Pharmaceuticals · Nov 7, 2026
Systemic Safety and Neuroprotective Potential of Chronic ∆9-THCA-Enriched Extract Administration: Divergent Effects on Molecular Neuroprotection and Physical Endurance in Aging Models
By Tudorancea IM, Ciorpac M, Alexa-Stratulat T et al.
Background: Aging is characterized by inflammaging, a progressive decline in metabolic homeostasis, and increased neuroinflammation. While the endocannabinoid system (ECS) regulates these processes, its tone diminishes with age. This study investigated the systemic safety and therapeutic potential of a full-spectrum, ∆9-THCA-enriched Cannabis extract in naturally aged rats. Methods: Aged Sprague–Dawley rats received intermittent oral doses (5 days on/2 days off) of a ∆9-THCA-enriched extract (0.5, 1.0, and 2.0 mg/kg) for six weeks. Assessments included body weight monitoring, physical endurance (treadmill), and neuromotor coordination (rotarod). Post-mortem evaluations encompassed systemic histopathology, serum biochemistry, and hippocampal immunohistochemistry for microglial (Iba-1), astrocytic (GFAP), and apoptotic (caspase-3) markers. Results: The extract demonstrated excellent systemic safety, with hepatic and renal markers remaining within physiological ranges. Treatment significantly attenuated age-related weight loss, with the 2.0 mg/kg dose achieving the most robust preservation (p < 0.001). In the hippocampus, the extract induced a reversal of neuroinflammation mediated by Iba-1, reducing Iba-1-positive microglial density by 93.5–97.9% across all doses (p < 0.001). Although the reduction was substantial at all doses, greater inter-individual variability was observed in the OLD-0.5 group. The extract also significantly attenuated apoptotic signaling (p = 0.029). Conversely, a dose-dependent reduction in peak physical endurance was observed, driven by increased task refusal rather than neuromotor impairment. Principal Component Analysis confirmed a phenotypic shift toward metabolic and neuroinflammatory stability at the cost of maximal aerobic power. Conclusions: Chronic intermittent administration of a ∆9-THCA-enriched extract reconfigures the aged phenotype, prioritizing metabolic maintenance and neuroprotection. These findings suggest full-spectrum cannabinoids serve as a viable geroprotective for neuroinflammatory stress, although their functional impact warrants careful consideration in the context of frailty.