Endocannabinoid enzymes: what they are and their therapeutic potential

Endocannabinoid enzymes are components produced by our body whose function is to synthesise and break down cannabinoids. They are intrinsically linked to the endocannabinoid system, offer enormous therapeutic potential and broaden our knowledge of cannabidiol (CBD) and its effects.

However, probably because the subject is somewhat complex, endocannabinoid enzymes don't usually get all the attention they deserve. If you're up for learning something new, today on the Cannactiva blog we tell you more about the enzymes responsible for metabolising endocannabinoids in our body. You'll find out about the effects of phytocannabinoids, such as CBD and THC, on these enzymes and their therapeutic potential. Get ready for this cannabinoid science post with some CBD flower (bear in mind that in some countries, such as the UK, hemp flower is controlled even when it is low in THC). Let's get into it!

Introduction to cannabinoid enzymes

What are endocannabinoid enzymes?

Endocannabinoid enzymes play a crucial role in the synthesis and degradation of endocannabinoids, which are the cannabinoids produced naturally by our body.

Endocannabinoid enzymes are responsible for the production and regulation of endocannabinoids, which are the cannabinoids produced by our body.

An enzyme is a specialised protein that performs a function, that does something. In this case, endocannabinoid enzymes are responsible for synthesising and transforming endocannabinoids.

The endocannabinoids in our body are produced by endocannabinoid enzymes.

Cannabinoid enzymes take part in biochemical processes that convert precursor substances into active endocannabinoids, and they are also responsible for breaking these compounds down so that their effect comes to an end. In this way, endocannabinoid enzymes are responsible for the production and regulation of endocannabinoids.

Differences between endocannabinoid enzymes and cannabinoid enzymes

These enzymes should not be confused with those found in the cannabis plant, which are responsible for the biosynthesis of phytocannabinoids. The endocannabinoid enzymes we are talking about today are produced in and found in our body, not in the cannabis plant.

How do endocannabinoid enzymes work?

Well, let's start at the beginning: with endocannabinoids. Endocannabinoids are cannabinoids produced by the human body that bind to the receptors of the endocannabinoid system, known as cannabinoid receptors, which we have inside our body [1]. The CB1 receptor is found in the brain, while the CB2 receptor is mainly associated with the immune system [1-4].

Endocannabinoids have been found in various organisms and, apparently, endocannabinoid receptors originated around 500 million years ago [5, 6]. Surprisingly, invertebrate organisms have also been found to have endocannabinoid receptors and to produce endocannabinoids [7]. It's interesting to know that we humans shared an ancestor with invertebrates around 600 million years ago! As well as with vertebrate animals, it seems we also share cannabinoid receptors with invertebrate animals.

As mentioned in previous articles, endocannabinoids play an important role in functions such as neurotransmission [1, 8], the regulation of appetite and stress, and metabolic and immune system functions [9], among many, many others. The two best-known endocannabinoids are anandamide and 2-AG (2-arachidonoylglycerol) [10].

Endocannabinoid enzymes work by playing two main roles: the synthesis or “activation” and the degradation or “inactivation” of the body's endocannabinoids.

As regards synthesis, these enzymes catalyse specific chemical reactions that convert precursors into “active endocannabinoids”, ready to bind to cannabinoid receptors in the body.

As regards degradation, endocannabinoid enzymes are responsible for breaking down endocannabinoids once they have done their job, or so that their action comes to an end. To do this, they catalyse reactions that convert endocannabinoids into other products, which allows endocannabinoid levels in the body to be precisely regulated.

This topic is quite complex since, from my review of the literature, there are still many unknowns about how these enzymes act, what exactly they produce and whether they might interact with other compounds not yet known or studied [10].

How many cannabinoid enzymes are there?

There appear to be five (5) enzymes involved in endocannabinoid metabolism [10]:

• NAPE-PLD (N-acylphosphatidylethanolamine-selective phospholipase D)
• DAGL α and β (diacylglycerol lipases)
• FAAH (fatty acid amide hydrolase, which in Spanish would be something like amida hidrolasa de ácidos grasos)
• MAGL (monoacylglycerol lipase)

Endocannabinoids and their enzymes

As I mentioned, anandamide is one of the best-known endocannabinoids. The enzymes NAPE-PLD and FAAH act on it.

