on any day or more than seven drinks a week is heavy drinking. For men, heavy drinking means more than four drinks on any day or more than 14 drinks a week.

Binge drinking is behavior that raises blood alcohol levels to 0.08%. That usually means four or more drinks within two hours for women and five or more drinks within two hours for men.

Heavy drinking can increase your risk of serious health problems, including:

• Certain cancers, such as colorectal cancer, breast cancer and cancers of the mouth, throat, esophagus and liver.
• Liver disease.
• Cardiovascular disease, such as high blood pressure and stroke.

Heavy drinking also has been linked to intentional injuries, such as suicide, as well as accidental injury and death.

During pregnancy, drinking may cause the unborn baby to have brain damage and other problems. Heavy drinking also may result in alcohol withdrawal symptoms.

When to avoid alcohol

In some situations, the risk of drinking any amount of alcohol is high. Avoid all alcohol if you:

• Are trying to get pregnant or are pregnant.
• Take medicine that has side effects if you drink alcohol.
• Have alcohol use disorder.
• Have medical issues that alcohol can worsen.

In the United States, people younger than age 21 are not legally able to drink alcohol.

When taking care of children, avoid alcohol. And the same goes for driving or if you need to be alert and able to react to changing situations.

Deciding about drinking

Lots of activities affect your health. Some are riskier than others. When it comes to alcohol, if you don't drink, don't start for health reasons.

Drinking moderately if you're otherwise healthy may be a risk you're willing to take. But heavy drinking carries a much higher risk even for those without other health concerns. Be sure to ask your healthcare professional about what's right for your health and safety.

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• Rethinking drinking: Alcohol and your health. National Institute on Alcohol Abuse and Alcoholism. https://www.rethinkingdrinking.niaaa.nih.gov/. Accessed Jan. 8, 2024.
• 2020-2025 Dietary Guidelines for Americans. U.S. Department of Health and Human Services and U.S. Department of Agriculture. https://www.dietaryguidelines.gov. Accessed Jan. 8, 2024.
• Scientific Report of the 2020 Dietary Guidelines Advisory Committee. Alcoholic beverages. U.S. Department of Health and Human Services and U.S. Department of Agriculture. https://www.dietaryguidelines.gov/2020-advisory-committee-report. Accessed Jan. 8, 2024.
• Canada's guidance on alcohol and health. Canadian Centre on Substance Use and Addiction. https://www.ccsa.ca/canadas-guidance-alcohol-and-health. Accessed Jan. 9, 2024.
• Science around moderate alcohol consumption. Centers for Disease Control and Prevention. https://www.cdc.gov/alcohol/fact-sheets/moderate-drinking.htm. Accessed Jan. 9, 2024.
• Alcohol use and your health. Centers for Disease Control and Prevention. https://www.cdc.gov/alcohol/fact-sheets/alcohol-use.htm. Accessed Jan. 9, 2024.

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Trusted Health Information from the National Institutes of Health

Why alcohol-use research is more important than ever

Nih's george koob talks about how addiction changes the brain and the rise in alcohol-related deaths.

Alcohol use disorder is a common but serious condition that affects how the brain functions.

  George Koob, Ph.D.

Alcohol use disorder (AUD) affects roughly 15 million people in the U.S. People with the condition may drink in ways that are compulsive and uncontrollable, leading to serious health issues.

"It's the addiction that everyone knows about, but no one wants to talk about," says George Koob, Ph.D., the director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

As NIAAA celebrates an important milestone this year—its 50th anniversary—the institute's research is more important than ever. Like NIAAA reported earlier this year, alcohol-related health complications and deaths as a result of short-term and long-term alcohol misuse are rising in the U.S.

"Alcohol-related harms are increasing at multiple levels—from emergency department visits and hospitalizations to deaths," Dr. Koob says. He spoke about NIAAA efforts that are working to address this and how people can get help.

What has your own research focused on?

I started my career researching the science of emotion: how the brain processes things like reward and stress. Later, I translated this to alcohol and drug addiction and investigating why some people go from use to misuse to addiction, while others do not.

What are some major breakthroughs NIAAA has made in this area?

We now understand how alcohol affects the brain and why it causes symptoms of AUD . This has far-reaching implications for everything from prevention to treatment. We also understand today that AUD physically changes the brain. This has been critical in treating it as a mental disorder, like you would treat major depressive disorder.

Other breakthroughs have been made in screening and intervention, and in the medications available for treatment. All of this has led to a better understanding of how the body changes when one misuses alcohol and the proactive actions we can take to prevent alcohol misuse.

What is a misconception that people have about AUD?

Many people don't realize how common AUD is. There are seven times more people affected by AUD than opioid use disorder, for example. It doesn't discriminate against who it affects. People also don't realize that AUD is a brain disorder that actually changes how the brain functions. Severe AUD is associated with widespread injury to the brain, though some of the effects might be partially reversible.

What's next for NIAAA?

For five decades, the institute has studied how alcohol affects our health, bringing greater awareness to alcohol-related health issues and providing better options for diagnosis and treatment. Recent research has focused on areas such as the genetics of addiction, links between excessive alcohol use and mental health and other disorders, harm to long-term brain health that can be caused by adolescent alcohol use, and the effects of prenatal alcohol exposure, among others.

"We want everyone from pharmacists and nurses to addiction medicine specialists to know more about alcohol and addiction." - George Koob, Ph.D.

Currently, we are working on a number of initiatives. One is education. We want everyone from pharmacists and nurses to addiction medicine specialists to know more about alcohol and addiction. We're also working on prevention resources for middle school-aged adolescents. Other goals include understanding recovery and what treatments work best for people and why. We're also learning more about alcohol's effects on sleep and pain, and we have ongoing efforts in medication development.

Finally, we're learning more about the impact of alcohol on women and older adults. Women have begun to catch up to men in alcohol consumption and alcohol-related harms. Women are more susceptible to some of the negative effects that alcohol has on the body, from liver disease to certain cancers. Further, more older adults are binge drinking and this places them at greater risk of alcohol-medication interactions, falls, and health problems related to alcohol misuse.

How can someone get help?

If alcohol is negatively affecting you or someone you know, seek help from someone you respect. For example, a primary care doctor or clergy member. There are a number of online resources from NIAAA, like the NIAAA Alcohol Treatment Navigator® , an online resource to help people understand AUD treatment options and search for professionally led, evidence-based alcohol treatment nearby. There's also Rethinking Drinking SM , an interactive website to help individuals assess and change their drinking habits. Also, know that there is hope. Many people recover from AUD and lead vibrant lives.

July 16, 2020

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Complications From Alcohol Use Are Rising Among Women

New research shows that alcohol-related liver disease and other health problems increased even more than expected among women ages 40 to 64 during the pandemic.

• Share full article

By Dani Blum

A new study adds to a mounting body of evidence showing that rising alcohol consumption among women is leading to higher rates of death and disease. The report, published Friday in the journal JAMA Health Forum , examined insurance claims data from 2017 to 2021 on more than 14 million Americans ages 15 and older. Researchers found that during the first year and a half of the coronavirus pandemic, women ages 40 to 64 were significantly more likely than expected to experience serious complications like alcohol-related cardiovascular and liver disease, as well as severe withdrawal.

The Background

Alcohol consumption in the United States has generally increased over the last 20 years , said Dr. Timothy Naimi, the director of the Canadian Institute for Substance Use Research at the University of Victoria. Dr. Naimi was a co-author on a recent paper that showed deaths from excessive alcohol use in the United States rose by nearly 30 percent between 2016 and 2021.

While men still die more often from drinking-related causes than women, deaths among women are climbing at a faster rate. “The gap is narrowing,” said Dr. Bryant Shuey, an assistant professor of medicine at the University of Pittsburgh and the lead author of the new study.

The Research

The study looked at serious health issues related to drinking, including alcohol-related liver and heart disease, inflammation of the stomach lining that led to bleeding, pancreatitis, alcohol-related mood disorders and withdrawal. Researchers compared insurance claims data for these complications with the rates they expected to see based on past prevalence of these conditions.

In nearly every month from April 2020 to September 2021, women ages 40 to 64 experienced complications from alcohol-related liver disease — a range of conditions that can develop when fat begins to accumulate in the liver — at higher rates than researchers predicted. If damage from drinking continues, scar tissue builds up in the liver and leads to a later stage of the disease, called cirrhosis. Some people with alcohol-related liver disease also develop severe liver inflammation, known as alcohol-associated hepatitis.

Rates of alcohol-related complications during the pandemic were also higher than predicted among men ages 40 to 64, but those increases were not statistically significant. But “men are not out of the woods” and still face health risks, Dr. Shuey said.

The Limitations

The study examined data only up until September 2021. Katherine Keyes, a professor of epidemiology at Columbia University who was not involved in the latest study, said she expected that alcohol use might keep rising among women — a pattern that could contribute to even more health issues.

And since the study relied on insurance claims, Dr. Shuey said it told an incomplete story. If someone is treated in the emergency room for an inflamed pancreas but doesn’t disclose a drinking history, for example, that instance may not be registered as an alcohol-related complication.

“The truth is, we’re probably underestimating this,” he said.

The Takeaways

These findings underscore how patterns of heavy drinking can translate into serious health consequences. Over the last 10 years, a growing number of American women — and particularly women in middle age — have reported binge-drinking, Dr. Keyes said.

“It used to be that 18- to 25-year-old males were the most likely to drink or the most likely to binge,” said Aaron White, a neuroscientist at the National Institute on Alcohol Abuse and Alcoholism. Now, binge drinking occurs more among people between the ages of 26 to 34, and is becoming more common among women. “Everything’s just getting pushed back later,” he said.

Demographic shifts can also help explain why women are drinking at higher rates, Dr. Keyes said. Women tend to marry and have children at later ages than in previous decades, so they spend more time in what Dr. Keyes calls a “high-risk period for heavy drinking.”

“People don’t realize the real health consequences these heavy drinking patterns can have,” she added.

These consequences take time to develop and often emerge between ages 40 and 60. Complications can occur after “years of heavy, persistent alcohol use,” Dr. Shuey said.

These longer-term increases in drinking predate the pandemic and might have increased the risk of health problems among women before Covid-19 hit. But higher levels of drinking during lockdowns may have exacerbated these issues or contributed to new complications, especially as women bore the brunt of family responsibilities, Dr. White said.

Even as research mounts on the harms of alcohol, many people might struggle to change their habits, Dr. White said.

