Picture the stereotypical pot smoker: young, dazed and confused. Marijuana has long been known for its psychoactive effects, which can include cognitive impairment. But new research published this week in Nature Medicine suggests the drug might affect older users very differently than young ones—at least in mice. Instead of impairing learning and memory as it does in young people, the drug appears to reverse age-related declines in the cognitive performance of elderly mice.
Researchers led by Andreas Zimmer of the University of Bonn in Germany gave low doses of delta 9-tetrahydrocannabinol, or THC, marijuana’s main active ingredient, to young, mature and aged mice. As expected, young mice treated with THC performed slightly worse on behavioral tests of memory and learning. For example, after THC young mice took longer to learn where a safe platform was hidden in a water maze, and they had a harder time recognizing another mouse to which they had previously been exposed. Without the drug, mature and aged mice performed worse on the tests than young ones did. But after receiving THC the elderly animals’ performances improved to the point that they resembled those of young, untreated mice. “The effects were very robust, very profound,” Zimmer says.
Other experts praised the study but cautioned against extrapolating the findings to humans. “This well-designed set of experiments shows that chronic THC pretreatment appears to restore a significant level of diminished cognitive performance in older mice, while corroborating the opposite effect among young mice,” Susan Weiss, director of the Division of Extramural Research at the National Institute on Drug Abuse who was not involved in the study, wrote in an e-mail. Nevertheless, she added, “While it would be tempting to presume the relevance of these findings [extends] to aging humans…further research will be critically needed.”
When the researchers examined the brains of the treated, elderly mice for an explanation, they noticed neurons in the hippocampus—a brain area critical for learning and memory—had sprouted more synaptic spines, the points of contact for communication between neurons. Even more striking, the gene expression pattern in the hippocampi of THC-treated aged mice was radically different from that of untreated elderly mice. “That is something we absolutely did not expect: the old animals [that received] THC looked most similar to the young, untreated control mice,” Zimmer says.
The findings raise the intriguing possibility THC and other “cannabinoids” might act as anti-aging molecules in the brain. Cannabinoids include dozens of biologically active compounds found in the Cannabis sativa plant. THC, the most highly studied type, is largely responsible for marijuana’s psychoactive effects. The plant compounds mimic our brain’s own marijuanalike molecules, called endogenous cannabinoids, which activate specific receptors in the brain capable of modulating neural activity. “We know the endogenous cannabinoid system is very dynamic; it goes through changes over the lifespan,” says Ryan McLaughlin, a researcher who studies cannabis and stress at Washington State University and was not involved in the current work. Research has shown the cannabinoid system develops gradually during childhood, “and then it blows up in adolescence—you see increased activity of its enzymes and receptors,” McLaughlin says. “Then as we age, it’s on a steady decline.”
That decline in the endogenous cannabinoid system with age fits with previous work by Zimmer and others showing cannabinoid-associated molecules become more scant in the brains of aged animals. “The idea is that as animals grow old, similar to in humans, the activity of the endogenous cannabinoid system goes down—and that coincides with signs of aging in the brain,” Zimmer says. “So we thought, what if we stimulate the system by supplying [externally produced] cannabinoids?”
That idea does not seem so outlandish, considering the role of cannabinoids in maintaining the body’s natural balance, says Mark Ware, a clinical researcher at McGill University in Montreal who was not part of the study. “To anyone who studies the endocannabinoid system, the findings are not necessarily surprising because the system has homeostatic properties everywhere we look,” meaning its effects may vary depending on the situation. For example, a little marijuana may alleviate anxiety but too much can bring on paranoid delusions. Likewise, cannabis can spark an appetite in cancer patients but in other people may produce nausea. So the detrimental effects seen in young brains, in which cannabinoids are already plentiful, may turn out to be beneficial in older brains that have a dearth of them.
These chemicals also work to maintain order at the cellular level, McLaughlin says. “We know the endogenous cannabinoid system’s primary function is to try to preserve homeostasis within a given brain circuit. It works like an internal regulator; when there’s too much [neuronal] activity, cannabinoids suppress activity to prevent neurotoxicity.” Restoring that protection might help safeguard the brain against cellular stress that contributes to aging. “A critical takeaway of this study is that they used low doses,” Ware says, considering that different doses could have entirely different effects. It would be difficult if not impossible to translate the dose they used in mice to a human equivalent, “but it’s clear we’re not talking about vast amounts. We don’t know what would happen with higher doses.”
The researchers don’t suggest seniors should rush out and start using marijuana. “I don’t want to encourage anyone to use cannabis in any form based on this study,” Zimmer says.
Older adults looking to medical cannabis to relieve chronic pain and other ailments are concerned about its side effects, Ware says. “They want to know: Does this cause damage to my brain? Will it impair my memory? If this data holds up in humans…it may suggest that [THC] isn’t likely to have a negative impact if you’re using the right dose. Now the challenge is thrown down to clinical researchers to study that in people,” Ware says.
Zimmer and his colleagues plan to do just that. They have secured funding from the German government, and after clearing regulatory hurdles they will begin testing the effects of THC in elderly adults with mild cognitive impairments.
credit:420intel.com
