As cannabis use continues to rise among older adults, researchers are trying to understand how it affects cognitive function during aging. A new study published in the journal Psychopharmacology provides evidence that cannabis and its primary psychoactive ingredient, THC, may actually improve certain types of memory in aged rats — though these effects depend on sex, the method of delivery, and the specific type of cognitive task.
In particular, the researchers found that acute cannabis smoke improved working memory in aged male rats but impaired it in aged females. Chronic oral THC, on the other hand, enhanced working memory in aged rats of both sexes, without harming spatial memory or affecting younger rats.
Cannabis use is becoming increasingly common in older adults. From 2015 to 2023, the percentage of people over 65 in the United States who reported using cannabis in the past year nearly tripled. Many use it regularly, often to manage chronic pain, anxiety, or sleep problems. But while cannabis is well known to impair memory and attention in young adults, very little is known about how it affects the aging brain, which is already more vulnerable to cognitive decline.
In fact, previous studies in aged mice suggested that low doses of THC might improve cognitive function — a surprising finding that raised new questions about whether cannabis could actually help remediate age-related memory problems under some conditions.
The current study, led by Jennifer L Bizon, aimed to explore this possibility in greater detail. The researchers wanted to know how cannabis affects two different kinds of memory — working memory (which relies on the prefrontal cortex) and spatial memory (which depends on the hippocampus) — in both young and aged rats, male and female. They also wanted to use delivery methods that reflect how people typically consume cannabis: by smoking and eating.
“Our interest in this topic arose from several directions. The first inspiration was a preclinical research program in which we were evaluating how cannabis smoke affects cognition and behavior,” said co-author Barry Setlow, a professor and co-Vice Chair for Research of the Department of Psychiatry at the University of Florida.
“Most prior preclinical research on cannabinoid effects on behavior employed routes of administration (e.g., injections) that did not mirror how humans actually use cannabis, and thus we wanted to develop a more translationally-relevant model of cannabis use.”
“The second inspiration was from some results from our cannabis smoke research program in which we found (to our surprise at the time) that acute exposure to cannabis smoke could actually improve a form of cognition (working memory), but ONLY in those subjects that happened to have poor performance under baseline conditions. The third inspiration was from our research on age-related cognitive decline, in which we found that, like in aged humans, working memory tends to decline in aged rats.”
“Putting together all of these lines of research, we initially evaluated how cannabis smoke affected cognition in aging,” Setlow explained. “We then extended this work to evaluate oral THC consumption (i.e., ‘edibles’), as this is an increasingly common route of consumption in older adults.”
The research team carried out three experiments using young adult (6–9 months old) and aged (24–28 months old) rats. In the first experiment, they exposed rats to cannabis smoke and tested them on two different touchscreen-based memory tasks. One task measured working memory using a delayed non-match-to-sample test that depends on the prefrontal cortex. The other task measured spatial memory using a trial-unique non-matching-to-location task, which relies more heavily on the hippocampus.
In the second experiment, the researchers examined the effects of chronic oral THC consumption, delivered through gelatin that the rats voluntarily consumed over three weeks. These rats were also tested on the working memory task and later in the Morris water maze, a widely used test of spatial memory.
The third experiment measured how THC and its metabolites circulated in the body over time, depending on the method of administration. This allowed the researchers to compare how young and aged rats metabolized THC after smoking or eating it.
When rats were exposed to cannabis smoke, the effects on working memory varied depending on age and sex. Among young rats, cannabis smoke had no detectable effect on memory performance. But in aged rats, the results were strikingly different. In males, cannabis smoke improved working memory performance, especially at longer delays — the point at which age-related deficits typically emerge. In contrast, aged females showed impaired performance after cannabis smoke exposure.
When THC was consumed orally over several weeks, it produced a more consistent improvement in working memory among aged rats. Both males and females showed enhanced accuracy after three weeks of THC consumption, particularly at longer delay intervals, where aging tends to impair performance. Importantly, this cognitive boost was not seen in young adult rats, suggesting that the effects are specific to age-related deficits.
These effects were specific to working memory; the same rats showed no significant changes in their performance on the spatial memory task, regardless of sex or age. In the spatial memory task (the Morris water maze), neither young nor aged rats showed any significant change in performance after chronic oral THC.
