Slightly stoned mice show marijuana may fight age-related memory loss..
Two levels below ground, under a small, drab building at the University of Bonn, is a wall of cages containing mice that, according to standard tests, are extraordinarily average. They learn and remember how to run mazes no better nor worse than other mice. It takes them a typical amount of time to figure out how to extricate themselves from a tank of water with hidden exit steps. There’s nothing out of line about how they interact with other mice, nor their willingness to explore open spaces. And yet these mice are the center of attention at the lab of Andreas Zimmer. That’s because their boringly average minds may well hold the key to beating Alzheimer’s and elderly dementia. Many of the mice are 18 months old, roughly equivalent to a 70-year-old human. Mice normally start to show mental decline at around a year old, and by 18 months, struggle with mazes and other mental tasks, as well as with socializing. But not these rodent seniors. “You can’t tell the difference between them and two-month-old mice,” says Zimmer. Even more surprising is what Zimmer has done to get these elderly mice remembering and behaving like younger ones. It’s not special genes, a particular training regimen, nor an unusual diet. They don’t get any approved memory drug, nor a new investigational procedure. Basically, Zimmer keeps them very slightly stoned. A longtime U.S. National Institutes of Health (NIH) researcher who is now one of Germany’s most respected neuroscientists, Zimmer has been on a long journey to answer a question that few researchers had thought to ask: Is it possible that weed, long seen as the stuff of slackers, might actually contain the secret to sharpening the aging brain?
His findings have suggested that may be the case. As the data continues to stream in, some in the lab have begun quietly encouraging their aging parents to toke away, laws be damned. “I sent my mother recipes for baking pot cookies,” says one researcher in Zimmer’s lab, who asked not to be identified because it’s still illegal in the mother’s country. In 2005, Zimmer’s research was the first to provide convincing evidence that synthetic THC seems to slow age-related brain degeneration. His results since then, combined with a general renaissance in cannabis research that parallels the growing popular and political acceptance of weed, has added more weight to that theory and spurred the interest of labs around the world. Until recently, most of the research has been conducted on mice. But newer research conducted at Johns Hopkins University, Harvard Medical School-affiliated McLean Hospital, and the University of Colorado, among other places, has already suggested that at least some of the benefits of THC — the component primarily responsible for marijuana’s psychoactive effects — accrue in humans’ aging brains. Taken together, this progress has set off a worldwide race to nail down solid proof that, as unlikely as it may sound, pot works in humans to slow, and possibly reverse, Alzheimer’s and other forms of dementia. It’s a race Zimmer intends to win.
There’s a lot happening in Zimmer’s sprawling lab, which takes up much of an upper floor in a research building just across from the facility housing the mice.
Scientists from all over the world work here on a range of research projects, investigating conditions from migraine to chronic stress to nerve damage. But for all the diverse activity at the lab, there’s a clear theme: decoding aging and failing brains by identifying how drugs affect various brain cell receptors. These small blobs of protein stick out of the surfaces of neurons and serve as sort of light switches for the cell, turning different activities in the cell on and off. The key receptor in this lab is known as CB1; CB refers to cannabinoid, the name given to a class of chemicals that includes THC.
How do you get mice high? Anyone who has been to a legal marijuana dispensary has probably seen the bewildering variety of oils, waxy blobs, fine powders, gummy treats and even inhalers. But put aside images of toking or dabbing mice. Rigorously studying the impact of pot requires a more reliable and measurable delivery vehicle. The solution is what’s called an osmotic pump, a plastic capsule the size of a pencil eraser, surgically implanted just under the abdominal skin, that’s designed to leak synthetic THC at a steady rate for 28 days.
The mildly baked mice, along with their THC-free counterparts serving as control subjects, are tested in a sort of rodent psychiatric playground near their cages. Under the gaze of video cameras and red light that’s friendly to nocturnal eyes, the mice navigate various cages and tanks. They face gizmos and structures designed to assess their mental prowess: their powers of recall, facility in learning new tasks, willingness to come out of hiding and interest in finding other mice.
The effect of THC has been clear and striking. Older mice that had forgotten how to run mazes recovered the knack. Mice whose aging brains couldn’t distinguish an empty can from a fellow mouse suddenly relearned the ability. “The effects are extremely robust and easy to see,” says Zimmer. “It works reliably on every measure of cognition we have for mice.”
Know Your Compounds
Despite their similar molecular structures, the two main compounds in marijuana — tetrahydrocannabinol (THC) and cannabidiol (CBD) — have different effects in the human body.
An active ingredient in marijuana that makes you high, THC binds to CB1 receptors in the brain to create a euphoric effect.