“If you’ve been drinking wine with dinner every night for the last 20 years, just seeing a headline is not going to be enough to make you throw your wine away,” he said. “I think it’s going to be a slow cultural shift.”

Dani Blum is a health reporter for The Times. More about Dani Blum

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Volume 39 Issue 1 January 1, 2018

Binge Drinking’s Effects on the Body

Part of the Topic Series: Binge Drinking: Predictors, Patterns, and Consequences

Patricia E. Molina and Steve Nelson

Patricia E. Molina, M.D., Ph.D., is the Richard Ashman, Ph.D., Professor; head of the Department of Physiology; and director of the Comprehensive Alcohol–HIV/AIDS Research Center and the Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

Steve Nelson, M.D., is the John H. Seabury Professor of Medicine and the dean of the School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana.

Studies have focused on the effects of chronic alcohol consumption and the mechanisms of tissue injury underlying alcoholic hepatitis and cirrhosis, with less focus on the pathophysiological consequences of binge alcohol consumption. Alcohol binge drinking prevalence continues to rise, particularly among individuals ages 18 to 24. However, it is also frequent in individuals ages 65 and older. High blood alcohol levels achieved with this pattern of alcohol consumption are of particular concern, as alcohol can permeate to virtually all tissues in the body, resulting in significant alterations in organ function, which leads to multisystemic pathophysiological consequences. In addition to the pattern, amount, and frequency of alcohol consumption, additional factors, including the type of alcoholic beverage, may contribute differentially to the risk for alcohol-induced tissue injury. Preclinical and translational research strategies are needed to enhance our understanding of the effects of binge alcohol drinking, particularly for individuals with a history of chronic alcohol consumption. Identification of underlying pathophysiological processes responsible for tissue and organ injury can lead to development of preventive or therapeutic interventions to reduce the health care burden associated with binge alcohol drinking.

Introduction

Alcohol misuse is the fifth-leading risk factor for premature death and disability worldwide, 1 and, adjusting for age, alcohol is the leading risk factor for mortality and the overall burden of disease in the 15 to 59 age group. 2 According to the World Health Organization, in 2004, 4.5% of the global burden of disease and injury was attributable to alcohol: 7.4% for men and 1.4% for women. 2

Alcohol can permeate to virtually all tissues in the body, resulting in significant alterations in organ function, which leads to multisystemic pathophysiological consequences. The effect of alcohol misuse on multiple organ systems outside the liver, mediated through direct and indirect effects beyond those associated with alterations in the nutritional state of the individual, has been well-established. 3,4 The resulting tissue injury has increasingly been recognized and examined as a contributing factor to alcohol-related comorbidities and mortality. Several pathophysiological mechanisms have been identified as causative factors of tissue and organ injuries that resulted from excessive alcohol consumption, including acetaldehyde generation, adduct formation, mitochondrial injury, cell membrane perturbations, immune modulation, and oxidative stress (Figure 1). Some of these mechanisms are the result of direct alcohol-induced cell perturbations, whereas others are the consequence of tissue alcohol metabolism (Figure 2). The oxidative stress caused by excess production of reactive oxygen species (ROS) or a reduction in reducing antioxidant equivalents in tissue has been consistently demonstrated to be an overall mechanism of the tissue injury that results from chronic alcohol misuse. Dose-dependent relationships between alcohol consumption and incidence of diabetes mellitus, hypertension, ischemic heart disease, dysrhythmias, stroke, pneumonia, and fetal alcohol syndrome have been reported. 4 However, recognition of alcohol as an underlying causal factor in comorbid conditions remains a challenge in the clinical setting.

Several factors associated with alcohol consumption, including pattern, amount, and frequency, and the type of alcoholic beverage, may contribute differentially to the risk for alcohol-induced tissue injury. The question of whether all types of alcohol produce similar pathophysiological consequences remains to be answered. However, the particularly detrimental effects of binge drinking have increasingly gained attention. Binge drinking, as defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is a pattern of alcohol consumption that brings blood alcohol concentration to .08 g/dL, which typically occurs following the intake of five or more standard alcohol drinks by men and four or more by women over a period of approximately 2 hours. 5 Results from the 2015 National Survey on Drug Use and Health show overall prevalence of binge drinking (during the past 30 days) of 26.9% among U.S. adults ages 18 and older. 6 Those data show that binge drinking prevalence and intensity are highest among those ages 18 to 24 but also occur in high frequency among older individuals (ages 65 and older). Thus, binge drinking prevails in two vulnerable segments of the population, raising their risks for greater severity of injury and frequency of comorbidities.

Understanding the Biomedical Consequences of Binge Drinking

A limitation to our understanding of the consequences of binge alcohol consumption on organ injury is the lack of information on the time period, duration, and number of binge occurrences that describe the long-term practice of binge drinking. Preclinical studies conducted under controlled conditions provide opportunities to examine quantity and frequency variables in the investigation of the effects of alcohol consumption on organ injuries. However, interpreting, comparing, and integrating the patterns of alcohol consumption described in clinical reports is difficult because of the different types of data collected across studies. This difficulty underscores the need for researchers to perform more rigorous comprehensive and systematic data collection on alcohol use patterns. The Timeline Followback (TLFB) tool, for example, uses a calendar and a structured interview to collect retrospective information on the types and frequency of alcohol use over a given time period. 7,8 Nevertheless, accounting for a lifetime pattern of binge alcohol consumption remains challenging when conducting clinical studies. Alcohol consumption patterns should be taken into consideration for future development of alcohol use screening tools, because binge drinking has been suggested to result in greater alcohol-related harm. 9

Different types of alcoholic beverages consumed in binge drinking episodes could also differentially affect the health consequences associated with binge drinking. Epidemiological studies that compared the prevalence of coronary heart disease in “wine-drinking countries” and beer- or liquor-drinking countries have proposed that red wine, but not beer or spirits, consumed with a meal may confer cardiovascular protection. 10 The proposed protective effects of red wine include decreased blood clot formation, vascular relaxation, and attenuation of low-density lipoprotein (LDL, or bad cholesterol) oxidation, an early event preceding formation of cholesterol-filled plaque. These effects are attributed to polyphenols, especially resveratrol, and their antioxidant properties.

However, not all reports support the link between consuming a specific beverage type (i.e., wine vs. beer or spirits) and health benefits. Some reports suggest that beverage amount is more directly linked to health outcomes. 11,12 The differential contribution of alcoholic beverages to beneficial or detrimental health outcomes remains to be examined in both preclinical and clinical studies. In binge drinking episodes, the form of alcohol consumed most frequently is beer (67.1%), followed by liquor (21.9%) and wine (10.9%). 13 Moreover, beer accounts for most of the alcohol consumed by drinkers who are at the highest risk of causing or incurring alcohol-related harm, including drinkers ages 18 to 20, those with more frequent binge episodes per month, and those drinking 8 or more drinks per binge episode. Therefore, dissecting how pattern of drinking and type of alcoholic beverage contribute to overall outcomes is challenging.

The Gastrointestinal Tract, Liver, and Pancreas

Of all tissues affected by binge-like alcohol consumption, the gastrointestinal tract bears the greatest burden due to its direct exposure to high tissue concentrations of alcohol following ingestion (Figure 3). Binge drinking often occurs apart from meals, which may also contribute to its deleterious effects on organs. Food consumed at the time of alcohol consumption influences not only the alcohol absorption rate and blood alcohol concentration, but also the direct effect of alcohol on the gastrointestinal mucosa. Hence, binge drinking is more likely to contribute to organ injury than paced, moderate alcohol drinking that is associated with a meal.

Figure 3 The systemic effects of chronic binge alcohol consumption and the principal organ systems affected.

The gut mucosa is particularly susceptible to alcohol-induced injury, and alcohol consumption can result in a loss of intestinal barrier integrity. Several direct and indirect mechanisms have been identified that disrupt the structural and functional components involved in maintaining the integrity of the gut mucosal barrier. Alcohol and its breakdown products directly damage epithelial cells through generation of ROS and through disruption of tight junction protein expression and signaling. 14 This process disrupts the integrity of the intestinal barrier, allowing bacteria and toxins to reach the bloodstream. Acute alcohol binge drinking in healthy human volunteers can produce a significant increase in serum endotoxin levels and bacterial 16S ribosomal DNA, suggesting the gastrointestinal microbial origin of endotoxin. 15-17

More recently, attention has focused on the changes in intestinal microbiome that contribute to alcohol-associated intestinal inflammation and permeability. Alcohol promotes both dysbiosis (decreased diversity or an imbalance in the types of microbes) and bacterial overgrowth in the gastrointestinal system. 18-21 Alcohol alters the balance between bacterial strains, decreasing the presence of beneficial bacteria, such as Lactobacillus and Bifidobacterium, and increasing that of Proteobacteria and Bacilli. 19 This imbalance adds to the possibility that bacterial overgrowth may contribute to local mucosal inflammation through bacterial metabolism of alcohol and enhanced local production of metabolites such as acetaldehyde. 22 Moreover, increased bacterial load, together with shifts in intestinal bacterial strains, brings about diverse profiles of bacterial-derived metabolites.

How these shifts in bacterial strains, load, and metabolites contribute to organ injury remains to be fully elucidated. However, it is reasonable to speculate that greater bacterial burden and altered bacterial profiles, together with increased permeability of the gut mucosa, would lead to continuous entry of bacterial toxins into the systemic circulation. These changes could produce chronic and sustained activation of immune responses that, in turn, could lead to immune exhaustion and dysfunction. Preclinical studies show that binge-on-chronic alcohol feeding alters the gut microflora at multiple taxonomic levels, influencing hepatic inflammation, neutrophil infiltration, and liver steatosis, 23 which highlights the need for clinical investigation into the relationship between gut microflora and hepatic liver disease.

