The endocannabinoid system and the ageing brain.

Zimmer A. · Nature reviews. Neuroscience · 2026

**Background & Methods** This is a narrative review examining the role of the endocannabinoid system in brain ageing mechanisms and its potential therapeutic applications. The review synthesizes current literature on endocannabinoid signalling dynamics across the lifespan and their relationship to age-related brain dysfunction. **Key Findings** - The endocannabinoid system is a lipid signalling network that maintains neuronal, glial, metabolic and inflammatory homeostasis; endocannabinoid activity follows a dynamic trajectory with relatively high function during early adulthood and progressive functional decline during ageing. - Genetic or pharmacological disruption of endocannabinoid system activity impairs multiple processes linked to brain ageing hallmarks, including neuroinflammatory control, adult neurogenesis, synaptic plasticity, cognitive performance, metabolic regulation and epigenetic stability. - Low-dose Δ9-tetrahydrocannabinol (THC) treatment demonstrated capacity to ameliorate several ageing-related brain phenotypes in aged animal models. **Dosage & Administration** The review references low-dose THC as a potential therapeutic approach but does not specify particular dosing regimens, routes of administration, or treatment protocols. Specific dosage recommendations are not provided. **Safety & Adverse Effects** Not reported. The review does not discuss adverse effects or safety concerns associated with cannabinoid interventions in aged populations. **Evidence Quality** This review has significant limitations regarding clinical translation. The evidence base consists primarily of preclinical animal studies demonstrating endocannabinoid system dysfunction in ageing and THC-related improvements in aged animal models. Clinical evidence in older humans remains explicitly acknowledged as limited. The authors note that therapeutic potential of cannabinoid-based interventions requires further evaluation, indicating insufficient human clinical trial data to support definitive recommendations. As a narrative review rather than a systematic review or meta-analysis, this summary does not employ rigorous methodology for study selection or bias assessment. The findings suggest a biologically plausible mechanism for cannabinoid involvement in brain ageing, but substantial gaps exist between preclinical efficacy and clinical applicability in human populations. Well-designed randomized controlled trials in older adults are needed to establish safety, efficacy, optimal dosing, and long-term outcomes before clinical recommendations can be made.

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