BLUNTED MEMORY: Few studies have investigated exactly how marijuana impairs working memory. Now it seems the answer might involve non-neuronal brain cells called astrocytes.
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In a 2006, season 2 episode of The Office entitled "Drug Testing," Dwight Schrute interrogates his fellow employees about the partially smoked joint he found in the parking lot. Dwight is determined to identify the culprit, but Jim Halpert turns the tables:
Jim: I'm just saying that you can't be sure that it wasn't you.
Dwight: That's ridiculous. Of course it wasn't me.
Jim: Marijuana is a memory-loss drug, so maybe you just don't remember.
Dwight: I would remember.
Jim: Well how could you if it just erased your memory?
Dwight: That's not how it works!
Half a joint is unlikely to obliterate entire memories, but studies have shown that regularly smoking marijuana for many years does impair working memory—the ability to temporarily hold information in your head, such as a telephone number or the name of someone you just met. Exactly what marijuana does to the brain to muddle up memory formation has remained unclear. Now, a team of researchers has proposed that marijuana hinders the process not by acting on neurons, but rather by acting on non-neuronal brain cells called astrocytes. The finding adds to a growing heap of evidence that such non-electrical structural cells, collectively known as glia, play a far more active role in neural activity than researchers once realized.
Memory depends on a balance of two opposing cellular processes: long-term potentiation, in which connected neurons learn to fire in sync, and long-term depression, the weakening of unnecessary connections among neurons. Xia Zhang of the University of Ottawa Institute of Mental Health Research and his colleagues think that marijuana impairs working memory by throwing off this balance, bolstering long-term depression (LTD) at the expense of long-term potentiation (LTP). Their new study suggests that marijuana increases LTD by triggering a chemical cascade that starts in astrocytes.
"It's probably the first time it's been shown that astrocytes are involved in the primary event [that regulates] memory," says Giovanni Marsicano of INSERM (The French National Institute for Health and Medical Research), one of Zhang's co-authors. Their study appears in the March 2 issue of Cell.
Zhang and his colleagues reached this conclusion after injecting mice with tetrahydrocannabinol (THC), the active component of marijuana, and giving them a series of memory tests, such as forcing the mice to remember the location of an underwater platform in order to emerge from a miniature swimming pool. THC fits like a puzzle piece into tiny cellular structures called cannabinoid type 1 receptors (CB1), which are found on both neurons and astrocytes in the hippocampus—a part of the brain crucial for memory. Marsicano genetically modified one group of mice to lack CB1 receptors on astrocytes and altered another group of mice to lack these receptors on neurons. To the researchers' surprise, mice lacking CB1s on astrocytes did much better on the memory tests than mice lacking the receptors on their neurons. In other words, marijuana impaired working memory only when it was able to bind to astrocytes.
Zhang and his colleagues describe a cascade of chemical changes in the brain that might explain how THC binding to astrocytes results in memory deficits. When THC binds to an astrocyte, the researchers propose, the astrocyte begins spewing a neurotransmitter called glutamate, which in turn binds to a glutamate receptor called NMDA on nearby neurons. As a consequence, the neurons begin absorbing another kind of glutamate receptor, called AMPA, which is a key process in the kind of long-term depression that eventually leads to impaired working memory.
Some earlier research suggests that this chain of events is plausible, but Zhang and his colleagues have not yet worked out all the details; it remains unclear why THC invokes this cascade when it binds to CB1 receptors on astrocytes but not CB1 receptors on neurons. Another unresolved issue is that some previous research contradicts the new findings. Studies by Alfonso Araque of the Cajal Institute in Spain suggest that stimulating the natural production of endocannabinoids—the brain molecules that the marijuana plant imitates—induces long-term potentiation, not long-term depression. Zhang and his colleagues speculate that the discrepancy could be due to the fact that Araque studied slices of brain tissue, rather than studying living animals with intact brains. Slicing up brains might have damaged the connections between astrocytes and neurons, Zhang and his colleagues argue, but they don't have good evidence that this is true. Regardless, future studies must address the new evidence that marijuana only impairs memory if it has access to CB1 receptors on astrocytes.
R. Douglas Fields, an internationally recognized authority on neural–glial interactions at the National Institutes of Health, found the new study very interesting. "This fits it in with what we have been learning about astrocytes regulating synaptic function," he says.
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20 Comments
Add CommentJim isn't so far off-base. I've always said that the test of a good joint is the fact that you forget where you put the roach.
Reply | Report Abuse | Link to thisWhat were we just talking about?
Reply | Report Abuse | Link to thisThis is an entirely false premise to start with. There is no proof that marijuana dulls memory and most certainly in my personal experience, after over thirty years of smoking I have no trouble remembering phone numbers. My memory, in fact, has been and remains almost photographic with no noticeable impairment whatsoever.
