Diet order significantly affects energy balance for diets varying in macronutrients but not ultraprocessing in crossover studies without a washout period.

BACKGROUND: Crossover studies can induce order effects, especially when they lack a washout period. OBJECTIVES: We performed secondary analyses comparing groups of subjects randomly assigned to different diet orders in 2 inpatient crossover studies originally designed to compare within-subject differences in ad libitum energy intake. One study compared minimally processed low-carbohydrate (LC) compared with low-fat (LF) diets, and the other matched macronutrients and compared minimally processed food (MPF) with ultraprocessed food (UPF) diets. METHODS: Diet order group comparisons of changes in body weight and body composition, and differences in energy expenditure and food intake were assessed over 4 wk in 20 adults randomly assigned to either the LC followed immediately by the LF diet (LC → LF) or the opposite order (LF → LC), and 20 adults randomly assigned to either the MPF followed by the UPF (MPF → UPF) diets or the opposite order (UPF → MPF). RESULTS: Subjects randomly assigned to LC → LF lost 2.9 ± 1.1 kg more body weight (P <0.001) and 1.5 ± 0.6 kg more body fat (P = 0.03) than the LF → LC group, likely because the LC → LF group consumed 921 ± 304 kcal/d less than the LF → LC group (P = 0.003). These energy intake differences were driven by the last 2 wk (-1610 ± 312 kcal/d; P < 0.0001), perhaps because of carryover effects of gut adaptations during the first 2 wk arising from large differences in the mass of food (1296 ± 215 g/d; P <0.00001) and fiber consumed (58 ± 6 g/d; P <0.00001). There were no significant diet order effects on energy intake, body weight, or body composition changes between UPF → MPF and MPF → UPF groups. CONCLUSIONS: Diet order significantly affected energy intake, body weight, and body fat in a 4-wk crossover inpatient diet study varying in macronutrients, but not in a similarly structured study varying in ultraprocessed foods. This trial was registered at clinicaltrials.gov as NCT03407053 and NCT03878108.

Brain dopamine responses to ultra-processed milkshakes are highly variable and not significantly related to adiposity in humans.

Ultra-processed foods high in fat and sugar may be addictive, in part, due to their purported ability to induce an exaggerated postingestive brain dopamine response akin to drugs of abuse. Using standard [11C]raclopride positron emission tomography (PET) displacement methods used to measure brain dopamine responses to addictive drugs, we measured postingestive striatal dopamine responses to an ultra-processed milkshake high in fat and sugar in 50 young, healthy adults over a wide body mass index range (BMI 20-45 kg/m2). Surprisingly, milkshake consumption did not result in significant postingestive dopamine response in the striatum (p=0.62) nor any striatal subregion (p>0.33) and the highly variable interindividual responses were not significantly related to adiposity (BMI: r=0.076, p=0.51; %body fat: r=0.16, p=0.28). Thus, postingestive striatal dopamine responses to an ultra-processed milkshake were likely substantially smaller than many addictive drugs and below the limits of detection using standard PET methods.

Diet order affects energy balance in randomized crossover feeding studies that vary in macronutrients but not ultra-processing.