Local and Systemic Consequences of Gut Injury

Toxins and bacterial products leaked from the gastrointestinal tract can be transported through the lymphatic system. This route of dissemination, which escapes hepatic clearance, may prove critical in the enhanced systemic delivery of toxins. Preclinical studies have shown that repeated binge-like alcohol intoxication increases lymphatic permeability and inflammation in the adipose tissue that immediately surrounds the mesenteric lymphatics. Inflammatory response in mesenteric perilymphatic adipose tissue is associated with altered adipose tissue insulin signaling and circulating adipokine profiles, which suggests a link between lymphatic leak, adipose tissue inflammation, and metabolic dysregulation. 24

Whether chronic alcohol consumption not in a binge pattern produces similar alterations in lymphatic permeability and mesenteric adipose inflammation remains to be determined. However, localized alterations in mesenteric adipose tissue metabolic regulation, including insulin signaling, may prove to be relevant to the enhanced risk for metabolic syndrome that is associated with binge alcohol consumption. 25 After burn injury and a binge-like pattern of alcohol intoxication, rodents showed similar exacerbation of adipose tissue inflammation. 26 This suggests that a possible synergism between binge-like alcohol intoxication and injury promotes a dysregulated adipose environment conducive to insulin resistance, and potentially metabolic syndrome, if these alterations are sustained beyond the immediate period following binge drinking or burn injury. 3

Second to the gastrointestinal tract, the liver has the most exposure to high alcohol concentrations during periods of binge drinking. Hepatocellular metabolism of alcohol and the resulting ROS generation; acetaldehyde formation and the resulting adducts; immune response activation, particularly in Kupffer and stellate cells; and alterations in cell signaling are all proposed as mechanisms that underlie liver injury associated with binge-like alcohol consumption. For people with chronic alcoholism, binge drinking augments liver injury 27,28 and is a major trigger for the progression from steatosis to steatohepatitis. 29-31 In one study, rodents that received binge-on-chronic alcohol exposure had accentuated elevation in liver enzymes (alanine aminotransferase), hepatic steatosis, and inflammatory cytokine expression compared to rodents subjected only to chronic or to acute alcohol exposure. 32 These results demonstrate that binge-on-chronic alcohol exposure results in greater insult than either chronic or acute alcohol exposure alone. Clinical studies have provided evidence of associations among alcohol binge drinking patterns, immune activation (high CD69 and low TLR4, CXCR4, and CCR2 expression), and decreased chemotactic responses to SDF-1 and MCP-1. 33 These associations reflect an altered immune profile that may be associated with liver injury and increased susceptibility to infection. More recently, attention has been drawn to the potential greater liver injury in individuals with metabolic syndrome. A population-based study showed a direct association between binge drinking frequency and liver disease risk, after adjusting for average daily alcohol intake and age. 34 In this study, binge drinking and metabolic syndrome produced supra-additive increases in the risk of decompensated liver disease. Because of increasing rates of obesity and metabolic syndrome, research on the effects of alcohol misuse and the biomedical consequences is needed for this particular segment of the population.

Located strategically between the liver and the gastrointestinal tract, the pancreas also has high susceptibility to alcohol-induced tissue injury. Heavy, chronic alcohol consumption is a recognized contributing factor in the development of pancreatitis. However, how dose and pattern of alcohol consumption affect pancreatic function and structure is not known. Studies show that alcohol consumption of more than 40 g per day is increasingly detrimental for any type of pancreatitis. 35 Retrospective clinical studies have shown that binge alcohol drinking is associated with aggravation of first-attack severe acute pancreatitis, which is reflected in higher admission levels of serum triglycerides, Balthazar computed tomographic score, and Acute Physiology and Chronic Health Evaluation II score, as well as higher mortality and incidence of complications. 36

Insight into the mechanisms involved in pancreatic injury is derived from preclinical studies that show detrimental effects of binge alcohol exposure on the pancreas. These effects include tissue edema, inflammation, acinar atrophy and moderate fibrosis, endoplasmic reticulum stress, oxidative stress, and apoptotic and necrotic cell death. These structural changes are associated with pancreatic dysfunctional changes, which are reflected by altered levels of alpha-amylase, glucose, and insulin, strongly suggesting a detrimental effect of acute binge alcohol exposure on the pancreas. Specifically, preclinical studies have proposed that, alone, chronic and binge alcohol exposure caused minimal pancreatic injury, but chronic plus binge alcohol exposure resulted in significant apoptotic cell death; alterations in alpha-amylase, glucose, and insulin; pancreatic inflammation; and protein oxidation and lipid peroxidation, which are indicative of oxidative stress. 37 The pathogenesis of alcoholic pancreatitis involves acinar cell alcohol metabolism. The direct toxic effects of alcohol and its metabolites on acinar cells, in the presence of an appropriate trigger factor, may predispose the gland to injury. In addition, pancreatic stellate cells are implicated in alcoholic pancreatic fibrosis. 38 Thus, experimental and clinical data suggest that alcohol consumption alone does not initiate pancreatitis, but it sensitizes the pancreas to disease from other insults, including smoking, exposure to bacterial toxins, viral infections, and binge alcohol consumption. 39

Cardiovascular Consequences

The effect of alcohol consumption on cardiovascular function has been the subject of much debate. The relationship between alcohol consumption and cardiovascular health is not linear and is thought to follow a J-shaped curve, with low amounts of alcohol consumption frequently reported as cardioprotective. 40 However, data suggest that binge drinking is associated with transient increases in systolic and diastolic blood pressure (Figure 3). 41-43 The prevalence of hypertension has been reported to be higher in individuals who consume more than six drinks per day. However, the pattern of alcohol consumption was not considered in these studies. 44 The effect of even a modest rise in blood pressure is considerable, as it is a recognized risk factor for cardiovascular mortality. 45,46 Binge drinking has been associated with increased risk of cardiovascular comorbidities, including hypertension, stroke, myocardial infarction, and sudden death, and this risk may extend to the younger population as well. 47-51 Acute elevations in blood alcohol levels resulting from binge alcohol consumption are associated with an increased risk of new-onset atrial fibrillation, a most common arrhythmia strongly associated with adverse cardiovascular events and sudden death. 52 A higher risk for myocardial infarction has been reported after 1 day of heavy alcohol consumption (which could reflect a binge-like pattern of alcohol consumption). 53

Few preclinical studies have examined the effect of binge drinking on cardiac function. In one study, over a 5-week period, rodents received repeated episodes of alcohol administration that modeled a binge drinking pattern. 54 These rodents did not show changes in cardiac structure, but this drinking pattern resulted in increased phosphorylation of myocardial p38 mitogen-activated protein kinase and transient increases in blood pressure, which became progressively higher with repeated episodes of binge drinking. These effects were partly mediated by adrenergic mechanisms. More recently, the combined binge-on-chronic pattern of alcohol feeding to rodents has been shown to result in alcohol-induced cardiomyopathy,characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis. 55,56 The role of oxidative stress has been confirmed by other preclinical studies. 57

Pulmonary Consequences

Preclinical studies have identified impairments in multiple aspects of lung function after chronic and binge-like alcohol administration, including altered epithelial barrier function, suppressed immunity, impaired bacterial clearance, depleted glutathione (GSH), and impaired pulmonary epithelial ciliary function (Figure 3). 58,59 Moreover, alcohol binge drinking increases the risk for sustaining traumatic injuries and aggravates outcomes from traumatic injuries, 60 such as burns, 26,58,61-63 bone fractures,64 and hemorrhagic shock. 65 For alcohol-intoxicated hosts, similar detrimental effects have been reported on bacterial pneumonia outcomes, a frequent comorbid condition associated with traumatic injury. 66 Binge-like alcohol administration impairs innate and adaptive immune responses in the lungs, thereby increasing infection susceptibility, morbidity, and mortality. 61,62 It is possible that, in hosts previously exposed to chronic alcohol consumption, binge drinking detrimentally affects pulmonary outcomes from traumatic injury by priming host defense mechanisms. This combined effect may prevent clear isolation of binge alcohol consumption effects from chronic alcohol consumption effects.

Musculoskeletal Consequences

The incidence of skeletal muscle dysfunction (i.e., myopathy) resulting from chronic alcohol misuse surpasses that of cirrhosis. 67 This progressive loss of lean mass is multifactorial and involves metabolic, inflammatory, and extracellular matrix alterations, which promote muscle proteolysis and decreased protein synthesis (Figure 3). 68 An additional severe complication of binge drinking is the development of acute muscle injury, rhabdomyolysis. Binge drinking that precedes coma or immobility can lead to rhabdomyolysis and, consequently, to renal injury, as documented in case reports in the literature. 69-71 The mechanisms are not well-understood, but they may involve acute hypokalemia.72 This phenomenon may warrant further study, as environmental factors such as high ambient temperature and individual drug-drug interactions can obscure presentation and hinder management of alcohol-induced rhabdomyolysis.

Preclinical studies suggest that, after binge-like alcohol administration, physical exercise may ameliorate cognitive impairment and suppressed neurogenesis. 73 The effect of binge alcohol consumption on exercise performance and recovery remains to be systematically investigated. One clinical study reported no change in isokinetic and isometric muscle performance, central activation, or creatine kinase release during or after acute moderate alcohol intoxication. 74 Short-term reductions in lower-extremity performance were reported in a study that investigated athletes after an alcohol drinking episode and the associated reduced sleep hours. 75 Another study found that alcohol consumption following a simulated rugby game decreased lower-body power output but did not affect performance of tasks requiring repeated maximal muscular effort. 76 However, the same researchers found that alcohol consumption following eccentric exercise accentuated the losses in dynamic and static strength in males. 77

In contrast, alcohol consumption following muscle-damaging resistance exercise did not alter inflammatory capacity or muscular performance recovery in resistance-trained women, 78 suggesting possible gender differences in alcohol’s modulation of exercise performance and recovery. These studies were conducted using healthy volunteers and athletes. Other studies that investigated patients with alcoholic liver disease showed lower muscular endurance, maximal voluntary isometric muscle strength, and total work of knee extensors. 79 Controlled studies are needed, particularly in light of the popularity of binge drinking events frequently associated with collegiate and professional sports.

