The role of anandamide in the human body

Anandamide is one of the first endogenous cannabis which is self-delivered by the brain, when it is needed, and may have the possibility of playing an important role of the experiences of the euphoric effects caused by cannabis.

Anandamida | Kalapa Clinic

What is anandamide? 

­CB1 and CB2 receptors along with the major endogenous cannabinoids (endocannabinoids, eCBs), anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), were found 20-25 years later after delta-9-tetrahydrocannabinol (THC) was discovered in the mid 1960s.[1]

Anandamide is a long-chain fatty acid amide and its name comes from the Sanskrit word “Ananda” meaning “internal bliss”, as this endocannabinoid produces feelings of euphoria. Since its discovery, it is now considered as the “bliss molecule” which is also responsible for the runner’s high which most athletes describe[2], as well as the euphoric effects of using drugs. Overall, several studies have indicated that AEA exerts an overall modulatory effect on the reward circuitry.[3]

Fatty acid amide hydrolase (FAAH) and monoacyl-glycerol lipase (MAGL) are the specific enzymes involved in modulating endocannabinoid tone. AEA and 2-AG, the two endogenous cannabinoids, belonging to the subclasses known as N-acylethanolamines (NAEs) and mono-acylglycerols (MAGs), are enzymatically metabolized by FAAH and MAGL, respectively. FAAH can also metabolize 2-AG, although to a lesser extent. [2] [3]

The endocannabinoids system (ECS) is divided into the three categories: Endogenous ligands, Membrane receptors and Deactivating enzymes.

A transport protein mechanism carries eCBs retrograde from post-synaptic cell membranes to bind to the cannabinoid receptors found on the pre-synaptic membrane. This transport mechanism then returns the eCBs to the post-synaptic membrane where they are degraded by the enzymes FAAH or MAGL, for anandamide and 2-AG. [2]

Although AEA and 2-AG can have similar structures, they offer crucial differences which is responsible for the different physiological and pathophysiological roles. For example, 1) they are regulated by different biosynthetic and degradative pathways, 2) brain tissue levels of AEA are 10–100 times lower than those of 2-AG  and 3) AEA (as well as THC) activates cannabinoid receptors with low intrinsic efficacy (partial agonist), whereas 2-AG is an agonist with high intrinsic efficacy (full agonist). [3]

Role of Anandamide

Multiple studies have shown how anandamide plays a role in the regulation of various places in the body.

Anandamide in Labour

There are different signals that contribute to the process of labour. Evidence has indicated that AEA is involved during this process and even regulating it. AEA is produced in the placenta along with a significant increase in plasma levels in women with labour compared to patients undergoing caesarean section before the onset of labour. Additionally, AEA plasma levels increase after the induction of labour.

On a side note, oxytocin (OT), a peptide hormone produced by the hypothalamus which plays a role in sexual reproduction and childbirth, regulates myometrial contractility (contractions) and an increase in OT synthesis as well as oxytocin receptor (OTR) expression was found in the placenta at term. In the rat hypothalamus AEA modulates the release of OT, suggesting a possible association between AEA and OT/OTR signalling.

Additionally, in the study, protein levels and enzymatic activity of FAAH (fatty acid amide hydrolase), the main regulator of AEA tone, are lower in placental samples from vaginal delivery than from caesarean section.

These observations suggest that placental AEA tone increases with labour. Additionally, the results suggest that AEA is a relevant molecule in the labour process, contributing to the modulation of the OT/OTR system in human placenta. [4]

Anandamide in chronic conditions

It is hypothesized that chronic conditions such as Post Traumatic Stress Disorder (PTSD), migraine, fibromyalgia, and inflammatory bowel disease are the result of deficiencies in endocannabinoid signalling. This is due to the decreased circulating levels of endocannabinoid signalling.  This decreased amount has also been related to behaviours such as anxiety and environmental stress.

