Exercise-induced anandamide-CB1R signaling and prefrontal-amygdala stress circuits in adolescent depression: a...

Adolescent depression emerges during a developmental period characterized by ongoing maturation of corticolimbic and stress-regulatory systems. This narrative review critically evaluates a hypothesis that acute exercise-related endocannabinoid mobilization, particularly changes in circulating anandamide (AEA), may be linked to CB1 receptor (CB1R)-dependent processes relevant to prefrontal-amygdala function and stress-sensitive symptom dimensions. The evidence base is fragmented across populations and experimental levels. Human exercise studies, conducted predominantly in healthy adults, indicate that acute aerobic exercise can increase circulating AEA, but peripheral AEA cannot be assumed to reflect AEA concentrations or CB1R engagement within the prefrontal cortex or amygdala. Separately, preclinical and translational studies show that endocannabinoid signaling can modulate presynaptic transmission, stress-related responses, and fear learning in a region-, cell-type-, and ligand-dependent manner. Neuroimaging studies implicate altered prefrontal-amygdala connectivity in some adolescents with depression, although findings vary across tasks, subregions, samples, and analytic approaches. Critically, no study has tested the complete sequence linking exercise, AEA responses, CB1R-dependent signaling, prefrontal-amygdala circuit change, and depressive symptom improvement in adolescents. We therefore treat this sequence as an unvalidated cross-level model rather than a demonstrated causal pathway. This review distinguishes direct from indirect evidence, examines conflicting findings, considers developmental and sex-related moderators, and proposes experiments that integrate exercise dose, circulating AEA and 2-arachidonoylglycerol, FAAH-related biology, circuit-level outcomes, and symptoms. The proposed framework is most appropriately viewed as a testable model for stress-sensitive and emotion-regulation-related symptom dimensions rather than an established antidepressant mechanism.