The other well-known endocannabinoid is 2-AG (2-arachidonoylglycerol), and physiological levels of 2-AG are higher than those of anandamide [13]. The enzymes DAGL α and β and MAGL act on 2-AG [10, 14].

Types of endocannabinoid enzymes

FAAH (fatty acid amide hydrolase)

The FAAH enzyme is a protein bound to cell membranes whose main known function is to break down anandamide.

It has been found in the brain and liver of mice, while in pigs it has been detected in the brain [15]. In humans, FAAH is found in the brain, the liver and also the placenta, together with the CB1 receptor. This suggests that the human placenta responds to molecules that bind to these receptors [16]. The FAAH enzyme may therefore play a critical role in controlling anandamide levels and in the outcome of pregnancy. However, it is not yet known what happens with high levels of anandamide, or with levels of other cannabinoids that can bind to CB1 receptors in the placenta [16].

The phytocannabinoids THC, CBD and CBN inhibit the activity of the FAAH enzyme [15], which could have therapeutic implications. By inhibiting FAAH, phytocannabinoids could increase the levels of endocannabinoids such as anandamide in the body, as well as their effects. Higher endocannabinoid levels could have effects on the sensation of pain, inflammation, mood and appetite. This provides a basis for further research into the potential therapeutic use of these phytocannabinoids in the treatment of various medical conditions.

Another curious fact about FAAH is that the genes that encode it in humans and mice are very similar [17], and they also have many exons and introns, which I talked about in a previous article.

Read the article on CBG

MAGL (monoacylglycerol lipase)

The MAGL enzyme catalyses the hydrolysis of monoacylglycerols into glycerol and fatty acids and, in the endocannabinoid system, it is responsible for breaking down 2-AG (2-arachidonoylglycerol). It is found in the brain and in other peripheral tissues, such as the kidneys, ovaries, testes and heart [18].

This enzyme has been associated with conditions such as pain, inflammation, neuronal degeneration and diseases such as Parkinson's or Alzheimer's. In addition, high levels of this enzyme have been found in breast and ovarian cancers and in melanoma [19].

DAGL α and β (diacylglycerol lipases)

The DAGL α and β (alpha and beta) enzymes break down diacylglycerol into 2-AG, which is the most abundant endocannabinoid and a full agonist of the CB1 and CB2 receptors.

This enzyme is involved in regulation during embryonic development and is required for the generation of neurons in the brain. It is also linked to a metabolic pathway associated with neuronal degeneration in Parkinson's disease [20].

Potential therapeutic implications of endocannabinoid enzymes

Endocannabinoid enzymes play a crucial role in the endocannabinoid system of the human body.

Inhibiting these endocannabinoid enzymes may have important therapeutic implications and potential medicinal uses in developing drugs with new pharmacological targets.

Two key enzymes, FAAH and MAGL, play a prominent role and are the most studied.

Inhibiting the MAGL enzyme means that the endocannabinoid 2-AG is not broken down, so its levels rise. This endocannabinoid is able to bind to CB1 and CB2 receptors, which leads to a reduction in pain [13].

On the other hand, inhibiting the FAAH enzyme increases anandamide levels in the brain, which also results in analgesic effects mediated by the CB1 receptor, as well as anxiolytic and antidepressant effects [21]. Inhibiting both enzymes, FAAH and MAGL, increases the levels of both anandamide and 2-AG in the brain, which produces an effect similar to directly activating the CB1 receptor with substances that have an affinity for these receptors (called agonists) [21].

Inhibition of endocannabinoid enzymes may have potential therapeutic uses

Inhibiting these enzymes can control signalling in the endocannabinoid system, which may open up therapeutic possibilities. For example, inhibiting the FAAH enzyme can produce analgesic, anxiolytic and antidepressant effects, induce sleep and reduce inflammation. These effects occur without adverse consequences such as weight gain or cognitive impairment. FAAH inhibition could therefore be a strategy for bringing about the properties of the CB1 receptor without many of the side effects that have been observed with direct receptor agonists [22].

What is the future of cannabinoid enzymes?

As our understanding of these enzymes and their interaction with phytocannabinoids and endocannabinoids deepens, new perspectives are opening up in terms of possible therapeutic applications.

Inhibiting these endocannabinoid enzymes holds therapeutic promise and, since the phytocannabinoids produced by the Cannabis sativa plant inhibit some of these enzymes, new medical possibilities are opening up.

I hope this article has opened a door for you into this fascinating field of study: cannabis and its effects. Until next time!