BACKGROUND: Crossover studies can induce order effects, especially when they lack a wash-out period. OBJECTIVE: To explore diet order effects on energy balance and food intake between randomized diet order groups in two inpatient crossover studies originally designed to compare within-subject differences in ad libitum energy intake between either minimally processed low carbohydrate (LC) versus low fat (LF) diets or macronutrient-matched diets composed of mostly minimally processed food (MPF) or ultra-processed food (UPF). METHODS: Diet order group comparisons of changes in body weight, body composition, and differences in energy expenditure, and food intake were assessed over four weeks in 20 adults randomized to either the LC followed immediately by the LF diet (LC→LF) or the opposite order (LF→LC) as well as 20 adults randomized to either the MPF followed by UPF (MPF→UPF) diets or the opposite order (UPF→MPF). RESULTS: Subjects randomized to LC→LF lost 2.9 ± 1.1 kg more body weight (p < 0.001) and 1.5 ± 0.6 kg more body fat (p = 0.03) than the LF→LC group likely because the LC→LF group consumed 922 ± 304 kcal/d less than the LF→LC group (p = 0.0024). Reduced energy intake in LC→LF vs LF→LC was driven by the last two weeks (-1610 ± 306 kcal/d; p<0.00001) perhaps due to carryover effects of gut adaptations over the first two weeks arising from large differences in the mass of food (1295 ± 209 g/d; p<0.00001) and fiber intake (58 ± 5 g/d; p<0.00001). There were no diet order effects on ad libitum energy intake, body weight, or body composition change between UPF→MPF versus MPF→UPF groups. CONCLUSIONS: Diet order influences daily ad libitum energy intake, body weight change, and fat change within the context of a 4-week crossover inpatient diet study varying in macronutrients, but not varying in extent and purpose of processing. Funding sources: Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Clinical Trial Registration: NCT03407053 and NCT03878108.

Striatal dopamine tone is positively associated with body mass index in humans as determined by PET using dual dopamine type-2 receptor antagonist tracers.

The relationship between adiposity and dopamine type-2 receptor binding potential (D2BP) in the human brain has been repeatedly studied for >20 years with highly discrepant results, likely due to variable methodologies and differing study populations. We conducted a controlled inpatient feeding study to measure D2BP in the striatum using positron emission tomography with both [18F]fallypride and [11C]raclopride in pseudo-random order in 54 young adults with a wide range of body mass index (BMI 20-44 kg/m2). Within-subject D2BP measurements using the two tracers were moderately correlated (r=0.47, p<0.001). D2BP was negatively correlated with BMI as measured by [11C]raclopride (r= -0.51; p<0.0001) but not [18F]fallypride (r=-0.01; p=0.92) and these correlation coefficients were significantly different from each other (p<0.001). Given that [18F]fallypride has greater binding affinity to dopamine type-2 receptors than [11C]raclopride, which is more easily displaced by endogenous dopamine, our results suggest that adiposity is positively associated with increased striatal dopamine tone.

Breaking down silos: the multifaceted nature of obesity and the future of weight management.

The continued global increase in the prevalence of obesity prompted a meeting at the Royal Society of London investigating causal mechanisms of the disease, 'Causes of obesity: theories, conjectures, and evidence' in October 2022. Evidence presented indicates areas of obesity science where there have been advancements, including an increased understanding of biological and physiological processes of weight gain and maintenance, yet it is clear there is still debate on the relative contribution of plausible causes of the modern obesity epidemic. Consensus was reached that obesity is not a reflection of diminished willpower, but rather the confluence of multiple, complex factors. As such, addressing obesity requires multifactorial prevention and treatment strategies. The accumulated evidence suggests that a continued focus primarily on individual-level contributors will be suboptimal in promoting weight management at the population level. Here, we consider individual biological and physiological processes within the broader context of sociodemographic and sociocultural exposures as well as environmental changes to optimize research priorities and public health efforts. This requires a consideration of a systems-level approach that efficiently addresses both systemic and group-specific environmental determinants, including psychosocial factors, that often serve as a barrier to otherwise efficacious prevention and treatment options. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Dietary fat restriction affects brain reward regions in a randomized crossover trial.

BACKGROUNDWeight-loss diets often target dietary fat or carbohydrates, macronutrients that are sensed via distinct gut-brain pathways and differentially affect peripheral hormones and metabolism. However, the effects of such diet changes on the human brain are unclear. METHODSWe investigated whether selective isocaloric reductions in dietary fat or carbohydrates altered dopamine D2/3 receptor binding potential (D2BP) and neural activity in brain-reward regions in response to visual food cues in 17 inpatient adults with obesity as compared with a eucaloric baseline diet using a randomized crossover design. RESULTSOn the fifth day of dietary fat restriction, but not carbohydrate restriction, both D2BP and neural activity to food cues were decreased in brain-reward regions. After the reduced-fat diet, ad libitum intake shifted toward foods high in both fat and carbohydrates. CONCLUSIONThese results suggest that dietary fat restriction increases tonic dopamine in brain-reward regions and affects food choice in ways that may hamper diet adherence. TRIAL REGISTRATIONClinicalTrials.gov NCT00846040 FUNDING. NIDDK 1ZIADK013037.

