Does Pot Really Improve Memory In the Elderly?

Chronically microdosing THC, the psychoactive ingredient in weed, boosts memory in aged mice, a study published last month in Nature Medicine claims.

I’m a bit late to the party, but I finally had the chance to look more deeply into the paper, and I’ll be blunt: although it made some pretty dope claims, it opens even more questions.

What does the study really say? Let’s hash it out.

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If you’re young, weed’s probably not the best thing for your memory. Yes, there are plenty of functional potheads and occasional stoners. But it’s tough to ignore the vast scientific literature that shows THC impairs spatial and working memory—the ability to keep things in your mind while using it towards a goal.

Scientists believe that THC screws with memory by acting through a partner-in-crime: the CB1 receptor. Within the brain, CB1 receptors are dotted along the lengthy branches of neurons, where they sit on synapses—little structures that neurons use to talk to each other. CB1 directly regulates the strength of those transmissions, which in turn changes neuronal network signaling, leading to changes in things like memory.

THC and CB1 receptor fit like key and lock: when the two hitch up, they open the door for other molecules in the cell to do their business.

Now here’s the quirky part: CB1 receptor has many keys. THC is just one of them. The brain itself produces other molecules that also spring CB1 to life—the “endocannabanoid system.” (This system may be part of the reason behind runner’s high.)

With age, the strength of our internal weed system drops. Scientists have found a decrease in both lock and key in aged mice roughly equivalent to 60-70 year old humans. Because the system directly controls synaptic transmission, this got the team wondering: how does the endocannabanoid system control brain aging? More specifically, can activating the system with THC alter memory in an old animal?

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So how the hell do you get a mouse high?

I had a brief moment of picturing scientists rolling up tiny little joints. But alas, reality was less entertaining. The team implanted tiny little pumps under the skin of mice that slowly released THC: 3mg/kg, roughly 0.09mg per mouse (or 17.5mg for a 154lbs person), for a total of 28 days.

The team “treated” three groups of mice: young adult mice, 12-month-old “mature” mice (~40yrs human age) and 18-month-old aged mice (~60yrs human). A few days after the end of the treatment—enough time for the last of the THC to leave their bodies—the scientists took the mice into a room with a big tub of murky water to test their memory.

While the fluffy rodents can swim, they’re not the biggest fans of water. Dunk them into a pool and they’ll swim around until they find land—in this case, a platform hidden under the water that the mice can stand on. Do it enough times, and eventually the mice learn to use cues in the environment to navigate to the platform.

As expected, chronically high young mice took longer to reach the platform than their sober peers. But surprisingly, the opposite happened for mature and aged mice: the THC-treated ones performed much better.

The scientists saw similar results in two other memory assays that test their ability to remember a familiar object.

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Why is THC boosting memory in older mice?

When scientists looked at the molecular makeup of their hippocampi—a brain region important for memory—they found that THC increased the amount of proteins associated with synapses. This suggests that THC-treated mice have more synapses, and thus more channels of communication.

What’s more, THC also shifted the gene expression profile of these aged mice so that they resembled young sober mice: genes for neuron transmission and development sprung to life, while genes for cell death dropped silent. Because only active genes makes proteins, this changes the entire protein landscape of a cell and how it functions.

 (In contrast, the gene expression profile of a young, THC-treated mouse looked like an aged, sober animal. That is, THC “ages” the brain of young mice, at least in terms of gene expression. Yikes!)

Digging deeper, the team then asked why and how gene expression is changing. They traced the effect to a protein called CREB, which is a “master memory molecule”.

Like a game of telephone, CREB transmits the message “we’ve got THC!” down to its receiver proteins. These receivers rush towards the nucleus. There, our DNA strands lie tightly wrapped around protein blobs, like strings tightly wound around beads.

DNA string wraps around histone "bead", before condensing further. The histone "bead" can have multiple chemicals tagged onto it (P, Ac or Me), which in turn changes the expression of DNA wrapped around it. From Nature Neuroscience 17, 192–200 (2014) doi:10.1038/nn.3628.

DNA string wraps around histone "bead", before condensing further. The histone "bead" can have multiple chemicals tagged onto it (P, Ac or Me), which in turn changes the expression of DNA wrapped around it. From Nature Neuroscience 17, 192–200 (2014) doi:10.1038/nn.3628.

The receivers call on other proteins that stick little chemicals onto the protein beads, which relaxes the DNA strands (a process dubbed “histone modification”). This creates some room for all the molecules involved in gene transcription to butt in—and voila, the DNA is made into proteins!

Or, at least in theory.  Is this process actually what’s causing THC’s memory-boosting effect?

To answer this question, the scientists repeated their previous THC treatment using mature mice, with one twist: this time, some of them were also given a drug that blocks histone modification. The result? THC-treated mature mice no longer showed any improvement in learning.

Finally, the researchers showed that middle-aged mice lacking CB1 receptors on neurons in the frontal regions of the brain didn’t benefit from THC. So CB1 receptors are likely necessary for THC’s brain-boosting effect (such a strange thing to say!).

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Before you run off and get your grandma high, hang around just a bit longer. One big problem about the study is that most experiments were done in middle-aged mice; only the initial learning tasks used old mice. This means that we’re actually not sure what’s going on in older brains after THC treatment.

What’s more, although the scientists wanted to use THC to boost the declining endocannabinoid system, it isn’t really a great replacement. That’s because compared to other internal “keys”, THC activates different molecules when it binds to the CB1 lock, including ones involved in inflammation.

Speaking of locks, CB1 receptors are also present on astrocytes, star-shaped non-neuronal brain cells that dominate our brains. Although once considered supporting cells, astrocytes play an active role in learning and memory; some even believe that weed acts directly on astrocytes, not neurons, to blunt memory.  Whether THC is actually acting on neurons, rather than astrocytes, to boost cognition remains to be seen.

The final verdict?  If just looking at the learning tests, then yes! Low dose THC absolutely shows potential in combating memory loss in aging, at least for spatial learning (for example, remembering where you left your car). But under the hood, we really don’t know what’s going on.

Why is it bad for young mice but not old ones? What happens if you give an old mouse a few giant hits, rather than a constant drip? And what is “low dose” anyways? Does THC have a preventative effect on memory decline with age as well? Are the pro-memory effects still there if you smoke or vape, rather than infuse THC? 

The good news is that the scientists are planning to test low doses of THC on people with mild cognitive impairment, at least once they clear regulatory hurdles. 

 

Bilkei-Gorzo et al. (2017) A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nature Medicine, doi: 10.1038/nm.4311