Low-Dose THC Shows Age-Dependent Effects on Brain Metabolism in Mice
A 2024 study in ACS Pharmacology & Translational Science offers new clues about how long-term, low-dose Δ9-tetrahydrocannabinol (THC) may affect the aging brain. The research did not test THC as an anti-aging treatment in people, but it identified a tissue- and age-dependent pattern of changes in brain signaling and metabolism in mice.
Researchers from the University of Bonn, University Hospital Bonn and the Hebrew University studied male mice that were either 4 months or 18 months old. The animals received THC continuously through subcutaneous osmotic pumps at a dose of 3 milligrams per kilogram of body weight per day, or a vehicle control, for up to 28 days. The team then analyzed brain tissue, blood plasma and visceral fat, focusing on the mechanistic target of rapamycin, or mTOR, as well as synaptic proteins and hundreds of metabolites.
mTOR is a central regulator of cellular growth, energy use and protein production. Its activity has complex effects in aging: reducing mTOR signaling can promote longevity in some tissues, while sufficient mTOR activity in the brain is important for synaptic plasticity and memory-related processes.
In the mice’s cortex and hippocampus, THC temporarily increased mTOR phosphorylation after 14 days of treatment. The hippocampus, a region involved in learning and memory, also showed elevated levels of metabolites associated with glycolysis, the citric acid cycle and other energy-producing pathways. By day 28, the researchers detected higher levels of two synaptic proteins in the cortex—synaptophysin and PSD-95—suggesting increased synaptic activity or protein production.
The response in peripheral tissues was different. THC-treated older mice showed lower mTOR activity in adipose tissue, along with changes in blood metabolites that resembled some effects associated with calorie restriction or increased energy use. Several polyunsaturated fatty acids, including the omega-3 fatty acid DHA, were also elevated in the blood plasma.
The researchers describe this as a possible “bidirectional” effect: THC initially appears to increase energy availability and synaptic protein production in the brain, while later reducing mTOR signaling and some metabolic activity in peripheral tissues. That pattern could help explain why the authors believe the treatment might combine pro-cognitive effects in the brain with broader anti-aging effects elsewhere in the body.
However, the study did not demonstrate that THC extended lifespan, prevented dementia or restored cognitive performance through new behavioral testing. Its main contribution was to identify molecular and metabolic changes that may help explain earlier behavioral findings. In a 2017 Nature Medicine study, the same broader research group reported that low-dose THC restored aspects of learning and memory in 12- and 18-month-old mice and increased hippocampal spine density.
Age mattered in the newer experiment as well. Although some metabolic responses were similar in young and old animals, many amino-acid and related metabolite changes moved in opposite directions. This supports the possibility that THC’s effects depend strongly on the age and biological state of the subject. Earlier research has likewise found that THC can impair memory at higher doses and produce different outcomes across developmental stages.
The findings should therefore be interpreted as preclinical evidence, not as a basis for using cannabis or THC to protect memory. The study involved small groups of male mice, used a controlled delivery system and examined a treatment period of only a few weeks. Mouse metabolism and cannabinoid sensitivity do not directly predict effects in older adults, and the dose used in the experiment cannot be translated into a safe human dose.
A broader National Academies review of cannabis and cannabinoids has emphasized that the evidence for potential benefits and risks varies substantially by condition, dose, age and pattern of use. THC can also cause short-term impairment of memory, attention and coordination, particularly at higher doses.
Future studies will need to determine whether the molecular changes observed in mice persist after treatment ends, whether they improve meaningful behavior over the long term, and whether similar effects occur in female animals and humans. For now, the Bonn research provides a mechanism worth investigating—but not evidence that THC is an established treatment for brain aging.