No significant salt or sweet taste preference or sensitivity differences following ad libitum consumption of ultra-processed and unprocessed diets: a randomized controlled pilot study.

Ultra-processed food consumption has increased worldwide, yet little is known about the potential links with taste preference and sensitivity. This exploratory study aimed to (i) compare sweet and salty taste detection thresholds and preferences following consumption of ultra-processed and unprocessed diets, (ii) investigate whether sweet and salty taste sensitivity and preference were associated with taste substrates (i.e. sodium and sugar) and ad libitum nutrient intake, and (iii) examine associations of taste detection thresholds and preferences with blood pressure (BP) and anthropometric measures following consumption of ultra-processed and unprocessed diets. In a randomized crossover study, participants (N = 20) received ultra-processed or unprocessed foods for 2 weeks, followed by the alternate diet. Baseline food intake data were collected prior to admission. Taste detection thresholds and preferences were measured at the end of each diet arm. Taste-substrate/nutrient intake, body mass index (BMI), and body weight (BW) were measured daily. No significant differences were observed in participant salt and sweet detection thresholds or preferences after 2 weeks on ultra-processed or unprocessed diets. There was no significant association between salt and sweet taste detection thresholds, preferences, and nutrient intakes on either diet arm. A positive correlation was observed between salt taste preference and systolic BP (r = 0.59; P = 0.01), BW (r = 0.47, P = 0.04), and BMI (r = 0.50; P = 0.03) following consumption of the ultra-processed diet. Thus, a 2-week consumption of an ultra-processed diet does not appear to acutely impact sweet or salty taste sensitivity or preference. Trial Registration: ClinicalTrials.gov Identifier NCT03407053.

Baseline brain and behavioral factors distinguish adolescent substance initiators and non-initiators at follow-up.

Background: Earlier substance use (SU) initiation is associated with greater risk for the development of SU disorders (SUDs), while delays in SU initiation are associated with a diminished risk for SUDs. Thus, identifying brain and behavioral factors that are markers of enhanced risk for earlier SU has major public health import. Heightened reward-sensitivity and risk-taking are two factors that confer risk for earlier SU. Materials and methods: We characterized neural and behavioral factors associated with reward-sensitivity and risk-taking in substance-naïve adolescents (N = 70; 11.1-14.0 years), examining whether these factors differed as a function of subsequent SU initiation at 18- and 36-months follow-up. Adolescents completed a reward-related decision-making task while undergoing functional MRI. Measures of reward sensitivity (Behavioral Inhibition System-Behavioral Approach System; BIS-BAS), impulsive decision-making (delay discounting task), and SUD risk [Drug Use Screening Inventory, Revised (DUSI-R)] were collected. These metrics were compared for youth who did [Substance Initiators (SI); n = 27] and did not [Substance Non-initiators (SN); n = 43] initiate SU at follow-up. Results: While SI and SN youth showed similar task-based risk-taking behavior, SI youth showed more variable patterns of activation in left insular cortex during high-risk selections, and left anterior cingulate cortex in response to rewarded outcomes. Groups displayed similar discounting behavior. SI participants scored higher on the DUSI-R and the BAS sub-scale. Conclusion: Activation patterns in the insula and anterior cingulate cortex may serve as a biomarker for earlier SU initiation. Importantly, these brain regions are implicated in the development and experience of SUDs, suggesting differences in these regions prior to substance exposure.

Introducing an adolescent cognitive maturity index.