Reply | Report Abuse | Link to thisThere is another possibility. In order to RE-member something, you have to member it in the first place. That takes effort and marijuana may dull the motivation to make that effort but that is not the same as saying that it prevents or prohibits the effort from being successful. Chalk this science up to paid propaganda to smear the pro-legalization efforts.
Here's another point that MUST be made with regards to memory impairment if, in fact, SA wants to make this issue a matter of criminal forgetfulness. How about you do some tests on alcohol and memory. Ask yourselves, how many people consuming alcohol can't remember large swathes of time from last night? Not just a f'n phone number! I mean total loss of any memory whatsoever!
Reply | Report Abuse | Link to thisOh, but when they're consuming alcohol that's recreation time and what could possibly so important to remember. Are they going to be quizzed on what transpired on American Idol? But, this bogus study is a subtle anti-legalization message that implies anyone who can't remember little details like a phone number deserves jail. Then let's through those dim Alzheimer patients in the pen, too! Sauce for the goose.
I'm really tired of the gargantuan gaping hole in every neurochemistry article I read that deals with receptors. There is never any focus on the fact that there are two sets of circumstances that must be dealt with: Immediate effects and long term effects. These two tend to be OPPOSITE.
Reply | Report Abuse | Link to thisDown-regulation people!! C'mon, it's not that hard.... seriously... We all know that you take something that hammers a receptor (like cocaine for instance) and the immediate effect is performance enhancement in a number of specific areas, but we're not going to prescribe coke for depression are we?
The long term effect is that there are fewer of those receptors in the long run. Long term is opposite of short term. Anyone seeing a pattern here?
My point is that I pour through journals and see the same thing everywhere. My point is that it is critically important to note that if you chronically or acutely agonize that glutamate receptor then it goes away and no longer functions as powerfully as it did before.
This means that while the process may occur under treatment, the cellular cascades and homeostatic mechanisms will cause it to rebound in the opposite direction after treatment ends. (IE the normal amount of endogenous ligand released will cause an attenuated response in downstream effects) Therefore, AMPA absorbed more under treatment and to a lesser extent therafter until the natural balancing process returns receptor densities to baseline levels.
Will someone please start pointing out these critically important concepts in the field of neurochemistry... Pretty please? For heaven's sake, who do I gotta beg?
Because of this oversight we regularly create drugs that make brains sicker: If the sine qua non of an illness is too many of a particular receptor, we idiotically create a drug that antagonizes the receptor and though it hides the symptoms (short term) the homeostatic cellular system upregulates the receptor (long term). This may make tons of money by causing an intense and growing dependency in the patient but it sure as heck isn't medicine.
Sometimes I feel like I'm watching monkeys with hammers doing brain surgery....
"regularly smoking marijuana for many years" - now there's a precise measurement, the kind we like to see our tax dollars paying for this kind of research, and better yet, results! In what way is this even interesting?
Reply | Report Abuse | Link to thisWell, I haven't had that problem in I don't know know how long!
Reply | Report Abuse | Link to this...in case anyone missed what I hinted at, neurons with lots of dopamine receptors light-up like a christmas tree under cocaine treatment and many downstream cascades are activated as well (part of the mechanism of downregulation) but after treatment, guess what, there's less sensitivity to dopamine... because there are fewer receptors for a good long while. Therefore endogenous dopamine activation is far lower for a number of reasons including the fact that the same amount of endogenous ligand (dopamine)that is normally released, won't hit as many of the same buttons(receptors) in the same time period of time.
Reply | Report Abuse | Link to thisThat's the simplified reason why every street rat can tell you it's never as good as the first time and you always need more..
Well, coke isn't the only chemical that causes downregulation of the receptors that end up acutely agonized my friend....
Yeah, well there's nothing new about pot's tendency to suppress short-term memories, and that's why people "in the know" do pot as much as they do, amd is why it's attractive - people can forget their basic slefish natures and deem irrelevant those feelings which do not correspond with Green theory. Pot influenced minds are open to seemingly ridiculous theories which cannot stand the test of time. Oh well.
Reply | Report Abuse | Link to thisAnyone defending the use of mood altering drugs is just silly. One may question the degree of damage their use does to the brain not that they do no damage3.
Reply | Report Abuse | Link to thisFor that matter, everything, including food and water, can be "toxic", depending how it's used. But this is really less about endlessly debating whether marijuana is totally "harmless", than whether it's being fairly "evaluated" or not.... or worse, whether it's being held to a higher standard than any currently legal drugs (alcohol, nicotine, opiates, etc.), already having well-known and way more harmful effects.
Reply | Report Abuse | Link to thisWhat?
Reply | Report Abuse | Link to thisIt's not the joint that wrecks your memory; it's the pizza ... and something else ...
Reply | Report Abuse | Link to thisMood altering drugs would include all psychiatric medications including antidepressants. Likewise, alcohol, nicotine and caffeine are mood altering drugs. I guess everyone is just "silly" although silliness is a mood that you would like altered.