This compound in cannabis is non-psychoactive, meaning it won’t give you a high. It has little affinity for binding with the CB1 or CB2 receptors, and can actually hinder THC’s effects when combined. Instead, CBD can activate other receptors, such as serotonin, and is more often sought out for its potential medicinal benefits, such as pain and anxiety relief.
In a newer series of experiments, the lab has begun mounting cameras on the shaved skulls of mice whose brains have been genetically engineered to literally glow with activity. Zimmer’s team can then image the increase in connections between brain cells in mice on THC — especially in the hippocampus, the part of the brain responsible for memory.
That work fits with mouse research at the Salk Institute for Biological Studies in San Diego and the University of Barcelona. Teams at both institutions have shown that THC clears up some of the tangled brain proteins and clogging plaques that are the biological hallmarks of Alzheimer’s. THC has also been shown to reduce inflammation in mouse brains, another physical tag of Alzheimer’s. (CBD, THC’s non-psychoactive fellow cannabinoid, also acts as an anti-inflammatory.)
The results of the Zimmer’s THC-charged cognitive findings were published in Nature Medicine in 2017, and soon validated by other labs.
Marijuana has been on Zimmer’s mind for decades. In 1989, the German native arrived at the National Institute of Mental Health, part of the NIH, as a newly minted neuroscientist. He quickly became an expert in genetically engineering and breeding generations of so-called knockout mice. These mice lack a particular protein or biological function, such as the ability to produce Carboxypeptidase E, a type of protein building block whose absence results in mice with obesity, or to produce the p53 protein, which leads to mice much more likely to develop any of several types of cancer. Scientists can then either study the protein or function via its absence, or use the mouse as a proxy for humans with similar symptoms. Zimmer was soon collaborating with the NIH team that ended up discovering the CB1 receptor, and eventually its activation by THC. “It sounds boring to try to find out what was activating a receptor,” he says. “But it didn’t turn out that way.”
In fact, the CB1 receptor was far more than just a mechanism for feeling stoned. Most receptors are confined to specific regions of the brain, or only show up in neurons associated with specific brain activities, such as memory, emotion, sight or motor control. But CB1 soon proved to be one of the most ubiquitous brain receptors ever discovered: It was found throughout the brains of humans, mice and most creatures, indicating it was involved with virtually everything that happens in the brain.
Zimmer returned to Germany in 2000, where the University of Bonn created the Institute of Molecular Psychiatry around him, along with providing the resources to build a lab that soon grew to 40 people. There, Zimmer started developing knockout mice that lacked the CB1 receptor. In testing them, one surprising change became apparent: The mice were, well, dumber. They soon forgot how to run mazes and became socially inept. “They were going into premature cognitive decline,” says Zimmer team member neuroscientist Andras Bilkei-Gorzo, who has been researching the aging brain for two decades. Yet the mice were only 6 months old — equivalent to a human at 35.
Researchers at the Free University of Brussels and elsewhere were also studying CB1 knockout mice. But, bafflingly, they were coming up with the opposite finding: that the knockouts were smarter than normal mice. It was as if two mechanics had removed the same part from two identical cars, and one found the car got better gas mileage and the other saw worse mileage.
Bilkei-Gorzo more closely compared notes with the other researchers, and the difference suddenly leapt out. While the Zimmer mice were always tested as mature adults, the others were using mice 6 weeks old — the age equivalent of human teenagers — to get test data sooner. Further tests at the Zimmer lab confirmed that the elimination of the CB1 receptor tended to dumb down only older mice, not younger ones.
Published in Nature Neuroscience in 2005, the finding mostly served to raise a more interesting question. If blocking CB1 sends mice slipping toward dementia ahead of their time, that implies the receptor does something to help older brains delay that decline — which in turn raised the possibility that increasing CB1’s activity beyond normal ranges might be a bigger benefit for older mice. “We thought maybe THC could be a brake on aging of the brain,” says Bilkei-Gorzo.
Suddenly, the lab had a new focus.
Calming the Brain
Zimmer could hardly have tackled a more pressing health problem. Roughly 50 million people worldwide have dementia, according to World Health Organization estimates. The number of dementia cases could skyrocket to 150 million by 2050. Globally, about 1 out of 9 people at least 65 years old has dementia; nearly a third of those 85 and older show some degree of cognitive decline. More than two-thirds of those with dementia have the Alzheimer’s type. There are four approved drugs for Alzheimer’s, but they are decades old and, on average, barely slow the progress of the disease.
In their CB1 work, scientists had a promising target, and in THC they had their arrow. By 2018, about a dozen labs around the world were looking at THC and its effects on dementia. But Zimmer had the funding and a big enough team to push further and faster with focus. With his 2017 Nature Medicine paper, his lab had become the first to clearly show that a THC treatment turned the clock back on mice’s aging brains. Now it had to shift into higher gear: proving that THC can do for humans what it does for mice.