Children show substantial variation in the rate of physical, cognitive, and social maturation as they traverse adolescence and enter adulthood. Differences in developmental paths are thought to underlie individual differences in later life outcomes, however, there remains a lack of consensus on the normative trajectory of cognitive maturation in adolescence. To address this problem, we derive a Cognitive Maturity Index (CMI), to estimate the difference between chronological and cognitive age predicted with latent factor estimates of inhibitory control, risky decision-making and emotional processing measured with standard neuropsychological instruments. One hundred and forty-one children from the Adolescent Development Study (ADS) were followed longitudinally across three time points from ages 11-14, 13-16, and 14-18. Age prediction with latent factor estimates of cognitive skills approximated age within ±10 months (r = 0.71). Males in advanced puberty displayed lower cognitive maturity relative to peers of the same age; manifesting as weaker inhibitory control, greater risk-taking, desensitization to negative affect, and poor recognition of positive affect.

Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder.

Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, ß-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.

Effect of a plant-based, low-fat diet versus an animal-based, ketogenic diet on ad libitum energy intake.

The carbohydrate-insulin model of obesity posits that high-carbohydrate diets lead to excess insulin secretion, thereby promoting fat accumulation and increasing energy intake. Thus, low-carbohydrate diets are predicted to reduce ad libitum energy intake as compared to low-fat, high-carbohydrate diets. To test this hypothesis, 20 adults aged 29.9 ± 1.4 (mean ± s.e.m.) years with body mass index of 27.8 ± 1.3 kg m-2 were admitted as inpatients to the National Institutes of Health Clinical Center and randomized to consume ad libitum either a minimally processed, plant-based, low-fat diet (10.3% fat, 75.2% carbohydrate) with high glycemic load (85 g 1,000 kcal-1) or a minimally processed, animal-based, ketogenic, low-carbohydrate diet (75.8% fat, 10.0% carbohydrate) with low glycemic load (6 g 1,000 kcal-1) for 2 weeks followed immediately by the alternate diet for 2 weeks. One participant withdrew due to hypoglycemia during the low-carbohydrate diet. The primary outcomes compared mean daily ad libitum energy intake between each 2-week diet period as well as between the final week of each diet. We found that the low-fat diet led to 689 ± 73 kcal d-1 less energy intake than the low-carbohydrate diet over 2 weeks (P < 0.0001) and 544 ± 68 kcal d-1 less over the final week (P < 0.0001). Therefore, the predictions of the carbohydrate-insulin model were inconsistent with our observations. This study was registered on ClinicalTrials.gov as NCT03878108 .

Omega-3 Fatty Acids and Vulnerability to Addiction: Reviewing Preclinical and Clinical Evidence.

Omega-3 (N3) fatty acids are dietary nutrients that are essential for human health. Arguably, one of their most critical contributions to health is their involvement in the structure and function of the nervous system. N3 fatty acids accumulate in neuronal membranes through young adulthood, becoming particularly enriched in a brain region known to be the locus of cognitive control of behavior-the prefrontal cortex (PFC). The PFC undergoes a surge in development during adolescence, coinciding with a life stage when dietary quality and intake of N3 fatty acids tend to be suboptimal. Such low intake may impact neurodevelopment and normative development of cognitive functions suggested to be protective for the risk of subsequent substance and alcohol use disorders (UD). While multiple genetic and environmental factors contribute to risk for and resilience to substance and alcohol use disorders, mounting evidence suggests that dietary patterns early in life may also modulate cognitive and behavioral factors thought to elevate UD risk (e.g., impulsivity and reward sensitivity). This review aims to summarize the literature on dietary N3 fatty acids during childhood and adolescence and risk of executive/ cognitive or behavioral dysfunction, which may contribute to the risk of subsequent UD. We begin with a review of the effects of N3 fatty acids in the brain at the molecular to cellular levels-providing the biochemical mechanisms ostensibly supporting observed beneficial effects. We continue with a review of cognitive, behavioral and neurodevelopmental features thought to predict early substance and alcohol use in humans. This is followed by a review of the preclinical literature, largely demonstrating that dietary manipulation of N3 fatty acids contributes to behavioral changes that impact drug sensitivity. Finally, a review of the available evidence in human literature, suggesting an association between dietary N3 fatty and neurodevelopmental profiles associated with risk of adverse outcomes including UD. We conclude with a brief summary and call to action for additional research to extend the current understanding of the impact of dietary N3 fatty acids and the risk of drug and alcohol UD.

