<h4>Background and hypothesis</h4>Cannabis use initiation during adolescence has increased globally, raising concerns about neurodevelopmental consequences during this critical period when the brain undergoes extensive remodeling in cannabinoid receptor-rich regions.<h4>Study design</h4>This systematic review examines neurodevelopmental consequences of adolescent cannabis use, focusing on structural brain changes, cognitive impacts, addiction vulnerability, and long-term outcomes. We searched PubMed, EMBASE, PsycINFO, and Web of Science (2000-2025) for studies examining cannabis effects in adolescent populations. Following PRISMA guidelines, two reviewers screened 3,421 records and assessed 156 full-text articles, including studies with neuroimaging, cognitive assessments, or longitudinal follow-up.<h4>Study results</h4>Thirty-six studies involving 8,432 participants met criteria: 23 longitudinal cohorts (62.2%), 8 cross-sectional (22.2%), 4 RCTs (11.1%), and 1 case-control study (2.8%). Neuroimaging revealed dose-dependent alterations including reduced prefrontal cortical and hippocampal/amygdala volumes, accelerated cortical thinning in longitudinal studies, and impaired white matter connectivity correlating with initiation age. Cognitive findings were mixed - some showed persistent deficits after prolonged abstinence in adolescent-onset users, others found no effects after controlling for confounders. Epidemiological studies consistently showed elevated addiction risk (ORs 3.9-7.2) in adolescents versus adults. Long-term associations included educational difficulties, mental health problems, and functional impairment, though causal relationships remained unclear.<h4>Conclusions</h4>Adolescent cannabis use associates with structural brain changes, elevated addiction risk, and variable cognitive effects, suggesting greater vulnerability versus adult-onset use. However, methodological limitations including confounders, heterogeneous definitions, and observational de No use, distribution or reproduction is permitted which does not comply with these terms. Abstract Background and hypothesis Cannabis use initiation during adolescence has increased globally, raising concerns about neurodevelopmental consequences during this critical period when the brain undergoes extensive remodeling in cannabinoid receptor-rich regions. Study design This systematic review examines neurodevelopmental consequences of adolescent cannabis use, focusing on structural brain changes, cognitive impacts, addiction vulnerability, and long-term outcomes. Conclusions Adolescent cannabis use associates with structural brain changes, elevated addiction risk, and variable cognitive effects, suggesting greater vulnerability versus adult-onset use. However, methodological limitations including confounders, heterogeneous definitions, and observational designs limit causal inference. Findings support age-specific prevention and specialized interventions while highlighting needs for rigorous longitudinal research establishing causality. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifierCRD420251165329. Keywords: addiction vulnerability, adolescent cannabis use, brain imaging, cognitive effects, neurodevelopment status released display-pdf yes is-olf no is-manuscript no is-preprint no is-journal-matter no is-scanned no is-retracted no Received 2026 Mar 3; Revised 2026 Apr 7; Accepted 2026 Apr 9; Collection date 2026. 1. Introduction The human brain undergoes extensive remodeling during adolescence, with prefrontal cortex maturation continuing into the mid-twenties ( 1 , 2 ). Clinicians need evidence-based guidance for adolescent risk assessment and treatment, while policy debates require Confounding control: Studies that controlled for or assessed key confounding variables including alcohol use, other substance use, and socioeconomic factors, or that provided sufficient data to evaluate the influence of these factors. Publication: Peer-reviewed articles published in English-language journals, plus high-quality grey literature (doctoral dissertations, government reports, conference abstracts) meeting rigorous methodological criteria. Methodological quality: Studies with clearly defined methodology and appropriate statistical analyses. Additional sources of bias specifically assessed included: -Selection bias: Differences between cannabis users and controls in baseline characteristics -Information bias: Recall bias in self-reported cannabis use, measurement error in neuroimaging or cognitive testing -Confounding bias: Inadequate control for alcohol, tobacco, other substances, socioeconomic status, genetic factors -Publication bias: Assessment through funnel plot examination and Egger’s test when sufficient studies were available 2.5. Neuroimaging evidence of age-related vulnerability 3.2.1. Early versus late-onset brain volume differences Neuroimaging studies consistently demonstrate that timing of cannabis initiation critically influences brain structural development. Wilson et al. ( 25 ) established that individuals beginning use before age 17 showed smaller whole brain volumes and reduced cortical gray matter compared to later-onset users. Jacobus et al. ( 34 ) revealed paradoxically thicker cortical estimates across 23 brain regions in heavy adolescent users over three years, suggesting disrupted neuromaturation. Crucially, this neurobiological vulnerability is not uniform across the adolescent population: earlier initiation age, higher frequency of use, and genetic predisposition—particularly variants in the CNR1 gene encoding the CB1 receptor—appear to compound risk in a dose-dependent fashion. Traditional addiction treatment models, designed for adults with extended use histories, appear inadequate. Adolescents require developmentally tailored approaches recognizing the intersection of substance use disorder with ongoing brain maturation, identity formation, and social development.