Neuropathological Consequences

The behavioral and cognitive effects of binge drinking include difficulties in decision-making and impulse control, impairments in motor skills (e.g., balance and hand-eye coordination), blackouts, and loss of consciousness (Figure 3). 80 All of these effects have serious health consequences ranging from falls and injuries to death. 81 In particular, adolescents are vulnerable to the cognitive manifestations and memory loss associated with binge drinking. National estimates suggest that significant numbers of people who binge drink report at least one incident of blacking out in the previous year. 82,83 Blackouts, defined as short periods of amnesia during which a person actively engages in behaviors (e.g., walking or talking) without creating memories for them, often occur at blood alcohol concentrations exceeding .25 g/dL. 84,85 Blackouts are common among college students who drink alcohol. Estimates suggest that up to 50% of students that engaged in drinking reported a blackout episode during the past year. 86,87 The pattern of rapid consumption of large doses of alcohol, frequently on an empty stomach, is characteristic of the adolescent period. 88

The consequences of binge drinking are not short-lived or limited to the period of intoxication. Imaging studies of binge drinking adolescents document long-lasting changes. Reports indicate structural changes in the prefrontal and parietal regions, as well as in regions known to mediate reward, and these changes are thought to reflect long-lasting effects of alcohol bingeing on critical neurodevelopmental processes. 89 Functional imaging studies of the brains of binge drinking and nondrinking adolescents found that binge drinking adolescents showed greater responses in frontal and parietal regions, no hippocampal activation to novel word pairs, and modest decreases in word-pair recall, which could indicate disadvantaged processing of novel verbal information and a slower learning slope. 90 In another study, adolescent binge drinking resulted in gender-specific differences in frontal, temporal, and cerebellar brain activation during a special working memory task, reflecting differential effects of binge drinking on neuropsychological performance and possibly greater vulnerability in female adolescents. 91 Other researchers have reported that degradations in neural white matter were linked with impaired cognitive functioning in adolescents who binge drank. 92

Adolescent rodent intermittent ethanol exposure that modeled human adolescent binge drinking produced a range of pathophysiological and neurobehavioral sequelae, including altered adult synapses, cognition, and sleep; reduced adult neurogenesis; increased neuroimmune gene expression; and increased adult alcohol drinking associated with disinhibition and social anxiety. 93 Preclinical studies indicated that binge drinking could produce brain structural abnormalities. Binge alcohol administration to rodents produced increases in cerebrospinal fluid volume in the lateral ventricles and cisterns, decreased levels of N -acetylaspartate and total creatine, and increased choline-containing compounds, glutamate, and glutamine, all of which recovered during abstinence. 94 Moreover, preclinical data suggested that adolescent binge drinking sensitized the neurocircuitry of addiction, possibly inducing abnormal plasticity in reward-related learning processes, which could contribute to adolescent vulnerability to addiction. 95

Although the effects of chronic alcohol consumption and the mechanisms of tissue injury underlying alcoholic hepatitis and cirrhosis have received much attention, less attention has been focused on the pathophysiological consequences of binge alcohol consumption. The differential duration of the intoxication period, excessive concentrations of alcohol at the tissue level, accelerated alcohol metabolism and generation of ROS and alcohol metabolites, and acute disruption of antioxidant mechanisms are some of the salient differences between chronic and binge-like alcohol-mediated tissue injury. Because of the differences in male and female alcohol metabolism rates, it is possible that greater tissue injury is produced in females who consume alcohol in binge-like patterns. Furthermore, in an aging population already riddled with polypharmacy, there is heightened potential for toxicity during an alcohol binge (Figure 4). Also, pre-existing comorbid conditions such as cardiovascular disease, renal failure, or steatohepatitis may predispose binge drinkers to accelerated tissue injury.

Additional research is needed to better recognize the differential effects of binge, chronic, and binge-on-chronic patterns of alcohol consumption. Animal models that reflect these patterns of alcohol exposure are needed. In addition, greater effort toward documenting a history of alcohol consumption, including the frequency, quantity, and quality of alcoholic beverages consumed, should help us better understand the effects of binge drinking on biological systems.

Acknowledgments

The authors are grateful for editorial support from Rebecca Gonzales and grant support from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) under award number P60AA009803 (LSUHSC-NO Comprehensive Alcohol–HIV/AIDS Research Center).

Disclosures

The authors declare that they have no competing financial interests.

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Teenagers and alcohol

Many young people start experimenting with alcohol during their teenage years, especially when they’re socialising. It can be difficult to strike a balance between keeping your teen healthy and safe and giving them the freedom to experience their teenage years to the fullest. By role modelling moderate drinking behaviours and setting clear expectations, you can teach your teen how to manage the effects of alcohol.

Why do teenagers drink alcohol?

Alcohol plays a significant role in Australian culture, and teens are generally aware of that. Most teens will want to join in on the cultural activities that their peers or role models are doing, so they may drink to celebrate an achievement or to fit in at a party.

If their drinking behaviour becomes excessive or irresponsible, it can have serious consequences. It’s important that teenagers understand the risks associated with alcohol and, if they still choose to drink, to learn ways to do it safely.

What are the effects of teenage drinking on the brain?

Alcohol affects a young brain more than a fully developed adult one. Developmental processes are still happening in the brain until around age 26.

If your teen drinks alcohol, it can cause irreversible changes to their brain, particularly to the area that’s responsible for rational thinking. Damage to this part of the brain before it’s fully developed can lead to learning difficulties, memory problems and impaired problem solving. The longer your teenager delays using alcohol, and the less they drink, the better their brain functioning will be, both now and in later life.

Other risks and effects of alcohol on teenagers

Alcohol can affect how teenagers function, how they recognise risks, and their ability to make good decisions. Underage drinking makes teens more likely to put themselves in risky situations, which may result in harm to themselves or others.

Alcohol is a depressant, which means that it slows down the brain. The more alcohol is consumed, the greater the effect. Other consequences of underage drinking can include:

slurred speech

poor judgement

lack of coordination

slower reactions

heightened sense of confidence

poor sleep.

What are the long-term effects of underage drinking?

The Alcohol and Drug Foundation cite the following as long-term effects of drinking: 

worsening of mental health conditions

poor memory and brain damage

difficulty getting an erection

difficulty having children

liver disease

high blood pressure and heart disease

needing to drink more to get the same effect

physical dependence on alcohol.

What to do if your teenager is drinking alcohol

It’s likely that at some stage your teenager will drink, in spite of all the risks.

The only way to eliminate the risks associated with alcohol use during the teenage years is to encourage your child not to drink. It can be useful to talk to them about the pros and cons of underage drinking, and talk about ways of having just as good a time without alcohol.

But, knowing that your teen will probably be exposed to alcohol, it’s probably more realistic that you set clear boundaries about how they consume it.

Reducing the harmful effects of alcohol on teenagers

Parents can help reduce the harmful effects of alcohol on their teenager by setting clear expectations about what is acceptable and unacceptable drinking behaviour during their child’s early teens and beyond. This conversation is one you’ll have to repeat throughout their teenage years. Set good standards that your teen can learn from by role modelling responsible drinking behaviours yourself .

It’s common for parents to think that if they allow their teenager alcohol in moderation while they’re in a safe environment, such as a glass of wine with dinner at home, this will lead to a better relationship with alcohol. But research tells us this isn’t the case . Parents should actively encourage their teenager to delay drinking any alcohol for as long as possible.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Data science tools for alcohol research.

Elizabeth Powell, Ph.D.

September 07, 2023

The goal is to promote data science concepts and tools in alcohol research, integrating data across disciplines and clinical and basic sciences realms.

Data science has been a major focus of NIH, including the establishment of the Office for Data Science Strategy. Data science approaches have been used to make key findings in other research areas such as cancer and Parkinson’s disease research. The flood of data generated by NIAAA supported studies in genomics, imaging, electrophysiology and optogenetics, electronic health records, and personal wearable devices presents new challenges in analyses and interpretations and opportunities for discovery. Since 2019, NIAAA has required that human research data be stored in the NIAAA Data Archive ( NOT-AA-23-002  for most recent notice).

Statement of Work/Project Objectives

The large databases of biological and behavioral and imaging studies supported by NIAAA provide ample information for data science approaches. However, the investigators lack the tools to participate in the data ecosystem and take advantage of current statistical and computational approaches. The state of the data science field in alcohol research has advanced only slightly since this concept was introduced in 2018. While the scope of the data is broad, many of the tools needed to answer questions in alcohol research require specific applications, algorithms or toolkits that are not currently available. This initiative is expected to:

• Generate intellectual property, analytical tools and methods for alcohol research that interface within modern data ecosystems for use by entire scientific community.
• Promote harmonization of data sets within specific disciplines of alcohol research to improve scientific reproducibility and increase sharing of data across multiple scientific teams.
• Transform fragmented sets of individual data components into a coordinated ecosystem.
• Enable multiscale analysis of clinical and basic science datasets, employ modern data science techniques of artificial intelligence, machine learning and deep learning.
• Promote interdisciplinary collaborations between neuroscientists and data scientists.
• Adapt NIH data science tools and tactics for use in alcohol research.

Justification

The volumes of data produced by NIAAA-supported research, along with publicly available databases and future results, can be analyzed using data science approaches to find new therapeutic targets and approaches for diagnosis and treatment of alcohol use disorder. Data science includes and extends beyond bioinformatics and computational neuroscience to discover new relationships and pathways for complex systems of normal human function and during adaptations due to disorders or disease. Data science is not widespread alcohol research, and thus the field is missing opportunities for discovery and treatment.

The Final NIH Policy for Data Management and Sharing ( NOT-OD-21-013 ) requires data sharing, yet there are limited tools and resources for combining and analyzing data from alcohol research. Since the concept was introduced in 2018, NIAAA has funded two SBIR projects for new algorithms and automated data harmonization and imputation tools. These projects are currently in Phase II. Additional tools and strategies are needed to analyze data from NIAAA research, and tools are needed to make best use of the investment in the NIAAA Data Archive.

niaaa.nih.gov

An official website of the National Institutes of Health and the National Institute on Alcohol Abuse and Alcoholism

Cross-substance Effects of Adolescent Exposure to Alcohol Content in Popular Movies on Cannabis Initiation

• Erin Corcoran, M.S. University of Florida, College of Public Health & Health Professions https://orcid.org/0000-0002-5562-5150
• Tim Janssen, Ph.D. Brown University School of Public Health  https://orcid.org/0000-0003-0012-2609
• Joy Gabrielli, Ph.D. University of Florida, College of Public Health & Health Professions https://orcid.org/0000-0001-8003-6078
• Kristina Jackson, Ph.D. Brown University School of Public Health  https://orcid.org/0000-0001-5449-5473

Objective: Alcohol is the most frequently depicted substance in the media, and adolescent exposure to alcohol in the media predicts alcohol use. There is relatively little research on exposure to cannabis in the media, but exposure to alcohol content may exert cross-substance effects on cannabis use. Given the social and health risks associated with early cannabis use, the present study aims to assess the cross-substance effects of exposure to alcohol media content on age of cannabis initiation. Method: A sample of 830 middle school students (53% female) reported on movie alcohol exposure and cannabis initiation longitudinally until high school completion. Discrete-time survival models examined whether movie alcohol exposure predicted subsequent initiation among students who were cannabis-naïve at baseline, controlling for demographic, social, and behavioral covariates. The interaction between sex and movie alcohol exposure was also explored. Results: One third (33%) of participants reported cannabis initiation with a mean of 5.57 estimated hours ( SD = 4.29) of movie alcohol exposure. A 1-hour increase in movie exposure predicted a significant 16% increased probability of cannabis initiation in models adjusted for demographic variables and a significant 14% increase in models adjusted for demographic, behavioral, and social variables. No differences were observed across sex. Conclusions: Greater adolescent exposure to alcohol content in the media was associated with earlier cannabis initiation above and beyond other etiologically relevant demographic, behavioral, and social variables. The influence of cross-substance media exposures warrants further exploration and should be taken into consideration in the development of preventive interventions for youth substance use.

