5 Ways NSAIDs and Cannabinoids Are Intertwined

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are related to cannabinoids in more ways than you might think. Here are the top 5.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the first lines of defense against mild to moderate pain. This class of drugs includes aspirin, ibuprofen, and naproxen. Acetaminophen is also sometimes included, although it has some significant differences from the others (which will be important soon!)

The main mechanism of NSAIDs is the inhibition of the cyclooxygenase-2 (COX-2) enzyme, thus blocking the production of pro-inflammatory prostaglandins which contribute to pain.

You probably are wondering what do NSAIDs have to do with cannabinoids? NSAIDs work through the prostaglandin system and cannabinoids work through the endocannabinoid system. NSAIDs are a well accepted part of medical practice, whereas cannabinoids are still (generally speaking) controversial. Nothing could be further apart, right?

Well prepare yourself, because these two classes of drugs are more intertwined than you could have imagined!


1. Cannabinoids and NSAIDs May Synergistically Reduce Pain

NSAIDs can reduce pain. Cannabinoids can reduce pain. So what happens when you take them together? Some studies have reported that cannabinoids and NSAIDs may reduce pain in a synergistic fashion. Here are 5 examples:

  • Local interactions between anandamide and ibuprofen in acute and inflammatory pain (2005 study)
  • Blockade of central COX pathways enhances cannabinoid-induced antinociceptive effects (2007 study)
  • Effect of cannabinoid receptor agonists on streptozotocin-induced hyperalgesia (2008 study)
  • Synergy between enzyme inhibitors of FAAH and COX in visceral nociception (2009 study)
  • The antinociceptive effect of acetylsalicylic acid is differently affected by a CB1 agonist or antagonist (2010 study)

Not every study has reported a synergistic interaction, but it seems likely in certain cases.


2. Acetaminophen Can Inhibit Endocannabinoid Reuptake

Image: Profofpot.com

Acetaminophen (paracetamol, Tylenol) has long been a mystery. It reduces pain even despite the fact that it does not have a strong effect on inflammation (thus, it is not truly an NSAID). Other NSAIDs reduce both pain and inflammation through the same mechanism, so the diverging effects of acetaminophen were not easily reconciled.

2005 study was the turning point where things started to make sense. It showed that acetaminophen could boost levels of anandamide leading to analgesia. Several studies have shown that acetaminophen loses its pain relieving activities in rodents when cannabinoid CB1 receptors are blocked or removed.

How acetaminophen boosts anandamide is a rather strange story. An active metabolite (called AM404) is formed which blocks reuptake of anandamide into cells, thus elevating its levels in the synapse. AM404 is formed by none other than fatty acid amide hydrolase (FAAH) – an endocannabinoid enzyme that is normally responsible for degradinganandamide.

To this day, we are still studying exactly how AM404 works. A recent 2018 studydemonstrated that AM404 exerts its analgesic effect through activation of CB1 receptors in a specific part of the brain called the rostral ventromedial medulla.

Note: the overall activity of acetaminophen is complex and involves other metabolites and receptors such as TRPV1and TRPA1.


3. NSAIDs Can Inhibit Endocannabinoid Degradation

The COX-2 enzyme is versatile. Not only does it form the pro-inflammatory prostaglandins, but it also metabolizes the anti-inflammatory endocannabinoids. A 2013 study showed inhibition of COX-2 with the NSAID indomethacin can raise brain anandamide and 2-AG levels in mice!

The endocannabinoid-boosting effect isn’t as strong as an inhibitor of FAAH or MAGL (the other two endocannabinoid-degrading enzymes). Yet, it was sufficient to reduce stress-induced anxiety behavior in mice according to a 2016 study. Although this has not been well studied in humans, there are extensive anecdotal reports online of NSAIDs helping with anxiety.

It’s strange to think of NSAIDs as being psychoactive, but this appears to be the case.


4. NSAIDs May Reduce Some Side Effects of THC

Chronic THC may impair certain types of memory through it’s actions on the CB1 receptor in a brain region called the hippocampus. A 2013 study presented a surprising finding – these effects were mediated through induction of the COX-2 enzyme. Inhibition of COX-2 was able to preserve learning and memory even after chronic THC treatment. It also blocked the decrease in locomotor activity from THC.

Despite these findings in mice, the effect of NSAIDs on THC-induced memory impairments has not yet been adequately validated in humans. A 1991 study did not show an effect of the NSAID indomethacin on verbal recall after consuming cannabis, although it did reduce several other effects of THC.


5. Phytocannabinoids Also Inhibit COX-2

It is not only the NSAIDs that can inhibit the COX-2 enzyme. A 2008 study and 2011 study showed that several minor cannabinoids can also directly inhibit COX-2. Those capable of inhibiting COX-2 activity by at least 30% included:

  • THC-A
  • CBD-A
  • CBG
  • CBG-A

However, the potencies of these cannabinoids were low relative to NSAIDs. The IC50 for COX-2 inhibition was over 100 μM for all cannabinoids according to the 2011 study. The 2008 study reported a (conflicting) IC50 of 2 μM for CBD-A. These concentrations may be achievable in the GI tract or in the skin (for a topical formulation), but probably not in the brain.

© 2018 Professor of Pot. All rights reserved. Original article at www.profofpot.com. Reposted by special permission.

Professor of Pot

I am the Professor of Pot. I have a Ph.D. with degrees in Neuroscience and Pharmacology. I have had a long-standing interest (20+ years) in the science of cannabis. I write about any story that involves interaction of cannabis or cannabinoids with the human body. I include all aspects of cannabis, whether it is medicinal, recreation, or drug testing. Please contact me at profofpot at gmail.com if there is a topic that you would like to see covered. Visit my website at www.profofpot.com for more articles. Enjoy!

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