3 of 3 Endocannabinoid Breakdown Enzymes

Jamie Hadfield

Endocannabinoid breakdown enzymes are the third major component of the Endocannabinoid System. These enzymes do exactly what their name describes: they help break down endocannabinoids that have already done their job.

While breakdown enzymes are probably the least well-known part of the ECS, they’re no less important than its other facets.

Without them, endocannabinoids would build up to excessive levels and quickly overrun the needs of their receptors. With them, the entire system runs smoothly and is able to be modulated in real time. How exactly does this work?

Keep in mind that Endocannabinoids like Anandamide have a very short life cycle. First, they’re synthesized out of the phospholipid membranes of nerve cells. Then they travel across the synaptic junction on the way to their destination - the presynaptic cell. That’s where other neurotransmitters are being sent from, and that’s where endocannabinoid receptors are located.

So, each endocannabinoid is ‘taken up’ into its receptor, triggers a conformational change in the receptor’s shape and function, and sends signals to other chemical messengers. Having done its job, the endocannabinoid is ready to be dissolved back into the more basic elements that formed it.

This is where endocannabinoid breakdown enzymes come in. Think of them as a the biochemical solvents that recycle eCB’s so they can return to their job again later. It’s more energy-efficient, after all, to recycle used molecules than it is to synthesize new ones.

Copyright @ Leafly.

There’s even some evidence that these breakdown enzymes pair their activity directly to endocannabinoid production. When stress is high, more eCB’s are ‘cleaved’ off of nerve cells and sent off for signalling, and more breakdown enzymes are activated to recycle them. This synchronized action means that eCB levels can easily stay within their desired range.

There are several known endocannabinoid breakdown enzymes:

  • FAAH (Fatty acid amide hydrolase): Primarily breaks down Anandamide
  • MAGL (Monoacylglycerol lipase): Primarily breaks down 2-AG
  • COX-2 Breaks down both Anandamide & 2-AG
  • Cytochrome P450 Breaks down eCB’s in the liver

A few more breakdown enzymes, like NAPE-PLD and DAGL...

Of all the enzymes, FAAH is the most active. Studies show that it’s almost always required to breakdown endocannabinoids in the brain. FAAH also has a unique structure that means it can simultaneously access several parts of its targets - resulting in quick breakdown and turnover.

While endocannabinoid breakdown enzymes are vital to our health, it’s still possible to have too much of a good thing. For someone deficient in endocannabinoids, enzymes like FAAH may be helping too much. This person’s endocannabinoids may be getting recycled prematurely - before they can fully impart their effects.

Thankfully, there is a way to remediate this: cannabinoid reuptake inhibitors.

The potential of some organic compounds to inhibit, or slow down, the FAAH enzyme marks an interesting area of medical research. Compounds that do this are called reuptake inhibitors or even endocannabinoid enhancers.

Once again, the versatility of Cannabidiol saves the day. CBD has been shown to reduce FAAH’s actions on endocannabinoids - meaning eCB’s stick around for longer and have stronger effects - which is probably one reason why it’s so good for ECS health.

A more extreme example: mice that have their FAAH production ‘knocked out’ demonstrate less sensitivity to heat and pain. These mice are also extremely sensitive to anandamide, which is now free to remain potent and continue ‘hitting’ eCB receptors. When it comes to breakdown enzymes, balance is everything.

So while knocking out FAAH production isn’t the most holistic approach, it does demonstrate an important concept. Boosting eCB’s via reduction of their breakdown enzymes holds potential for those who are endocannabinoid deficient. It’s simple enough: slow down eCB breakdown so that eCB will be allowed to catch up.  

And the best, most natural way to slow this breakdown (and reduce FAAH) is by taking CBD. CBD’s selective nature means that it inhibits reuptake only as needed. Together with other cannabinoids in hemp, CBD helps ensure that a person has just the right amount of endocannabinoids in their system.