Author Biographies

Erin corcoran, m.s., university of florida, college of public health & health professions.

Doctoral Candidate, Department of Clinical and Health Psychology

Tim Janssen, Ph.D., Brown University School of Public Health 

Assistant Professor, Center for Alcohol and Addiction Studies

Joy Gabrielli, Ph.D., University of Florida, College of Public Health & Health Professions

Assistant Professor, Department of Clinical and Health Psychology

Kristina Jackson, Ph.D., Brown University School of Public Health 

Professor (Research), Department of Behavioral and Social Sciences

Copyright (c) 2024 Erin Corcoran, M.S., Tim Janssen, Ph.D., Joy Gabrielli, Ph.D., Kristina Jackson, Ph.D.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License .

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Effect of alcohol use on the adolescent brain and behavior

Briana lees.

1 University of Sydney, The Matilda Centre for Research in Mental Health and Substance Use

Lindsay R. Meredith

2 University of California, Los Angeles, Department of Psychology

Anna E. Kirkland

3 American University, Department of Psychology

Brittany E. Bryant

4 Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences

Lindsay M. Squeglia

Adolescence is a particularly vulnerable neurodevelopmental period marked by high rates of engagement with risky alcohol use. This review summarizes the cognitive and neural consequences following alcohol use during adolescence from longitudinal design studies in humans and animals. Findings from human adolescent studies suggest that binge drinking and heavy alcohol use is associated with poorer cognitive functioning on a broad range of neuropsychological assessments, including learning, psychomotor speed, attention, executive functioning, and impulsivity. adolescence is memory, visuospatial functioning, Alcohol use during associated with accelerated decreases in gray matter and attenuated increases in white matter volume, and aberrant neural activity during executive functioning, attentional control, and reward sensitivity tasks, when compared to non-drinking adolescents. Animal studies in rodents and non-human primates have replicated human findings, and suggest cognitive and neural consequences of adolescent alcohol use may persist into adulthood. Novel rodent studies demonstrate that adolescent alcohol use may increase reward responsiveness of the dopamine system to alcohol later in life, as well as disrupt adolescent neurogenesis, potentially through neuroinflammation, with long-lasting neural and behavioral effects into adulthood. Larger longitudinal human cognitive and neuroimaging studies with more diverse samples are currently underway which will improve understanding of the impact of polysubstance use, as well as the interactive effects of substance use, physical and mental health, and demographic factors on cognition and neurodevelopment.

1. Introduction

Adolescence is a critical developmental phase involving significant physical, cognitive, emotional, social, and behavioral changes. Cognitive features of adolescence include heightened reward sensitivity, sensation seeking and impulsive action, and diminished self-control to inhibit emotions and behaviors ( 1 , 2 ). This contributes to the high rates of engagement in risky behaviors, including the initiation and escalation of alcohol use. Adolescent-specific brain developments may predispose young people to be particularly vulnerable to the potentially serious and long-lasting alcohol-related consequences ( 3 ).

Cross-sectional design studies have established a relationship between adolescent alcohol use, brain development, and cognitive function ( 4 ). Over the past decade, researchers have attempted to understand the direction of this relationship. Considering that it would be highly unethical to randomize youth to different alcohol-using groups, human research is limited to natural observational studies. This makes it difficult to discern correlational from causal findings. Prospective, longitudinal designs have been used to help delineate between pre-existing alterations and post-alcohol effects on brain development by assessing youth before they have ever used alcohol or other drugs and continuing to assess them over time as a portion of the participant population naturally transitions into substance use. This design allows for examination of normal developmental neural trajectories in youth who have never used alcohol or drugs during adolescence, and compares their brain maturation to youth who transition into substance use.

A recent review summarized potentially pre-existing neurobiological markers of alcohol use in humans ( 5 ). While previous reviews have explored the neurobiological consequences of alcohol use, limitations exist. Some previous reviews have summarized studies examining the impact of one adolescent drinking pattern ( 4 ), or one study type (i.e., neuropsychological studies ( 6 ), neuroimaging studies ( 7 )). Broader, more inclusive, reviews on the effects of alcohol use exist, although they require updating due to the rapidly expanding evidence base ( 8 , 9 ). The aim of this review is to therefore provide an update on the growing literature by summarizing the neural and cognitive consequences of varying patterns of alcohol use during adolescence, from prospective longitudinal studies in humans, rodents and non-human primates. In order to provide a broader context of the neural and cognitive consequences of alcohol use, this review begins with an overview of adolescent brain development, and the global prevalence rates of adolescent alcohol use before summarizing the effects of adolescent alcohol use on the brain and behavior from both human and animal studies. A focus has been placed on neuroimaging, neuropsychological, and neurophysiological studies as a means to provide a better understanding of the underlying neurobiological consequences of early alcohol use. Findings from cross-sectional studies are not included.

2. Overview of the adolescent brain

The brain undergoes significant neurodevelopment during adolescence, with maturation continuing until around age 25 ( 10 , 11 ). Brain gray matter, which includes mostly nerve cell bodies and dendrites, tends to decrease during normal adolescent brain development via removal of weak synaptic connections and changes in the extracellular matrix ( 11 – 16 ). Concurrently, white matter volume and white matter integrity increase over this period with continued myelination of axons, allowing for more efficient communication between brain regions ( 17 – 20 ). Some research suggests that through this process, distributed connectivity and circuitry between distant brain regions is increased relative to more local connectivity ( 21 – 23 ); however, this finding has been debated ( 24 ).

Various regions of the brain have time-varying developmental trajectories, with lower order sensorimotor regions maturing first, followed by limbic regions important for processing rewards, and frontal regions associated with higher order cognitive functioning developing later in adolescence and young adulthood ( 15 , 16 , 25 , 26 ). Adolescent brain developmental trajectories tend to differ by sex, with female brains developing one to two years earlier than males. For instance, cortical gray matter reaches peak thickness in the parietal lobes at ages 10 (female) and 12 (male), and in the frontal lobes at ages 11 (female) and 12 (male). Although this pattern is reversed for the temporal lobes, which reaches maximal thickness at ages 16 (male) and 17 (female; 17).

Neurotransmitter systems, which transmit chemical signals across synapses, also undergo significant change in adolescence. Dopamine projections to the limbic and frontal regions often peak during adolescence ( 27 , 28 ). This is associated with amplified neural sensitivity following rewards, compared to adulthood ( 29 , 30 ). Inhibitory control is generally lower in adolescence than adulthood, reflecting greater excitatory synapses and less GABAergic inhibitory neurotransmitters in higher-order frontal regions, with the ratio reversing in later adolescence and into adulthood ( 31 ). Reward hypersensitivity in combination with low inhibition is thought to increase adolescents’ drive for risky and novel experiences, such as alcohol use ( 30 , 32 ). Neurotoxin exposure, particularly alcohol use, during adolescence can affect healthy brain development, with even minor changes in neurodevelopmental trajectories affecting a range of cognitive, emotional, and social functioning ( 4 ). Alcohol use during adolescence could therefore set the stage for cognitive problems into adulthood, conferring functional consequences throughout life.

3. Global prevalence of adolescent alcohol use

Alcohol use among adolescents is heterogeneous, ranging from low, normative use to heavy, pathological use. Alcohol is the most frequently used substance, as it is generally the easiest for adolescents to access ( 33 ). The average age of initiation for alcohol use among US and Australian adolescents is 15 years ( 34 , 35 ). Across Europe, most adolescents begin drinking alcohol between ages 12 and 16, with 25% of adolescents in this region first consuming alcohol by age 13 ( 36 ). The worldwide estimate of adolescents (age 15–19) who drank alcohol in the past month is 27%, ranging from 1 to 44% across countries ( Figure 1 ; 33 ). Higher rates of past month adolescent drinking occur in higher income countries; the highest rates are observed in the European region (44%), and the lowest rates are observed in the Eastern Mediterranean region (1.2%; 33 , 37 ). Past month alcohol use among adolescents in other countries ranges from 38% in the Americans and Western Pacific regions, to 21% in Africa and Southeast Asia, and 14% in Japan ( 33 , 38 ).

Prevalence of current alcohol use and binge drinking in adolescents aged 15 to 19. In this data, binge drinking was defined as 60+ grams of pure alcohol (~4 standard US drinks) on at least one occasion per month ( 33 ).

It is also important to consider common drinking patterns among adolescents, therefore many studies use the alcohol use classification summarized in Figure 2 ( 39 , 40 ). While rates of heavy drinking are highest among young people aged 20 to 24, heavy alcohol use among adolescents remains a concern. Binge drinking is a pattern of alcohol use that raises blood alcohol concentration (BAC) levels consumption of four or more standard drinks for females and five or more drinks for to 0.08 g/dL, which typically occurs after the males within a two hour period ( 39 ). Binge drinking in young people aged 15 to 19 is particularly prevalent ( Figure 1 ), with global estimates of 14% reporting this drinking pattern over the previous month ( 33 ). The highest rates of binge drinking are in the European region (24%; 33), particularly in Austria, Cyprus, and Denmark where more than 50% of students report this binge drinking pattern ( 41 ). In the US, 4% and 14% of US adolescents aged 14 and 18, respectively, report binge drinking in the previous two weeks ( 42 ). Similarly in Australia, 2% and 17% of 14 and 17 year olds report binge drinking in the previous week ( 43 ). Approximately 13% of adolescents in Africa and 10% of adolescents in South East Asia report past month binge drinking ( 33 ).

Alcohol use classification chart.

1 Binge drinking is typically ≥4 drinks within 2 hours (females) and ≥5 drinks within 2 hours (males), where the blood alcohol concentration (BAC) level rises to 0.08 g/dL ( 39 ). The chart is based on the National Institute on Alcohol Abuse and Alcoholism, and Substance Abuse and Mental Health Services Administration levels of alcohol use definitions ( 39 , 40 ).