Reply | Report Abuse | Link to thisIn the defense of the many intelligent thoughtful and considerate, folk who find occasion to tickle their cannabinoid receptors. We understand that smoking anything is bad for our lungs, in the same way that we know it is even more dangerous to have casual unprotected sex. Those who smoke marijuana have simply chosen their "poison".
Reply | Report Abuse | Link to thisgeojellyroll, we, with heightened perception, "get" that you feel people shouldn't use drugs, maybe for health reasons maybe even more so for ethical reasons. Despite this, when I turn to commenting on the actual experiment I see the report as fallible, and not really worth much as a piece of "conclusive" evidence of anything.
I may swim a path in a river dozens of time, but if I were to be stoned by pharmaceutically purified I.V. injected tetrahydracannabinol and then thrust under a pool of water by a human being, or assuming the tables were turned and it were a giant mouse, while still keeping in mind that I am a GMO product which likely means I have been inbred to some degree, I might be caught a little off kilter too.
How is torturing these mice in such an unusual way a serious study of anything? Seriously. If this experiment is trying to get at anything scientific at all, it has nothing to do with whether it is "ethical" or "healthy" to smoke the good green gracious ganja.
This is an experiment regarding the effects of antagonizing cannibanoid receptors on astrocytes vs neurons and the impairment of memory development. The actual qualitative information here probably has more to do with how memories are actually formed in the neural network than long term effects of marijuana use. Cannabis just helped discover the link. See how useful weed is now?
This experiment has little to do with smoking a little reefer. Keep in mind, the cannabinoid receptors and using them isn't bad. Eating doses of processed Na+Cl- three times a day is! Simply put, antagonizing any cellular protein receptor to the point of maxing it out is bad.
I'm not sure what conclusion we are supposed to draw from this study.
Reply | Report Abuse | Link to thisWe know that T.H.C. is stored in human fat cells for up to 2 weeks. Regular usage over a long term will cause a significant buildup that is continually being discharged. Does an observed physical effect of marijuana on the human brain last well beyond any possible residual release of T.H.C. into the system?
If so how long and by what mechanism?
I have no doubt that a mouse that is placed in a life threatening situation in a swimming environment with which he has previous experience will do much better than one that is _injected_ with T.H.C. and is consequently overwhelmed with drug enhanced fear of drowning.
Put two humans in a similar test and the only hazard would be that the stoned human might drown from laughing so hard at the absurdity that anyone would think he might not be able to remember where the ladder out of the pool is.
Even the authors acknowledge that their results are counter-intuitive, have no discernible cause and effect and are contradicted by previous studies.
I emphasized _injected_ because I have some experience with the much more intense, slower to start but longer lasting, more difficult to manage, high that comes from eating marijuana in brownies rather than smoking it. I have absolutely no experience with injecting it and can't even imagine what short and long term physical and mental effects such a method of consumption would produce.
Injecting mice with T.H.C. and then scaring the crap out them seems to offer little insight into common place human drug use.
Sorry. You posted your comment while I was composing mine.
Reply | Report Abuse | Link to thisYou made my point better than I. If I had read yours first I wouldn't have bothered posting.
@ #10
Reply | Report Abuse | Link to thisUm...you do know that human mood alteration through substance use pre-dates recorded history, right? Even other animal species are known to seek out such substances. Do you own a cat?
I'm all for those who want to puff to have at it. But certainly this is research and a study so your own rebuttal to the premise is one would have to say is false itself. Knowledge comes from information. So in that case, regardless of a stand on smoking vs. non-smoking, this is something to read and take in and ponder.
Reply | Report Abuse | Link to thisI agree. Cannabis use never stopped me from breaking the curve in my university calculus + statistics exams,much to my classmates' chagrin. Nor did using cannabis prevent me from graduating with cum laude honors. In fact, since cannabis alleviates the terrible insomnia I endured until I tried it in my teens, I'm not exhausted + irritable. I have a better memory for carrying numbers short term, whether phone #s or doing arithmetic in my head.
Reply | Report Abuse | Link to thisIn fact, a study published in 2009 by the Institute of Psychiatry at Norway's University of Oslo found that patients with bipolar disorder who used cannabis performed better on neurocognitive tests than non-users. There have been a number of reputable studies indicating a protective effect of cannabinoids on the brain relating to injury, alcohol use, + Alzheimer's.
The addle-brained stereotypical stoner isn't actually that common among cannabis users, either. Prohibition's draconian repercussions make the majority of pot smokers strive to maintain invisibility to the rest of society. Indeed, many advocating an end to Prohibition speculate that Stephen Hawking would not be alive today if he didn't (secretly, of course) use this amazing plant. Richard Feynmann also admitted to using it.
Bottom line, "Reefer Madness" was a lie. Prohibition does far more harm than any purported good + it's time to end it!