These behaviours have an effect on the endocannabinoids as they down-regulate CB1 receptors as well as reducing levels of AEA (anandamide) at the same time as increasing levels of 2-AG.  One study examined people who were administered 300 mgs of purified CBD isolate to treat their anxiety for a “stressful public speaking test” (SPST), which was determined to have effects that were comparable to the anxiolytic pharmaceutical benzodiazepam (ValiumTM). CBD can counteract the undesirable effects of THC when administered concurrently. [2]

Anxiety in rats

In another study, there have been multiple data which have shown that methanandamide (a stable analogue of anandamide) injected into the prefrontal cortex of rats leads to an anxiolytic response. These results implies that anandamide has antianxiety properties due to the mechanism of anandamide release and formation.

Anandamide is not stored in synaptic vesicles.  However, it is synthesized and released in the synaptic cleft following neuronal activation. Seemingly its levels and those of FAAH in anxiety and depression will be highest in the brain areas involved in the regulation of mood and emotions. Therefore, inhibition of anandamide metabolism would enhance CB1 activation mainly where AEA levels are highest.

However, researchers reported an elevation of anandamide levels in rats with URB597 (a relatively selective inhibitor of the enzyme fatty acid amide hydrolase), which was found to reduce anxiety associated with alcohol withdrawal.

Other researchers have also reported that MGL (Monoglyceride lipase which influences energy metabolism) knockout mice, with elevated levels of 2-AG, show improved learning in an object recognition and water maze task showing that both AEA and 2-AG enhance learning and memory under some conditions. [1]

Modulation of pain

Anandamide and 2-AG are produced in tissues that have been injured and activate cannabinoid receptors to suppress the sensitization of the nerve to nociceptive signals and/or to suppress inflammation. Therefore, a study shows that AEA can modulate pain by 1) inhibiting nociceptive signals at the synapse by activating CB1 receptors, by 2) becoming transformed by COX-2 enzymes into prostamides (pain-relieving molecules), and by 3) reducing inflammation by activating CB2 and other receptors. [2]

Schizophrenia

Synthesis of anandamide has been proposed to occur by multiple pathways. Assuming that the pathways can differ, it may be differed by distinct physiological and pathophysiological processes. Several groups have found alterations in levels of AEA and related acylamides in schizophrenic individuals.

Interestingly, D2-like dopamine receptor stimulation increases anandamide levels in the striatum and CB1 receptor antagonists suppress the increased locomotion seen with a D2-like receptor agonist. This can clarify that anandamide synthetic pathways may be important for understanding the aetiology of schizophrenia. [5]

Anandamide in the kidneys

The kidneys are enriched in anandamide and in enzymes that metabolize AEA, but the information of its roles in the kidneys are still insufficient and must be researched further.

Given that AEA and its metabolites can be seen as modulators of signalling in inflammation, they can influence the states associated in inflammation and cardiovascular diseases associated with hyperhomocysteinemia such as in chronic kidney diseases.

With over 60% of the world population developing hypertension or chronic kidney diseases in their lifetime, AEA and its prostamide metabolites can have the capacity to modulate key renal functions that impact these diseases.

However, better understandings and more research of the pathophysiologic roles and mechanisms of anandamide, prostamides, and other AEA metabolites will help improve current therapies and diagnostic markers for these diseases. [6]

Conclusion

In conclusion, the role of the naturally producing endocannabinoid, anandamide, plays various roles in the functions of our body which can help several pathologies if medical cannabis is to be administered to help these. Treatments with medicinal cannabis should be guided by a specialist.

[1] Mechoulam, R., & Parker, L. A. (2013). The Endocannabinoid System and the Brain. Annual Review of Psychology, 64(1), 21–47.

[2] Silver, R. J. (2019). The Endocannabinoid System of Animals. Animals, 9(9), 686.

[3] Scherma, M., Masia, P., et alt (2018). Brain activity of anandamide: a rewarding bliss? Acta Pharmacologica Sinica.

[4] Accialini, P., Etcheverry, T. et alt (2020). Anandamide regulates oxytocin/oxytocin receptor system in human placenta at term. Placenta, 93, 23–25.

[5] Lu, H.-C., & Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry, 79(7), 516–525.

[6] Ritter, J. K. (2016). Anandamide and its metabolites what are their roles in the kidney. Frontiers in Bioscience, 8(2), 264–277.