This Simple Drug Combo Turns THC Into a Potential Alzheimer’s Therapy

New research suggests THC’s cognitive drawbacks may be mitigated when combined with a targeted anti-inflammatory drug.

Cannabis research has highlighted a scientific paradox. Its best-known psychoactive compound, Δ⁹-tetrahydrocannabinol (THC), has been linked to medical effects that could be useful in the brain, including anti-inflammatory and neuroprotective activity. Yet the same molecule is also associated with worse learning and memory, a major obstacle for any therapy meant to help neurological diseases.

A new study suggests that the tradeoff might be softened by pairing THC with a second, targeted drug. The work was led by Chu Chen, PhD, a professor in the Department of Cellular and Integrative Physiology and the Joe R. and Teresa Lozano Long Chair in neural physiology in the Long School of Medicine at The University of Texas at San Antonio. His team tested whether THC’s benefits could be preserved while dialing down the biological changes that appear to drive its cognitive downsides.

In the study, published in Aging and Disease, the researchers combined a low-dose THC extract with celecoxib, a selective anti-inflammatory medication. In mice, the combination improved cognition and reduced brain pathology associated with Alzheimer’s disease.

The results are preclinical, but the idea stands out because both drugs are already Food and Drug Administration-approved for use in humans, which could make follow-up clinical testing more straightforward than developing a new compound from scratch.

Inflammation at root of many diseases

Chen’s interest in this question goes back more than a decade, when he began investigating why THC can interfere with learning and memory. In a 2013 study, his lab identified a molecular clue centered on cyclooxygenase-2 (COX-2).

This enzyme is widely known for its role in inflammation and pain. In the brain it is usually present at low levels, but it ramps up during injury, infection, or disease. COX-2 is also involved in synaptic plasticity, including long-term potentiation, a cellular process essential for learning and memory.

“When THC is given, it unexpectedly increases COX-2 in the brain. That increase is closely associated with learning and memory impairment,” Chen said.

That finding helps explain why THC has been difficult to use safely for neurological conditions. It also explains why simply blocking COX-2 across the board is not an easy fix. Previous Alzheimer’s clinical trials that used high doses of COX-2 inhibitors did not improve cognition and were linked to harmful cardiovascular side effects.

Same receptor, opposite outcomes

The brain produces its own cannabinoid molecules, called endocannabinoids, which act on the same receptors as THC but can push the system in a more balanced direction. One of the most important is 2-arachidonoylglycerol (2-AG), which activates signaling pathways that reduce COX-2 activity and lower neuroinflammation.

Taken together, those threads led Chen to a specific question: could a carefully chosen partner drug block THC’s pro-inflammatory effects while allowing its potentially beneficial actions to remain?

Combination drug in Alzheimer’s models

Chen’s team chose to add celecoxib, a selective COX-2 inhibitor widely prescribed for arthritis and pain. The researchers used very low doses, far below those associated with cardiovascular risk in earlier Alzheimer’s trials. For the study, they administered 3 mg/kg of THC and 1 mg/kg of celecoxib per day to mice. This is the human-equivalent in a 165-pound person of 18 mg THC and 6 mg of celecoxib per day.

In the new study, the researchers tested low-dose THC alone and in combination with celecoxib in beta-amyloid and tau mouse models of Alzheimer’s disease. Beta-amyloid plaques and tau tangles are central hallmarks of Alzheimer’s.

Treatment was initiated prior to the development of memory symptoms to concentrate on the combination’s effect in preventing or delaying the onset of Alzheimer’s symptoms. Oral doses were given once daily for 30 days.

The results were consistent across both the beta-amyloid and tau models. Although low-dose THC alone improved cognitive performance and reduced some pathological markers, it also increased inflammatory signaling. In contrast, the combination of THC and celecoxib produced better outcomes, including improved learning and memory performance, reduced beta-amyloid and tau pathology, and decreased markers of neuroinflammation.

Single-cell RNA sequencing revealed that genes involved in synaptic function, inflammation, and Alzheimer’s disease risk were shifted back toward a healthier profile following the treatment.

“What really mattered was behavior. If cognition is not improved, then the treatment doesn’t matter. And that’s where the combination clearly worked better than THC alone,” Chen said.

Clearer path to translation

THC is currently available in synthetic form for chemotherapy-related nausea and appetite loss in cancer and HIV patients and celecoxib has been prescribed for decades for arthritis and other pain. By pairing THC with a COX-2 inhibitor, the scientists effectively reduced THC-related inflammation while preserving its positive cognitive effects.

The findings point toward a pharmaceutical strategy that could be quickly tested in clinical trials.

“If you develop a new compound, it can take 10 to 20 years to reach patients,” Chen said. “In this case, both drugs are already approved. That gives us a real advantage.”

What’s next?

This study focused on preventing or delaying the onset of cognitive symptoms. Chen’s future studies will determine whether the drug combination can slow disease progression or reverse deficits after symptoms have already appeared.

Still, even preventing or delaying the onset of Alzheimer’s disease by a few years could have a profound impact on patients, families, and health systems.

“This work has taken many years. But now we’re at a point where basic neuroscience discoveries are pointing toward something that could realistically move into the clinic,” Chen said.

Interest in cannabis-based therapies is on the rise, and this latest study offers a unique focus on THC’s functional mechanisms and solutions to its side effects. The study moves the field closer to safely applying these therapies in clinical care for Alzheimer’s disease and other neurodegenerative diseases.

Reference: “A Combination of Low-Dose Δ9-THC and Celecoxib as a Therapeutic Strategy for Alzheimer’s Disease” by Jian Zhang, Dexiao Zhu, Mei Hu, Mingzhe Pan and Chu Chen, 18 December 2025, Aging and Disease.
DOI: 10.14336/AD.2025.1206

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