A new study suggests a combination approach may provide the benefits of THC treatment in Alzheimer’s with fewer negative side effects.
Researchers from The University of Texas at San Antonio paired a low-dose THC extract with the selective anti-inflammatory drug celecoxib. Their findings, published in Aging and Disease, show that when used in mice, the combination improved cognition and reduced Alzheimer’s-related brain pathology.
The role of inflammation
Lead author, Chu Chen, PhD, professor in the Department of Cellular and Integrative Physiology, began investigating the effects of THC on learning and memory more than a decade ago.
In a 2013 study, his lab uncovered a key molecular driver, Cyclooxygenase-2 (COX-2), an enzyme known for its role in inflammation and pain.
It is normally expressed at low levels in the brain but becomes activated during injury, infection, or disease.
COX-2 also plays a role 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 explained.
Previous clinical trials using high doses of COX-2 inhibitors for Alzheimer’s disease did not show cognitive benefits and additionally produced detrimental cardiovascular side effects.
Same receptor, opposite outcomes
Endocannabinoids act on the same cannabinoid receptors as external THC but often exert opposite or regulatory effects.
Among them, 2-arachidonoylglycerol (2-AG) is a key endocannabinoid that engages signaling pathways that lead to reduced COX-2 activity and less neuroinflammation.
This insight prompted Chen to consider whether the pro-inflammatory effects of THC could be blocked while preserving its beneficial actions.
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.
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.
They administered 3 mg/kg of THC and 1 mg/kg of celecoxib per day to mice – the human equivalent in a 165-pound person of 18 mg THC and 6 mg of celecoxib per day.
Treatment was initiated before 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 signalling.
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 behaviour,” Chen said.
“If cognition is not improved, then the treatment doesn’t matter. And that’s where the combination clearly worked better than THC alone.”
Fast-track to clinical trials
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.
Both drugs are already Food and Drug Administration-approved for use in humans, pointing to a potential fast track to clinical trials, the researchers say.
“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.”
Chen’s future studies will determine whether the drug combination can slow disease progression or reverse deficits after symptoms have already appeared.
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,” Chen added.
“But now we’re at a point where basic neuroscience discoveries are pointing toward something that could realistically move into the clinic.”
