NSAID Cannabinoid Agonism

[iksaxophone]

Studies suggest that NSAIDs such as ibuprofen, acetaminophen, and indomethacin interact with the cannabinoid receptors.(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056416/)

If this is so, why is it that:
a) They only potentiate the effects of more classic CB agonists, rather than exhibiting psychoactive THC-like effects, or the (admittedly anecdotal) perceptable effects of cannabidiol? That is, why do they only seem to be active on inflammation?
b) How is it that they are so much more toxic than other chemicals that effect the CB system (herniation for example, when cannabinoids are fairly good for the digestive tract)?

 

[Jonneh]

Studies suggest that NSAIDs such as ibuprofen, acetaminophen, and indomethacin interact with the cannabinoid receptors.(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056416/)

If this is so, why is it that:
a) They only potentiate the effects of more classic CB agonists, rather than exhibiting psychoactive THC-like effects, or the (admittedly anecdotal) perceptable effects of cannabidiol? That is, why do they only seem to be active on inflammation?
b) How is it that they are so much more toxic than other chemicals that effect the CB system (herniation for example, when cannabinoids are fairly good for the digestive tract)?

a) CB1 vs CB2 agonism? (Only skimmed the paper)
b) Because have completely different structures, and their effects on the digestive tract have nothing to do with cannabinoid activity.

 

[AlphaMethylPhenyl]

From what I can surmise...

Yeah, it looks to met that most of these act non-selectively (inhibiting FAAH, reuptake of anadamide). Also, yeah, CB2 is very involved in the immune response, so it would seem to be much more responsible. The ones that lead to CB1 activation are of very low efficacy, around just enough to deal with physical problems.

Because they have other effects too.

 

[serotonin2A]

It's a crappy review article and the authors are basically regurgitating findings without critically evaluating them or putting them in context. There are much better reviews that you could consult to understand these interactions.

 

[aced126]

Studies suggest that NSAIDs such as ibuprofen, acetaminophen, and indomethacin interact with the cannabinoid receptors.(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056416/)

If this is so, why is it that:
a) They only potentiate the effects of more classic CB agonists, rather than exhibiting psychoactive THC-like effects, or the (admittedly anecdotal) perceptable effects of cannabidiol? That is, why do they only seem to be active on inflammation?
b) How is it that they are so much more toxic than other chemicals that effect the CB system (herniation for example, when cannabinoids are fairly good for the digestive tract)?

a) The concentrations required for significant CB1 activation are probably way above the normal therapeutic dosages. And as others said they might increase CB1 activation indirectly. Also, the NSAIDs you mentioned all are quite polar, and would struggle to get into the brain. CB1 receptors are expressed all over the brain, but only really in the brain, and this is the receptor implicated in psychoactive effects of CB agonists. CB2 receptors are expressed outside the CNS (meaning that NSAIDs would more readily be able to increase activation of these receptors through whatever means) and are involved in the immune response.

b) Firstly, synthetic CB agonists have proved themselves to be significantly more dangerous than cannabis, for reasons that I'm not sure of.

Non-selective NSAIDs inhibit the enzymes cyclooxygenase 1 and COX2. These enzymes are involved in prostaglandin synthesis, which in turn regulates inflammation along with many other roles. Inhibition of COX2 is primarily responsible for analgesic activity of NSAIDs, because this enzyme is induced at inflammation sites and its activation results increased PGE2 synthesis which in turn sensitises nociceptors. COX1 inhibition, however results in inhibition of prostaglandins in the stomach which normally protect the gastric mucous membrane from stomach HCl.

COX2 selective inhibitors (like rofecoxib) avoid this problem, but also inhibit prostacyclin (which inhibits platelet aggregation) synthesis, while not inhibiting thromboxane A2 (stimulates platelet aggregation) synthesis. This is because only COX1 and not COX2 is expressed in platelets, and thus only COX1 is involved in TXA2 synthesis. Thus these compounds caused thrombosis which led them to being removed off the market.

I guess that's a detailed overkill way of saying that NSAIDs can have toxic effects because of mechanisms completely unrelated to CB system modulation.

 

[Jonneh]

^ Detailed, but not overkill. Nice post.

 

[Anxious.Individual]

Metamizole's(it's an NSAID) metabolites are well-known CB1 agonists, but it's impossible to take large enough doses without causing agranulocytosis.

 

[iksaxophone]

Thanks for your detailed response. The polarity thing is interesting, I didn't know about that affecting chemicals at the blood-brain barrier.
And also thank you for explaining the mechanism of COX inhibition, I'm glad I understand why NSAIDs damage the stomach.

 

[Limpet_Chicken]

Doesn't flurbiprofen have true cannabinoidergic agonist actions of its own? I know that taking a significant quantity of flurbiprofen throat lozenges always makes me hungry. It does not get me stoned at those dosages at least, but it DOES make me really, really hungry.

Indometacin is not a trillion miles removed from some of the indoleaklylamine type cannabinoids.
Anecdotally, without getting 'stoned' taking it, I always found indometacin and flurbiprofen to be the most effective out of all the NSAIDs, especially flurbiprofen.