Relationship between whole blood omega-3 fatty acid levels and dorsal cingulate gray matter volume: Sex differences and implications for impulse control.

During adolescence, the prefrontal cortex (PFC) undergoes substantial structural development, including cortical thinning, a process associated with improvements in behavioral control. The cingulate cortex is among the regions recruited in response inhibition and mounting evidence suggests cingulate function may be sensitive to availability of an essential dietary nutrient, omega-3 fatty acids (N3; i.e. EPA + DHA). Our primary aim was to investigate the relationship between a biomarker of omega-3 fatty acids -- percent of whole blood fatty acids as EPA + DHA (N3 Index) -- and cingulate morphology, in typically developing adolescent males (n = 29) and females (n = 33). Voxel-based morphometry (VBM) was used to quantify gray matter volume (GMV) in the dorsal region of the cingulate (dCC). Impulse control was assessed via caregiver report (BRIEF) and Go/No-Go task performance. We predicted that greater N3 Index in adolescents would be associated with less dCC GMV and better impulse control. Results revealed that N3 Index was inversely related to GMV in males, but not in females. Furthermore, males with less right dCC GMV exhibited better caregiver-rated impulse control. A simple mediation model revealed that, in males, N3 Index may indirectly impact impulse control through its association with right dCC GMV. Findings suggest a sex-specific link between levels of N3 and dCC structural development, with adolescent males more impacted by lower N3 levels than females. Identifying factors such as omega-3 fatty acid levels, which may modulate the neurodevelopment of response inhibition, is critical for understanding typical and atypical developmental trajectories associated with this core executive function.

Altered cortical structure and psychiatric symptom risk in adolescents exposed to maternal stress in utero: A retrospective investigation.

Maternal exposure to stress during pregnancy is associated with increased risk for cognitive and behavioral sequelae in offspring. Animal research demonstrates exposure to stress during gestation has effects on brain structure. In humans, however, little is known about the enduring effects of in utero exposure to maternal stress on brain morphology. We examine whether maternal report of stressful events during pregnancy is associated with brain structure and behavior in adolescents. We compare gray matter morphometry of typically-developing early adolescents (11-14 years of age, mean 12.7) at a single timepoint, based on presence/absence of retrospectively-assessed maternal report of negative major life event stress (MLES) during pregnancy: prenatal stress (PS; n = 28), comparison group (CG; n = 55). The Drug Use Screening Inventory Revised (DUSI-R) assessed adolescent risk for problematic behaviors. Exclusionary criteria included pre-term birth, low birth weight, and maternal substance use during pregnancy. Groups were equivalent for demographic (age, sex, IQ, SES, race/ethnicity), and birth measures (weight, length). Compared to CG peers, adolescents in the PS group exhibited increased gray matter density in bilateral posterior parietal cortex (PPC): bilateral intraparietal sulcus, left superior parietal lobule and inferior parietal lobule. Additionally, the PS group displayed greater risk for psychiatric symptoms and family system dysfunction, as assessed via DUSI-R subscales. These preliminary findings suggest that prenatal exposure to maternal MLES may exact enduring associations on offspring brain morphology and psychiatric risk, highlighting the importance of capturing these data in prospective longitudinal research studies (beginning at birth) to elucidate these associations.

Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake.

We investigated whether ultra-processed foods affect energy intake in 20 weight-stable adults, aged (mean ± SE) 31.2 ± 1.6 years and BMI = 27 ± 1.5 kg/m2. Subjects were admitted to the NIH Clinical Center and randomized to receive either ultra-processed or unprocessed diets for 2 weeks immediately followed by the alternate diet for 2 weeks. Meals were designed to be matched for presented calories, energy density, macronutrients, sugar, sodium, and fiber. Subjects were instructed to consume as much or as little as desired. Energy intake was greater during the ultra-processed diet (508 ± 106 kcal/day; p = 0.0001), with increased consumption of carbohydrate (280 ± 54 kcal/day; p < 0.0001) and fat (230 ± 53 kcal/day; p = 0.0004), but not protein (-2 ± 12 kcal/day; p = 0.85). Weight changes were highly correlated with energy intake (r = 0.8, p < 0.0001), with participants gaining 0.9 ± 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 ± 0.3 kg (p = 0.007) during the unprocessed diet. Limiting consumption of ultra-processed foods may be an effective strategy for obesity prevention and treatment.

