Tuesday, June 25, 2013

Chronic Cannabis Exposure Induces Cerebellar Inflammation?

The cerebellum, also known as the "little brain" is at the base of brain. Originally thought to be involved in the "fine tuning" of motor function we now know it plays an important role in wide variety of behaviors. This news item from Live Science highlights a potential risk from chronic cannabis exposure but after reading the full journal article I realise there are some important reservations about the claims made in the Live Science article.

The journal article makes it clear that the increase in inflammatory mediators occurs after THC administration, not during it. As the authors note this arises because the receptor for THC, CB1R, is very much down regulated by chronic THC exposure, this finding being consistent with the literature. Thus ...
 Similarly, the neuroinflammatory markers Il1bTnfaCox2Cxcl2, and Il10 were not altered in the cerebellum at the end of THC treatment (Supplemental Figure 7G).
When the time course of these effects mediated by THC exposure was studied, we observed that CD11b expression increased in the cerebellum only 5 days after THC cessation, while the downregulation of CB1R expression reached its maximum level at the end of subchronic THC treatment, slowly recovering afterward (Supplemental Figure 8A).
By using minocycline, known to inhibit microglial activation, the authors found they could inhibit the the elevation of inflammatory markers. As an aside I found this interesting:
We evaluated the relationship between microglial activation and cerebellar deficits using minocycline, a second-generation tetracycline antibiotic with inhibitory effects on microglial activation (35) that are probably due to its ability to block 5-lipoxigenase expression (45).
Interesting because a few days ago I read some abstracts strongly suggesting that 5-Lox inhibition is a useful candidate for some cancer therapies. Specific 5-Lox inhibitors have recently become available for asthma so the drugs have been trialled and this should present opportunities for further cancer treatments. The inhibition of 5-Lox prevents the production of inflammatory related leukotrienes derived from arachidonic acid. Minocycline is also known to inhibit the release of  nitric oxide, which can act as a pro-oxidant under certain conditions and is possibly a downstream effect of 5-Lox inhibition.

Does this study suggest that chronic cannabis exposure induces cerebellar atrophy?

I'm doubtful about that because cannabinoids have been consistently demonstrated to be neuro-protective across a surprisingly wide range of neurological insults. As noted in the study:

A possible mechanism to explain this neuroinflammatory process would be the putative glutamate mishandling by CB1R-containing deregulated terminals, since extracellular glutamate concentrations are tightly regulated at synapses onto Purkinje cells (47).

Yes, that make sense because CB1R activation typically impedes glutamate release, probably by inhibiting calcium influx. CB1R activation does involve post synaptic inhibition of the pre-synaptic cell. The endogenous cannabinoids, those produced by our brains, travel back across the synapse to inhibit the pre-synaptic cell. The loss of CB1R, which occurs very quickly in this study, only 5 days, will increase glutamate release until CB1R levels are restored. As microglia express glutamate receptors it is conceivable that microglia are becoming activated by the extra glutamate.

This is confusing, it appears the increase in inflammation 5 days after THC administration is cerebellar specific:
Notably, the microglial activation phenotype was not detectable in other brain areas where CB1Rs are heavily expressed such as the hippocampus, frontal cortex, or striatum (Supplemental Figure 4).
While neuroinflammation is generally a bad thing in this instance the results are confusing:
Fluoro-Jade B assay revealed no signs of cellular death in the cerebellum at the end of subchronic THC treatment, suggesting that the microglial reactivity was not associated with cytotoxicity processes (Supplemental Figure 7, A and B). 
Additionally the deficits were reversible, again this is consistent with other studies.

What are the Implications for Chronic Marijuana Users?

There is so much literature surrounding this question that at present it is impossible to draw any firm conclusions. A recent New Zealand study made the headlines because results pointed to very worrying declines in IQ as a result of heavy teenage marijuana consumption. This study has already been challenged and generally it not supported by the bulk of the literature. My personal view is that if there is a risk it is rather small and probably confined to a subset of individuals who have other risk factors that cumulatively lead to cognitive deficits.

What this study does not highlight though is that the "post chronic marijuana blues", which can last for some weeks, may be a result of low level cerebellar inflammation that will resolve. However because cannabinoids are lipid soluble it could take some weeks for sufficient washout to occur that will allow restoration of CB1R levels. For a regular consumer of cannabis it could anything from 1 to 3 month for a sufficient washout to occur.

While many will disagree with me I have no doubt that chronic marijuana use does induce couch potato syndrome, is next to disastrous for academic performance because it seriously disrupts working memory capacity, and the chronic cognitive apathy it induces is much more damaging to our cerebral health than any direct effects of cannabis.


Matuas Seeker said...

Another pseudo-science blog? "If you read this, you will see that they did not test cannabis, they tested the Big Pharma Poison Synthetic THC used in the drug Marinol (since this is the only source of pure THC for study, and they sure as hell aren't using RSO!) So, their poison THC without the other 400+ mitigating cannabinoids found in REAL cannabis results in brain inflammation and then they blame cannabis use"
The drug is really quite a remarkably safe one for humans, although it is really quite a dangerous one for mice and they should not use it."

-J.W.D Henderson Director of the Bureau of Human Drugs, Health and Welfare, Canada
please stop spread quackery

John said...

Did you read the post or just decide the title explained everything? I challenged this study in a number of ways and I challenged the NZ IQ study.

Matuas Seeker said...

Sorry i dont want post it here. My bad