Unfortunately, the majority of drugs that work well in mice never prove successful in human clinical trials. On the other hand, many studies over the years have shown that marijuana appears to work in similar ways in mice and humans. For example, a study from the University of Birmingham in the U.K. had already shown by 1975 that THC makes mice more social, and a 2010 University of Mississippi study demonstrated THC’s antidepressant effect on mice.
“THC can’t be super-harmful — we’d know about it by now,” says Britta Schürmann, a biologist on the Zimmer team.
In addition, THC has some unusual strengths as a potential Alzheimer’s drug. Most Alzheimer’s drugs aim to reduce either the disease’s inflammation, or brain plaques and tangles. But THC attacks on all three fronts at once. Whether suppressing any or all of these Alzheimer’s indicators diminishes the actual progress of the disease, or just treats the symptoms, is still an open question. But Zimmer believes it’s a question that gives a CB1-based approach its biggest edge, because he thinks it works via a novel approach: managing energy expenditure and reducing excess activity in the brain.
Think of the brain as a car. In children and teenagers, brains are in the throes of rapid development and change, like a car that tends to speed dangerously. To help calm things down, the brain’s CB1 system naturally steps up and acts as a brake, no external THC needed. This slows down brain activity and ensures a safe drive. (It may also explain why THC could be harmful for young people: The receptor is highly active on its own, and extra THC may overload the brakes and impair development.)
But with age, the CB1 receptor slowly loses much of its function, becoming less and less internally activated. And that makes sense, from an evolutionary point of view. Why would older people need a brake on brain activity? While evolution might not care, though, it ought to concern us. Like an old car driven too hard, too much energy and activity in the older brain may lead to the neurodegenerative effects of aging, including Alzheimer’s and other forms of dementia. THC seems to restore the cautious braking that keeps the brain in good shape.
THC for Symptom Relief
While the Zimmer lab’s mouse research supports the idea, setting up a human trial specifically for pot as an aging-brain treatment poses challenges. Alzheimer’s trials have to last as long as a decade, because the disease progresses so slowly. And marijuana and THC, natural or synthetic, are still tightly restricted — though it may help that Zimmer’s mice are treated at doses below any measurable psychoactive effects, suggesting that people in the trial wouldn’t have to get high to see the benefits. Major pharmaceutical companies, meanwhile, tend to ignore the drug because it’s increasingly available from dispensaries or local dealers, or even for free. As Angela Bryan, a neuroscientist at the University of Colorado at Boulder who studies marijuana, puts it, “Why would patients buy it when you can grow it in your backyard?”
Zimmer hopes that despite these issues, the German government will fund a multi-year human trial to determine if the brain-preserving effects of THC seen in mice carry over to people. That’s not a sure thing: “We don’t know when we can start,” he says. Even so, given the obstacles to a clinical trial, a delay of a few years might still leave Zimmer at the front of the pack.
THC is already being used to relieve the most challenging behavioral symptoms of Alzheimer’s. “Agitation, aggression, violence — this is what drives the severity of the disease, and it’s the burden that causes families to place patients in care facilities,” says Brent Forester, chief of geriatric psychiatry at McLean Hospital. “Almost anyone with dementia exhibits these problems to some extent.”
The FDA hasn’t approved drugs to treat these symptoms, he adds. But several studies have indicated that THC helps with the behavioral symptoms. Forester and colleagues are starting an 80-patient randomized clinical trial to further test the benefits. An unexpected challenge, says Forester, is getting his colleagues to refer their patients to the study — the drug is working so well that they’re afraid their patients will end up in the placebo arm instead of getting THC. “They’d rather just put their patients on THC directly instead of putting them in a trial where they might or might not get it,” he says.
Reducing Alzheimer’s agitation is still a far cry from proving that THC can slow and even reverse cognitive and memory damage, as Zimmer has done with mice. But Forester adds he’s hopeful the benefits will spill into memory restoration. He points out that fellow McLean researcher Staci Gruber found THC-treated older patients improved their performance in a number of cognitive tasks. Other researchers are seeing similar results. A study by Johns Hopkins researcher Lauren Hersch Nicholas found older people become more likely to stay employed after medical marijuana becomes legal in their states. “Productive engagement in work is an important measure of the impact of a treatment,” says Nicholas. The University of Colorado’s Bryan has also been studying older medical marijuana users. “If anything, they seem to do a little better cognitively,” she says. Perhaps that’s one reason people over 65 are the fastest-growing group of pot users in the U.S.
Zimmer himself won’t yet go as far as recommending that seniors take up pot specifically to treat or fend off dementia. “I’m not a clinician, so on this question I yield to physicians,” he says. “But as a scientist, I’m confronted by my observations on mice, and my knowledge that in the THC field, what works on mice works on humans. And that leaves me quite enthusiastic.”