A Combination of Low-Dose Δ⁹-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ⁹-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ⁹-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ⁹-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ⁹-THC-induced neuroinflammatory responses. Furthermore, Δ⁹-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ⁹-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ⁹-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.