“We were somewhat surprised that cannabis/THC only seemed to benefit working memory (mediated by prefrontal cortex), and forms of learning and memory mediated by the hippocampus/medial temporal lobe,” Setlow told PsyPost. “This surprise was in part due previous work in rodents showing that the latter forms of cognition can benefit from low doses of THC.”
To better understand why THC affected the rats differently based on age and sex, the researchers analyzed how it was metabolized. After smoking cannabis, peak blood levels of THC occurred about 10 minutes later in both young and aged rats, with no statistically significant differences between groups. After oral THC, peak levels of its main metabolite (11-COOH-THC) appeared around 30 to 60 minutes later.
Interestingly, aged rats showed lower levels of this metabolite than younger rats, but only after oral administration. These findings suggest that differences in THC metabolism alone are unlikely to explain the observed cognitive effects.
“Although cannabis tends to have adverse or neutral effects on cognition in young adults (which is the population most studied in the context of cannabis use), our data, alongside other preclinical and clinical research, suggests that it may have beneficial effects on cognition as well,” Setlow said. “This said, it is important to emphasize that such beneficial effects likely occur only at low doses, and only in specific areas of cognition.”
The researchers offered a few possible explanations for the age-specific benefits of THC. One theory involves the brain’s inhibitory signaling systems. In the prefrontal cortex, cannabinoid receptors are located on inhibitory neurons that help regulate the activity of pyramidal neurons, which are essential for working memory. Aging is associated with increased inhibition in the prefrontal cortex, which may contribute to cognitive decline. By activating cannabinoid receptors, THC might reduce this inhibition, allowing for more effective neuronal signaling — especially in brains that have become too suppressed.
Another possibility involves inflammation. Aging is linked to increased brain inflammation, which can interfere with cognition. THC has known anti-inflammatory effects, including reducing the activity of microglia (immune cells in the brain) and decreasing levels of inflammatory molecules. These effects may take time to emerge, which could explain why chronic oral THC improved memory only after several weeks of consumption.
And what about the impairments in working memory in aged females? One explanation for this could be related to baseline performance. In this study, aged female rats performed at levels similar to young adults before cannabis exposure, while aged males were more impaired. Earlier work showed that cannabis improves memory only in animals with lower baseline performance, which might explain why the same dose helped males but harmed females.
As with all research, there are caveats to consider. “Although rats mirror many (maybe most) features of human cognitive aging, there are still obvious differences,” Setlow noted. “In addition, we evaluated only a few aspects of cognitive performance, using a small number of cannabis/THC doses and schedules of administration that do not reflect the full range of human cannabis use. Finally, the doses of cannabis/THC we used were fairly low, and thus any cognitive benefits in older adults might not be obtained with higher doses such as those that might produce intoxication.”
But the findings are in line with a long-term study of over 5,000 Danish men, which found that those who had used cannabis at some point in their lives experienced slightly less cognitive decline over a 44-year period compared to those who had never used it.
The researchers suggest that future studies should investigate how other components of cannabis, especially CBD, affect cognitive aging. They also recommend longer-term studies to determine whether the benefits of chronic THC persist over time or lead to tolerance or other unwanted effects. Finally, understanding the biological mechanisms that drive sex differences in response to cannabis will be important for developing age- and sex-specific treatments.
“Some of our long-term goals include expanding our investigation of routes and regimens of cannabis/cannabinoid administration, to determine the breadth of conditions in which they influence cognitive performance in aging,” Setlow said. “Other goals include investigation of the neurobiological mechanisms by which cannabis/THC provides cognitive benefits in aging, so as to be able to more selectively target these mechanisms and ultimately develop more efficacious treatments for age-related cognitive decline.”
The study, “Effects of cannabis smoke and oral Δ9THC on cognition in young adult and aged rats,” was authored by Sabrina Zequeira, Emely A. Gazarov, Alara A. Güvenli, Erin C. Berthold, Alexandria S. Senetra, Marcelo Febo, Takato Hiranita, Lance R. McMahon, Abhisheak Sharma, Christopher R. McCurdy, Barry Setlow, and Jennifer L. Bizon.