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The reefer connection: Brain's "internal marijuana" signaling system implicated in very early stages of Alzheimer's pathology

The reefer connection: Brain's "internal marijuana" signaling system implicated in very early stages of Alzheimer's pathology

funny brain cactusIt’s axiomatic that every psychoactive drug works by mimicking some naturally occurring, evolutionarily adaptive, brain-produced substance. Cocaine and amphetamines mimic some aspects of a signaling chemical in the brain called dopamine. Heroine, morphine, and codeine all mimic neuropeptides called endorphins.

Tetrahydrocannabinol, the active component in mariuana and hashish, is likewise a doppleganger for a set of molecules in the brain called endocannabinoids. The latter evolved not to get us high but to perform numerous important signaling functions known and unknown. One of those is, as Stanford neuroscientist Dan Madison, PhD, puts it, to “open up the learning gate.”

In a key mammalian brain structure called the hippocampus,  which serves as (among other things) a combination GPS system and memory-filing assistant, endocannabinoids act as signal boosters for a key nerve tract – akin to transformers spaced along a high-voltage electrical transmission cable.

But the endocannabinoid system is highly selective in regard to which signals it boosts. Its overall effect in the hippocampus is to separate the wheat from the chaff (or in this case, would it be appropriate to say “the leaves from the seeds and stems”?). This ensures that real information (e.g., “that looks like some food!” or “I remember being here before”) gets passed down the line to the next relay station in the brain’s information-processing assembly line.

A new study in Neuron by Madison and his colleagues shows a likely link between the brain’s endocannabinoid system and a substance long suspected of playing a major, if mysterious, role in initiating Alzheimer’s disease. As I wrote in a release accompanying the study’s publication:

A-beta — strongly suspected to play a key role in Alzheimer’s because it’s the chief constituent of the hallmark clumps dotting the brains of people with Alzheimer’s — may, in the disease’s earliest stages, impair learning and memory by blocking the natural, beneficial action of endocannabinoids in the brain.

This interference with the “learning gate” occurs when A-beta is traveling in tiny, soluble clusters of just a few molecules, long before it aggregates into those textbook clumps. So does it follow that we should all start smoking pot to prevent Alzheimer’s disease?

Hardly. Again, from my release:

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta’s nefarious effects on memory and learning ability… “Endocannabinoids in the brain are very transient and act only when important inputs come in,” said Madison … “Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It’s like listening to five radio stations at once.”

It may even be that A-beta (ubiquitously produced by all the body’s cells), in the right amounts at the right times, is itself performing a crucial if still obscure service: fine-tuning a process that fine-tunes another process that tweaks the circuitry of learning and remembering.

Previously: The brain makes its own Valium: Built-in seizure brake?, How villainous substance starts wrecking synapses long before clumping into Alzheimer’s plaques and Black hat in Alzheimer’s, white hat in multiple sclerosis?
Photo by Phing

6 Responses to “ The reefer connection: Brain's "internal marijuana" signaling system implicated in very early stages of Alzheimer's pathology ”

  1. Lee Trainor Says:

    Once again, I have saved precious brain cells! Due to a supposedly lower than average IQ, I have been systematically avoiding all things that negatively interfere with brain cells, and brain chemistry. Whew! Saved by stupidity!

  2. Hugh Stoner Says:

    I feel they dismiss marijuana’s antiinflammatory properties. Unlike other Scientists like Dr Gary Wenk at Ohio State university, who asserts that marijuana is a preventative for Alzheimer’s. One way they can find out is postmortem autopsies of heavy pot smokers versus non users. Until then, I will continue to protect myself every day.

  3. Bruce Goldman Says:

    Hugh Stoner: Madison does not rule out the possibility that marijuana could be protective. Rather, he cautions against the ASSUMPTION that it’s protective — an assumption you may be making if you’re smoking pot every day to stave off neuroinflammation. You should be aware that the drugs Gary Wenk and his colleagues worked with (endocannabinoid reuptake inhibitor CM707 and endocannabinoid-receptor agonist WIN-55,212-2, respectively) are by no means pharmacologically the same as THC, the active ingredient in marijuana. If you want to get a tooth cavity fixed, note well the difference between a dental drill and a jackhammer.

  4. Bruce Goldman Says:

    [Typo correction: The endocannabinoid reuptake inhibitor mentioned in the comment I just posted (above) is UCM707, not CM707.]

  5. bob day Says:

    cannabis reduces amyloid plaque ,detoxifies the brain, reducesb inflammation, increases blood flow and creates neurogenesis. these studies are flawed and hurt people who might take cannabis to help themselves

  6. DVMadison Says:

    Bruce is correct. We don’t dismiss potential neuro-protective properties of marijuana. We just don’t discuss it because our data don’t speak to the issue. Our caution on the comparison between internal and external cannabinoids comes from the fact that the internal system relies on precisely timed “on demand” cannabinoid production on a seconds-to-minutes time scale to work properly – so it’s difficult to imagine a mechanism whereby the steady application that ingesting marijuana provides, can counteract the ABeta blockade of the internal system. Reuptake inhibitors actually are an attractive area for future research in this area, because they have more potential to at least partially improve the “timed” endocannabinoid function in the face of ABeta blockade.


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