Dietary Long-Chain Omega-3 Fatty Acids Are Related to Impulse Control and Anterior Cingulate Function in Adolescents.

Impulse control, an emergent function modulated by the prefrontal cortex (PFC), helps to dampen risky behaviors during adolescence. Influences on PFC maturation during this period may contribute to variations in impulse control. Availability of omega-3 fatty acids, an essential dietary nutrient integral to neuronal structure and function, may be one such influence. This study examined whether intake of energy-adjusted long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] was related to variation in impulse control and PFC activity during performance of an inhibitory task in adolescents (n = 87; 51.7% female, mean age 13.3 ± 1.1 years) enrolled in a longitudinal neuroimaging study. Intake of DHA + EPA was assessed using a food frequency questionnaire and adjusted for total energy intake. Inhibitory control was assessed using caregiver rating scale (BRIEF Inhibit subscale) and task performance (false alarm rate) on a Go/No-Go task performed during functional MRI. Reported intake of long-chain omega-3 was positively associated with caregiver ratings of adolescent ability to control impulses (p = 0.017) and there was a trend for an association between intake and task-based impulse control (p = 0.072). Furthermore, a regression of BOLD response within PFC during successful impulse control (Correct No-Go versus Incorrect No-Go) with energy-adjusted DHA + EPA intake revealed that adolescents reporting lower intakes display greater activation in the dorsal anterior cingulate, potentially suggestive of a possible lag in cortical development. The present results suggest that dietary omega-3 fatty acids are related to development of both impulse control and function of the dorsal anterior cingulate gyrus in normative adolescent development. Insufficiency of dietary omega-3 fatty acids during this developmental period may be a factor which hinders development of behavioral control.

Neurodevelopmental Precursors and Consequences of Substance Use during Adolescence: Promises and Pitfalls of Longitudinal Neuroimaging Strategies.

Neurocognitive and emotional regulatory deficits in substance users are often attributed to misuse; however most studies do not include a substance-naïve baseline to justify that conclusion. The etiological literature suggests that pre-existing deficits may contribute to the onset and escalation of use that are then exacerbated by subsequent use. To address this, there is burgeoning interest in conducting prospective, longitudinal neuroimaging studies to isolate neurodevelopmental precursors and consequences of adolescent substance misuse, as reflected in recent initiatives such as the NIH-led Adolescent Brain Cognitive Development (ABCD) study and the National Consortium on Alcohol and Neurodevelopment (NCANDA). To distinguish neurodevelopmental precursors from the consequences of adolescent substance use specifically, prospective, longitudinal neuroimaging studies with substance-naïve pre-adolescents are needed. The exemplar described in this article-i.e., the ongoing Adolescent Development Study (ADS)-used a targeted recruitment strategy to bolster the numbers of pre-adolescent individuals who were at increased risk of substance use (i.e., "high-risk") in a sample that was relatively small for longitudinal studies of similar phenomena, but historically large for neuroimaging (i.e., N = 135; 11-13 years of age). At baseline participants underwent MRI testing and a large complement of cognitive and behavioral assessments along with genetics, stress physiology and interviews. The study methods include repeating these measures at three time points (i.e., baseline/Wave 1, Wave 2 and Wave 3), 18 months apart. In this article, rather than outlining specific study outcomes, we describe the breadth of the numerous complexities and challenges involved in conducting this type of prospective, longitudinal neuroimaging study and "lessons learned" for subsequent efforts are discussed. While these types of large longitudinal neuroimaging studies present a number of logistical and scientific challenges, the wealth of information obtained about the precursors and consequences of adolescent substance use provides unique insights into the neurobiological bases for adolescent substance use that will lay the groundwork for targeted interventions.