As noted previously with neurodevelopment trajectories, gender differences are also reported in alcohol use estimates. Worldwide estimates of alcohol use also show higher rates of drinking occur among young males than females ( 33 ). Globally, 22% of males and 5% of females binge drink during adolescence. When focusing on country-specific adolescent binge drinking, rates are reported as 36% of males and 12% of females in Europe; 30% of males and 6% of females in the Americas and Western Pacific Regions; and approximately 17–21% of adolescent males and 3–4% of adolescent females binge drink in Africa and South East Asia.

Overall, these general and gender-specific in general alcohol use prevalence rates represent a recent decline and binge drinking that parallels an increase in the number of adolescents who abstain from alcohol use altogether ( 44 – 47 ). Despite these declines, adolescent alcohol consumption remains a major public health concern. There is clear evidence that adolescent alcohol use is associated with a wide range of adverse outcomes in both the short and long term. Negative consequences of adolescent alcohol use include gradual attrition of cognitive functions and aberrant neural development trajectories ( 4 ).

4. Adolescent alcohol effects on the human brain

Prospective longitudinal neuropsychological, neuroimaging, and neurophysiological studies have identified cognitive and neural consequences directly related to initiation and escalation of adolescent alcohol use. Overall, adolescent alcohol use has been found to negatively affect cognition, brain structure, and function ( Table 1 ); however, the level to which alcohol use and different patterns of drinking affects male and female brain functioning has been debated. Research in this field is also limited to natural observational studies, and it is common for a portion of adolescents to use multiple substances (e.g., alcohol and cannabis use). While studies may try to statistically control for other drug use to parse the relative contribution of alcohol use on brain functioning, this method is imperfect given the high collinearity between alcohol and other drug use variables as well as potential interactive effects. Longitudinal studies with very large sample sizes are currently underway and may help to answer these important issues ( 48 – 50 ).

Summary of consequences of adolescent alcohol use in humans and rodents

Neuropsychological consequences of alcohol use

Neuropsychological test batteries enable tracking of cognitive skills over time to detect potential effects of alcohol use on cognition and intellectual development. Alcohol-induced deficits are arguably even more impactful for adolescents than adults, given that educational attainment, learning, and ongoing neural development are the most critical developmental tasks of adolescence. Notably, alcohol use behaviors at ages 12 to 14 predict lower educational achievement in later years, even after accounting for confounding factors such as sex and externalizing behavior ( 51 ). A recent meta-analysis of cross-sectional studies reported adolescent binge drinking was associated with an overall cognitive deficit and specific impairments in decision-making and inhibition ( 4 ). Herein, we report on longitudinal studies that have identified potential negative effects of adolescent binge drinking and heavy alcohol use on memory, learning, visuospatial function, executive function, reading ability and impulsivity.

The Avon Longitudinal Study of Parents and Children is an ongoing population-based study in the UK. Utilizing data from 3,141 adolescents, frequent binge drinkers exhibited poorer working memory compared to the low alcohol group. However, this association was attenuated when adjusting for sociodemographic variables, tobacco, and cannabis use ( 52 ). In a sample of 89 young people who did not have a history of psychiatric disorders and did not regularly consume other drugs, consistent binge drinking over two years in late adolescence was associated with poorer immediate and delayed recall, retention, and working memory, compared to non-binge drinkers ( 53 ). Conversely, a four-year study of 234 adolescents unexpectedly found that more alcohol use predicted better working memory, driven largely by a relationship between recent blackout history and auditory attention scores, when controlling for age, socioeconomic status, abstinence, gender, and baseline performance ( 54 ). Although, this was in contrast to other findings in this study which demonstrated that more alcohol use days predicted worse verbal memory and visuospatial ability. Approximately 40% of the cohort had tried cannabis, and 18% had tried other illicit drugs. No follow-up tests supported the unexpected working memory finding, such as removing gender and other covariates from the regression models. The authors conclude that unreliability of self-report alcohol use data may have also contributed to the unexpected result. A study using eight years of data from 2,226 youth in the Tracking Adolescents’ Individual Lives Survey (TRAILS) found that light and heavy adolescent alcohol use was not associated with deterioration in executive functioning, compared to no alcohol use, when controlling for baseline performance, age, and tobacco use ( 55 ). A four-year study of 92 adolescents found low alcohol consumption was associated with subtle improvements in inhibitory control ( 56 ). No negative effect of low-level alcohol use on the development of school grades, spatial working memory or rapid visual processing was found. Therefore, binge drinking may have specific detrimental effects on executive functioning, in comparison to lighter doses. Inconsistent findings may also partly reflect psychiatric and other substance use comorbidities.

A 10-year longitudinal study followed heavy alcohol using and control youth from age 16 until early adulthood (~age 25). Youth diagnosed with a psychiatric disorder, besides conduct disorder, were excluded from the study at intake. Heavy alcohol use and withdrawal symptoms were associated with worsening verbal memory and learning over time ( 57 , 58 ), as well as relative declines in visuospatial function ( 58 ). Heavier use patterns, and greater hangover and withdrawal symptoms over time were related to worse cognitive functioning, suggesting a dose-dependent relationship between alcohol use and cognitive functioning ( 57 ). Dose-dependent relationships between alcohol use and cognitive impairment have been replicated in other studies. Higher total life-time drinks predicts escalated impulsive choice ( 59 ), and poorer cognitive flexibility, verbal recall, semantic clustering, and reading skills ( 60 ). Higher drinking days over a four-year period predicted worse verbal memory and visuospatial ability ( 54 ). Higher estimated peak BAC over six years predicted worse verbal learning, and immediate, short and long-term delayed and cued recall ( 61 ). Greater post-drinking effects predict worse psychomotor speed ( 54 ), and more withdrawal symptoms over the past month are associated with greater decrements in cognitive functioning ( 60 ). Overall, heavy alcohol use during adolescence has been associated with a range of cognitive deficits, with some cognitive domains showing dose-dependent relationships where greater alcohol use is associated with poorer cognitive functioning (see Table 1 ).

Sex-related neuropsychological consequences of alcohol use

Adolescent alcohol use may differentially impact male and female cognitive function, furthering the implications of noted gender differences within brain development and alcohol use estimates. A five-year longitudinal study followed 89 young adolescents from ages 14 to 19, where a portion transitioned into moderate (14%) or heavy (33%) alcohol use ( 62 ). Conduct disorder was present in 15% (female) and 39% (male) of drinkers, and 0% of controls. Drinkers had consumed alcohol at moderate or heavy levels for an average of 2.8 years since initiation (SD=1.3). For females, more drinking days in the past year predicted a greater reduction in visuospatial performance from baseline to follow-up. For males, a tendency was seen for more hangover symptoms in the previous year to predict relative worsening of sustained attention. While drinkers had used cannabis and other drugs, these substances did not predict any change in cognitive functioning. A six-year study followed 155 older adolescents from age 18 every 22-months. Consistent binge drinkers, who continued to engage in binge drinking behavior throughout the entirety of the study, represented 35%, 23% and 10% of the sample at first follow up one, two and three, respectively. Consistent binge drinkers presented difficulties in immediate and delayed recall, with similar deficits for males and females compared to controls ( 63 ), while no disadvantage for either sex was observed for decision-making ability ( 64 ). This suggests that some cognitive domains may be differentially impacted in adolescent males and females who drink, while other domains may be similarly affected. Further longitudinal research on sex differences in other cognitive domains known to be affected by alcohol use (i.e., learning, executive functions, impulsivity) should be conducted.

Structural brain consequences

Adolescent alcohol-induced alterations in neurodevelopmental trajectories (including accelerated decreases in gray matter volume, attenuated increases in white matter volume and density, and poorer white matter integrity) may underlie some long-term cognitive deficits. Here, longitudinal studies reporting on structural brain changes following alcohol use in adolescence are discussed. The National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) is a nationally representative prospective longitudinal study being conducted in the US, designed to disentangle the complex relationships between onset, escalation, and desistance of alcohol use in adolescence and neuromaturation ( 50 ). At baseline all adolescents were no/low alcohol, tobacco, cannabis and other drug use consumers. Approximately 50% of the cohort endorsed ≥1 externalizing and ≥2 internalizing symptoms. By the two-year follow-up assessment, 356 participants were no/low alcohol consumers, 65 had initiated moderate drinking, and 62 had initiated heavy drinking ( 65 ). Adolescents who remained no/low alcohol consumers served as a control group for estimating typical developmental trajectories over the same age range as the drinkers. Youth who initiated heavy drinking showed abnormal neurodevelopmental trajectories compared to continuously non-/low-drinking controls with accelerated decreases in frontal gray matter volume. Marginal differences in frontal gray matter were also observed in moderate drinkers, and although not significant, their intermediate position between no/low and heavy drinkers suggests a dose-dependent effect ( 65 ). By the three- to four-year follow up assessment, 328 youth were no/low drinkers, 120 were moderate drinkers and 100 were heavy drinkers ( 66 ). Moderate and heavy drinkers continued to exhibit altered neurodevelopmental trajectories, including accelerated cerebellar gray matter declines, white matter expansion, and cerebrospinal fluid volume expansion relative to controls. Cannabis co-use did not contribute to these effects ( 65 , 66 ).

These findings replicate earlier longitudinal studies with smaller sample sizes showing adolescent heavy drinkers had altered neurodevelopmental trajectories, including accelerated decreases in gray matter in frontal and temporal lobes ( 67 – 69 ), and attenuated increases in white matter growth over time of the frontal, temporal and occipital lobes, cingulate, corpus callosum, and pons, compared to non-using controls ( 67 , 69 ). A prospective four-year study measured within-subject changes in brain volume for males and females. Heavy-drinking males and females showed similar deviations in neural developmental trajectories compared to continuously non-drinking controls, including accelerated decreases in gray matter volume (particularly in frontal and temporal regions), and attenuated increases in white matter volume over the follow-up, even after controlling for cannabis and other substance use ( 67 ).

In a sample of 113 alcohol-naïve adolescents aged 11 to 16 at baseline, 45 went on to binge drink before turning 21. Binge drinking throughout adolescence predicted altered frontostriatal white matter microstructural development when compared to developmental trajectories of non-using healthy adolescents ( 70 ). Three studies examining adolescents who used alcohol and cannabis showed these youth had consistently poorer white matter integrity across 7 to 20 clusters compared to controls, as well as poorer cognitive functioning over an 18-month ( 71 ) to three-year period ( 72 , 73 ). Mixed findings were reported for the specific effects of alcohol, with two studies reporting that heavy drinking predicts worsening white matter integrity ( 71 , 72 ) with either no effect ( 71 ) or added effect ( 72 ) of co-occurring cannabis use. A third study reported that white matter integrity effects were driven by heavy cannabis initiation ( 73 ). The right superior longitudinal fasciculus, connecting the frontoparietal-temporal networks, was the only consistent white matter tract across studies to show poorer white matter integrity among alcohol users compared to control.

Overall, binge and heavy drinking appears to affect the normal developmental trajectories of gray and white matter maturation during adolescence, particularly in the frontal and temporal lobes, and interconnecting networks. Some studies have reported accompanying cognitive deficits alongside aberrant neurodevelopmental trajectories. Patterns observed among alcohol-using youth may represent accelerated but non-beneficial pruning of gray matter, attenuated connective efficiency of white matter tracts, or alternatively, premature cortical gray matter decline similar to volume declines related to accelerated aging in adult alcoholics ( 74 ) or even “normal” aging ( 75 , 76 ). Adults who engage in sustained problematic drinking exhibit similar structural alterations and have speeded gray and white matter decline, which suggests alcohol use is associated with accelerated brain aging ( 74 , 75 , 77 ). Existing studies tend to group youth by “drinkers” versus “controls”. To address this methodological limitation, the Adolescent Brain Cognitive Development (ABCD) Study is underway with a larger sample size (~12,000) which will allow more nuanced investigation of the dose-dependent effect of alcohol on neural development ( 48 , 78 ).

Functional brain consequences

Task-based functional neuroimaging studies measure brain activation by detecting changes in blood direction while participants complete tasks. These studies can help link structural brain changes with behavioral and cognitive deficits following alcohol initiation in adolescence. Functional neuroimaging studies have identified potential effects of alcohol use on adolescent brain activation during tasks of working memory, inhibitory control, and reward sensitivity. In a longitudinal study, 40 12- to 16-year-old adolescents were scanned before they ever used alcohol or drugs and then were rescanned approximately three years later ( 79 , 80 ). In total, 15% of adolescents who transitioned into heavy drinking by late adolescence presented with conduct disorder. These heavy drinking adolescents showed less baseline brain activation in frontal and parietal regions during a visual working memory ( 79 ) and inhibition task ( 80 ) when compared to controls. Neural activation during these tasks increased from baseline to follow-up in youth who initiated drinking compared to decreased activation in those who remained abstinent over the follow-up. This suggests that youth who initiate heavy drinking may require more executive cognitive control to perform at the same level as non-users.

Heavy alcohol use may also affect reactivity and sensitivity to reward. Adolescent binge drinking was associated with less cerebellar ( 81 ) and dorsal striatum ( 82 ) activation during a monetary reward and decision making task, respectively. More drinks per drinking day predicted less activation within these regions among binge drinkers ( 81 ). This suggests binge drinking may affect the emotional component of reward processing and decision making, as damage to the posterior cerebellum has been associated with cognitive and emotional deficits ( 83 ), while the dorsal striatum is integral to incorporating emotional information into reward and decision-making ( 84 ).

Neurophysiological studies conducted in Spain over a two-year period have measured event-related potential (ERP) components among consistent binge drinking and non-binge drinking youth during inhibitory and complex attention tasks ( 85 – 87 ). In separate studies of 38 to 57 participants, consistent binge drinkers exhibited increased P3 amplitude (related to working memory and inhibitory control) in the central, parietal and frontal regions, as well as increased activation in the prefrontal cortex and insula during inhibitory responses, compared to non- or low-drinkers ( 86 , 87 ). Consistent binge drinkers also reported increased P3b amplitude in the central and parietal regions during an attentional control task compared to controls, with more pronounced differences observed after two years of consistent binge drinking ( 85 ).

Taken together these studies suggest that neural differences are observable as a consequence of alcohol use, mirroring the behavioral findings from neuropsychological and neurostructural studies. Functional changes were not examined in relation to neuropsychological deficits; thus, it is not possible to infer whether changes in neural response were related to poorer cognitive outcomes. Sex differences in neural activation following the uptake of alcohol use in adolescence remains unknown. Of note, these functional findings come from small samples (< 30 drinkers in each study) and include mostly Caucasian participants from high socioeconomic status groups. More longitudinal fMRI and ERP studies in larger, more diverse samples are needed to better understand the specific effect of alcohol on neural functioning in adolescence.

Neurobiological consequences: Integrating findings from human studies

Determining how adolescent alcohol use may lead to overt cognitive and behavioral deficits is critical, and early structural and functional brain changes may help us understand this relationship. Following adolescent alcohol initiation, structural brain changes appear to occur. Studies have consistently reported accelerated decreases in gray matter volume and attenuated white matter growth of the frontal and temporal lobes, with poorer white matter integrity throughout related networks ( 65 – 73 ). The frontal lobe is thought to be critical for higher-order cognitive control, and the temporal lobe plays an important role in learning and memory ( 88 , 89 ). Damage to these regions may result in overt cognitive impairments. Likewise, neuropsychological studies demonstrate a possible dose-dependent response of alcohol use on executive functioning ability ( 53 , 55 ) and learning and memory ( 54 , 60 , 61 ). Preliminary functional neuroimaging and neurophysiological research complements findings from neuropsychological and structural neuroimaging studies; transitions into heavy alcohol use and binge drinking result in increased neural activation in fronto-parietal regions during executive functioning and attentional control tasks ( 79 , 80 , 85 – 87 ). This suggests that heavy alcohol use initiation and continuation may have a cumulative effect on brain activity, and anomalous activity may reflect degradation of underlying attentional and executive functioninging mechanisms. Heavy drinkers may therefore require more executive cognitive control to perform at the same level as non-users. Overall, integration of human neuroimaging, neuropsychological, and neurophysiological studies suggest that moderate to heavy alcohol use may initially result in structural brain changes, and with heavier binge doses, the resulting neural impairments may lead to more overt functional consequences (i.e., cognitive functioning deficits).

It is important to note that previous reviews illustrate that pre-morbid cognitive and neural vulnerabilities predispose some adolescents to initiate, and misuse, alcohol ( 4 , 5 ). Presently, it is not clear whether neurobiological deficits are the direct results of adolescent alcohol use, irrespective of predispositions, or whether those youth exhibiting vulnerability markers prior to alcohol initiation then experience worse neurobiological outcomes following uptake. Larger prospective longitudinal studies that are currently underway will help disentangle these complex relationships ( 48 , 78 ).

5. Cognitive and neural functioning following alcohol remittance

Studies have examined the effects of alcohol remittance (i.e., discontinuation of alcohol use) in adolescence on cognitive and neural functioning. A 10-year study found remitted youth, who had previously met criteria for an alcohol use disorder, performed similarly to youth with persistent disorders on tasks measuring visuospatial functioning and language abilities ( 58 ). The majority of youth in this study also met criteria for at least one other substance use disorder. Similarly, no improvements were reported for immediate or delayed recall in a sample of 20 young people who had stopped binge drinking for two years ( 63 ). However, another two-year study which included 16 ex-binge drinkers found some improvement in delayed recall which reflected an intermediate position between binge and non-drinkers at age 21 ( 53 ). Longer-term abandonment of binge drinking (two to four years) in healthy older adolescents who occasionally report cannabis and/or tobacco use, was associated with improvements in immediate recall which matched non-drinking control performance ( 63 ), and improvements in long-term memory ( 63 ) and working memory ( 90 ) which again reflected an intermediate position between binge and non-drinkers.

One functional neuroimaging study reported that, after one month of abstinence, adolescents who previously drank heavily no longer exhibited alterations in reward activation to alcohol cues, highlighting the potential for adolescents to benefit from early intervention and recover from the short-term effects of alcohol ( 91 ). Overall, these results provide mixed evidence as to whether cognitive functioning in adolescents who drink heavily can be modified or improved after abstinence, reductions in drinking, or treatment. While there is preliminary support that abstinence may be related to recovery in brain functioning, more evidence is required. Future research is needed to clarify when cognitive and neural recovery is most likely, and if certain cognitive and neural domains are more malleable than others following changes in substance use. This knowledge will benefit practitioners working with adolescents and can ultimately inform alcohol use treatment practices.

6. Adolescent alcohol effects in animals

Human research is limited to natural observational studies which have typically assessed youth into early adulthood at the latest. Conversely, researchers have much higher levels of control over experimental conditions in animal studies, including frequency, amount and duration of alcohol exposure, and have often assessed rodents or non-human primates into late adulthood after the termination of alcohol use. Therefore, animal studies can provide helpful insight into knowledge gaps from human literature on consequences of adolescent alcohol use. Notably, much of the work using rodent models has been conducted only in males; where possible, rodent research testing both sexes is reported.

Comparable cross-species findings

Animal studies can never completely reproduce all human features, and there have been notable differences in analyses used to examine the consequences of alcohol use on the adolescent human (e.g., cognitive, neuroimaging) and rodent brain (e.g., molecular, cellular). However, rodent studies have started to use measures that are similar to those used in human studies, and have provided evidence for cross-species similarities in findings. Partly consistent with human research, cognitive studies in male rodents have shown that adolescent alcohol use predicts poorer executive functioning in adulthood, including cognitive flexibility ( 92 , 93 ), set shifting ( 94 ), and extinction of responses following termination of reinforcer cues ( 94 – 96 ). Adolescent alcohol use in male rodents has also been associated with poorer inhibition, reflecting heightened impulsivity and risk taking in adulthood ( 94 , 95 , 97 – 100 ). Similar to human studies, moderate alcohol use and binge drinking in male and female rodents predicts alterations in learning and memory during adolescence ( 101 – 103 ), however this may have minimal effects on later learning and memory in adulthood ( 104 , 105 ). In terms of neural consequences of adolescent alcohol use, adult male and female rodents show attenuated neurodevelopment, including reduced volume in the corpus callosum ( 106 ), attenuated thickness in frontal regions ( 107 ), decreases in connectivity between frontal regions, the nucleus accumbens and dorsal striatum ( 108 ), poorer white matter integrity ( 106 , 109 – 112 ) and impaired synaptic plasticity ( 101 ), similar to human adolescent studies. Interestingly, greater volume reductions were predictive of later relapse drinking in adult rats ( 106 ). Experimental rodent studies also support cross-sectional findings in human studies ( 113 , 114 ) that females may be more vulnerable than males to the neurotoxic effects of alcohol ( 106 ).

Non-human primate findings parallel rodent and human findings. In a recent study, rhesus macaques were imaged before and after one year of alcohol exposure. Findings showed that brain volume increased in controls throughout adolescence into early adulthood; however, heavy drinking macaques showed reduced rates of brain growth over the follow-up period, particularly in white matter regions and the thalamus, in a dose-dependent fashion ( 115 ). These structural changes may be associated with cognitive aberrations continuing into adulthood.

Adolescent versus adult alcohol use in rodents

Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adulthood are generally less pronounced than after comparable alcohol exposure in adolescence ( 116 ). Adolescents are less sensitive than adults to many of the intoxicating alcohol effects that serve as cues to stop drinking, such as alcohol’s motor-impairing, sedative, social-inhibiting, and hangover-inducing effects ( 117 ). Comparatively, adolescents are more sensitive than adults to desirable consequences of low levels of alcohol use, including social facilitation and rewarding effects ( 117 ). Rodent studies show that as adults, former adolescent alcohol-exposed animals still exhibit ‘adolescent-like’ insensitivities to alcohol’s motor-impairing, sedative, and taste aversive effects ( 118 – 120 ), while retaining adolescent-typical increased sensitivities to alcohol’s rewarding effects ( 119 , 121 ). This may contribute to consistent drinking patterns from adolescence into adulthood.

Novel rodent findings

Rodent studies provide novel insight into areas which have not yet been studied in great detail in humans, such as effects of adolescent alcohol use on neurotransmitters, neurogenesis, and neuroinflammation. There are marked developments that occur in the dopamine neurotransmitter system during adolescence, important for reward-motivated behavior. Limited human research shows dopamine system development is disrupted following alcohol use, although most studies have focused on older, alcohol-dependent adults ( 122 ). Findings from rodent studies suggest the dopamine system is particularly sensitive to the effects of alcohol use during adolescence (for review, see 123). Following alcohol use, adolescent male rodents show increased GABA inhibitory tone on the dopamine system neurons in the nucleus accumbens ( 124 ). This decreases tonic dopamine tone and increases phasic dopamine responses to rewarding and risky activities, and in turn, appears to increase risky decision-making following alcohol use. Preliminary evidence also suggests these dopamine system changes enhance later reactivity to the rewarding, but not harmful, effects of alcohol ( 123 ), although this requires further investigation in both animal and human studies.

Adolescent alcohol use also appears to disrupt other neurotransmitter systems, including the cholinergic system of the basal forebrain ( 116 ). These neurons play critical roles in cognitive functions, including learning and memory. Multiple studies show that repeated alcohol use during adolescence reduces the number of neurons showing immunoreactivity to choline O-acetyltransferase (ChAT) in the basal forebrain ( 92 , 99 , 107 , 125 – 127 ). This decline in ChAT immunoreactivity is associated with greater disinhibitory behavior ( 99 ), increased risky behavior ( 125 ), and decreased performance on set-shifting tasks ( 127 ) in adulthood following alcohol remittance. This suggests adolescent alcohol use leads to loss of cholinergic tone which has lasting functional consequences.

Neurogenesis involves formation of new neurons and integration into functional neural networks, which is a critical component of nervous system development ( 128 ). Rates of neurogenesis are influenced by environmental factors. Repeated alcohol use in adolescence, but not adulthood, decreases neurogenesis ( 129 ), and such changes may be evident long after alcohol use has stopped ( 129 – 131 ). The mechanisms underlying neurogenesis disruptions following adolescent alcohol use remains unclear. One suggestion is the suppression of neurotrophins, such as brain-derived neurotrophic factor (BDNF), which is a regulator of the survival and differentiation of newly generated neurons. Adolescent alcohol use appears to decrease BDNF expression in the hippocampus and interrupts neurogenesis ( 132 – 135 ). Further evidence of the role of BDNF in neurogenesis disruption comes from a study where a BDNF agonist was administered to male rodents previously exposed to alcohol ( 133 ). Administration resulted in neurogenesis, and reversed depression-like symptoms observed during alcohol withdrawal and abstinence following repeated alcohol use in adolescence.

Repeated exposure to alcohol during adolescence also induces long-lasting neural and behavioural changes via the induction of neuroinflammation. Alcohol stimulates the release of innate pro-inflammatory cytokines that can disrupt synaptic plasticity and lead to neuropathology and cell death ( 136 , 137 ). Studies including male and female mice demonstrate that females are more vulnerable than males to the neuroinflammatory effects of alcohol ( 138 ). Rodent studies have examined ways to reduce neuroinflammation caused from adolescent alcohol use. For instance, administration of a neuroimmune drug, ibudilast, reduced alcohol drinking in dependent male rodents by 50% ( 139 ), and administration of an anti-inflammatory drug, indomethacin, prevented cell death, and reduced cognitive and motor deficits that were evident after adolescent alcohol exposure ( 140 ). Furthermore, female rodents with altered gene expression of TLR4, which reduced inflammatory activation following alcohol use, did not show behaviors consistent with adolescent alcohol use, such as anxiety and heightened reward sensitivity to alcohol ( 141 ). Overall, animal studies provide evidence of lasting impacts of adolescent alcohol use into adulthood, with growing evidence of retention of adolescent-like phenotypes.

7. Future directions and conclusions

Recent prospective, longitudinal designs have greatly increased our knowledge of the complex relationship between adolescent brain development and alcohol use by parsing out the pre-existing vulnerabilities from the consequential effects of use ( 142 ). However, with high heterogeneity in patterns of alcohol and other substance use during this critical neurodevelopmental period, more research is needed to determine what developmental processes and cognitive domains may be most responsive to prevention and treatment initiatives. The larger multi-site studies currently underway (e.g., ABCD, NCANDA) will hopefully help disentangle the complicated picture of substance co-use, the interactive effects of adolescent substance use and psychopathology, sex and other demographic factors, health habits, and genetic vulnerabilities, among other important factors related to substance use. It is necessary to understand substance-specific effects, especially given growing US legalization and rise in rates of cannabis use, the dramatic rise in adolescent e-cigarette use, and global concerns regarding opioid dependency and associated deaths. These larger studies are positioned to differentiate the specific neural developmental effects of alcohol as well as cannabis, tobacco, e-cigarettes, opioids, cocaine, hallucinogens, and amphetamines. Future studies also need to make concerted efforts to enroll more adolescents with diverse backgrounds, as substance use effects may not generalize across ethnicities and cultures (most research to date has been in Caucasian youth from upper middle class families), various family structures, or psychopathology profiles. This knowledge will benefit practitioners working with adolescents, and hopefully, inform future substance use prevention and intervention initiatives

Better understanding the dose-dependent effects of substances will enable improved public health information to inform policies regarding limiting amounts of adolescent use and controlling potency of substance-containing products. Specifically, it will be useful to know how adolescent binge drinking compared to lower levels of drinking differentially affects cognition and behavior. Additionally, a greater understanding of short compared to longer-term neural and cognitive effects of alcohol use and remittance in adolescence through to adulthood is needed to better inform treatment. Researchers are starting to track these changes in short and longer-term effects using neural markers of substance use to better understand how an individual is responding to treatment ( 143 ). Targeting cognitive makers of substance use through cognitive retraining treatment strategies has demonstrated some success in reducing alcohol use ( 144 ), as well as in a range of clinical populations including various substance use disorders ( 145 ). Researchers are also beginning to investigate the effectiveness of cognitive training as a prevention initiative for adolescent substance use ( 146 – 148 ), although early findings suggest this method may need to be supplemented with a substance use prevention program ( 149 ).

Of note, all of the human longitudinal studies in this review relied on youth self-report of substance use. Some of the existing studies also used ranges for self-report questionnaires, which weakens the ability to understand dose-dependent relationships. Substance use researchers are beginning to incorporate real time measures via smart phone technology, more sophisticated biological markers (i.e., blood, urine, saliva, and hair samples), as well as daily reporting or real-time tracking of drug use through youths’ smart phones and wearable devices ( 150 ). These nuanced tools will help improve the accuracy and reliability of reports to better quantify the frequency and amount of alcohol consumed. Better neuroimaging standards, such as scanning under neutral conditions to control for factors like time since last alcohol use, and more consistency in measures used to assess cognitive functioning are also suggested as an area of future research.

Cross-species findings show comparability in effects of alcohol use on the adolescent brain and behavior, and novel experimental rodent studies on the consequences of alcohol use can guide future work in human adolescents. For instance, researchers are now focused on quantification of various neurochemicals and transmitters in the brain measured through Magnetic Resonance Spectroscopy (MRS; ( 151 ). Understanding such neurochemical changes could help us better understand the neurobiological effects of substance use, the mechanisms of change, and alterations incurred through psychotherapy or pharmacological treatment.

Overall, it is clear that adolescent alcohol use is associated with neural and cognitive consequences (see Table 1 for summary). Drawing on the most recent longitudinal studies, this review has integrated findings from human neuropsychological and neuroimaging studies, and the animal literature. Neurobiological research suggests a dose-dependent relationship may occur between alcohol use with brain differences and cognitive deficits. Structural and functional brain changes may initially occur following moderate to heavy alcohol doses, while more overt cognitive deficits may be the result of neural insults from heavy and binge doses. Future longitudinal studies should examine the mediating role of brain structure and function on associations between adolescent alcohol use and cognitive and behavioral consequences. Emerging work has begun to characterize the time-limited and potentially recoverable, versus persisting neural and cognitive effects of alcohol use. Current findings and future research has the potential to significantly improve global health by informing the development of prevention and intervention strategies to address alcohol mechanisms associated with neural and cognitive consequences in adolescence.

• Adolescence is a critical neurodevelopmental period marked by rising alcohol use.
• This review summarizes the neural and cognitive effects of alcohol use.
• Adolescent alcohol use is related to changes in brain structure and function.
• Heavy alcohol use is associated with poorer cognitive functioning.

This work was supported by the National Health and Medical Research Council (GNT1169377; Lees), the National Institute on Alcohol and Alcoholism (K23 AA025399; Squeglia, U01 DA041093; Squeglia), and the National Institute on Drug Abuse (5T32DA024635; Meredith).

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