In my recent years working within the CBD sector and at Formula Swiss, I have dedicated much of my focus to the study of cannabinoids and their connection to the body’s natural processes. Two of the most notable components within this biological framework are 2-AG and anandamide, both naturally occurring endocannabinoids produced by the human body.
These compounds have been explored for their potential involvement in supporting the body’s own regulatory functions. Through continuous research and staying informed about scientific progress, I have seen how a deeper understanding of the endocannabinoid system sheds light on the ways the body works to maintain its internal harmony.
Looking into the distinct roles of 2-AG and anandamide offers valuable perspectives on how the body’s internal systems operate, highlighting the complexity of these interactions. I hope that learning more about 2-AG and anandamide will provide useful insights, helping to develop a greater appreciation for the endocannabinoid system’s contribution.
With a foundation of scientific research and practical experience, we can gain a better understanding of how these compounds engage with the body’s natural functions.
Prefer watching over reading? This video covers the key points from the article:
Key takeaways
- The first cannabinoid receptor (CB1) was identified in 1988, and in 1992 a team including William Devane, Lumír Hanuš and Raphael Mechoulam identified anandamide, the first known endocannabinoid.
- CB1 receptors are primarily located in the brain, spinal cord and central nervous system, while CB2 receptors are found mainly in immune tissues.
- 2-AG and anandamide are endogenous lipids that interact with cannabinoid receptors in the body.
- The discovery of endogenous cannabinoids helped explain the natural function of cannabinoid receptors in humans.
- Both 2-AG and anandamide are synthesised on demand rather than stored in the body.
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The role of endocannabinoids in the ECS
I often consider how the discovery of the cannabis plant contributed to identifying and naming the endocannabinoid system (ECS). Compounds found in the plant share notable similarities with the body’s endocannabinoids. Research continues to investigate how the ECS may be associated with various natural processes.
Role of 2-arachidonoylglycerol (2-AG)
One molecule that captures my attention is 2-arachidonoylglycerol, commonly referred to as 2-AG. A review in the journal Molecules describes it as the most abundant endocannabinoid and a full agonist at both CB1 and CB2 receptors, contributing to retrograde signalling between nerve cells.
A study in the Obesity Research & Clinical Practice journal examined associations between circulating 2-AG and anandamide and appetite-regulating substances, such as leptin, in women with obesity. 2-AG has also been detected in human breast milk, with animal studies examining its possible role in suckling and early development.
Endocannabinoids and cognitive ageing research
The relationship between endocannabinoids and ageing remains a fascinating area to study. While there are still many unanswered questions, particularly around conditions that affect cognitive function, researchers continue to study how the ECS may influence normal ageing processes.
The intricate nature of the system indicates that endocannabinoids could play a role in influencing neural networks as time progresses, though additional studies are required to deepen understanding in this area.
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Communication between endocannabinoids and glial cells
Another point that stands out is the way endocannabinoids interact with glial cells. Unlike many neurons, astrocytes (a type of glial cell) in the adult mouse brain express CB1 receptors only at low levels, which makes their communication with the endocannabinoid system more complex.
A mouse study by Bilkei-Gorzo et al. (2018) found that deleting CB1 receptors from GABAergic neurons was accompanied by age-related changes in the shape and inflammatory activity of astrocytes, suggesting that neurons may act as intermediaries that influence glial cell responses through CB1 signalling. These findings offer valuable insights into how the ECS could be involved in maintaining a balanced internal environment within the nervous system.
| Study | Key findings | Details | Conclusion |
|---|---|---|---|
| Bilkei-Gorzo et al. (2018) | Neurons influence glial cell responses through CB1 receptors. |
|
In mice, disrupting CB1 receptor signalling on GABAergic neurons was accompanied by functional changes in astrocytes relevant to brain ageing. |
Glial cells and 2-AG endocannabinoids
In mice, glial cells appear to detect disruptions such as bacterial infections and can alter their functioning in response.
During these changes, the body increases its production of endocannabinoids. Neurons respond by activating nearby CB1 receptors and relaying signals to other nerve cells while influencing immune responses. They also use proteins to send status updates back to the glial cells, helping to regulate inflammatory activity.
One of the key endocannabinoids produced and released by neurons during this process is 2-arachidonoylglycerol (2-AG).
What happens when the brain slows down endocannabinoid production?
Whether endocannabinoid levels naturally decline with ageing is still unclear, but reduced CB1 receptor signalling has been linked to changes in brain function in animal studies. In mice lacking CB1 receptors, early cognitive decline and nerve cell loss were accompanied by neuroinflammatory changes, suggesting that reduced CB1 receptor stimulation may affect glial cell activity and communication between neurons.
In Alzheimer's disease, advanced stages are associated with the loss of nerve cell populations.
Research by Bilkei-Gorzo (2012) highlights alterations in the endocannabinoid system during neurodegenerative conditions. Scientific interest has explored how phytocannabinoids such as THC and CBD interact with biological systems, including those involved in oxidative balance and inflammation.
What is THC (tetrahydrocannabinol)?
Anandamide
I have found that anandamide, also known as arachidonylethanolamide, is one of the most studied endocannabinoids after 2-AG. It is derived from the unsaturated fatty acid arachidonic acid, which is found in significant amounts within the central nervous system.
Anandamide was first identified in 1992 by pharmacologist William Anthony Devane and analytical chemist Lumír Ondřej Hanuš. Its name is taken from the Sanskrit word "Ananda", meaning joy, delight or bliss, a fitting reference to its role within the body.
Interaction with the endocannabinoid system
From what I have observed, anandamide interacts with CB1 and CB2 receptors, similar to plant-derived cannabinoids. At higher concentrations, it can even inhibit the effects of compounds such as THC within the endocannabinoid system. Although both anandamide and THC are highly fat-soluble, their molecular structures are quite different.
Production and stability
Anandamide is synthesised in tissues and cell membranes. In my review of the literature, I have noted several described pathways for its production. The main route involves a phosphodiesterase enzyme (NAPE-PLD) that cleaves the membrane phospholipid precursor N-arachidonoyl phosphatidylethanolamine (NAPE), while the direct combination of arachidonic acid with ethanolamine is generally considered less likely to be physiologically significant because it requires very high concentrations of both substances.
Despite its significance, anandamide has a very short half-life within the body because, after being taken up into cells, it is rapidly broken down, mainly by the enzyme fatty acid amide hydrolase (FAAH).
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Other receptor targets
Anandamide does not only interact with cannabinoid receptors. It also binds to other targets, including the TRPV1 receptor, sometimes referred to as the vanilloid receptor, according to a study by Zygmunt et al. (1999).
This receptor, present in sensory nerve cells throughout the central and peripheral nervous system, is associated with the detection of painful stimuli, heat and sharp tastes.
Other endogenous ligands in the endocannabinoid system are:
| Ligand | Full name |
|---|---|
| NADA | N-arachidonoyldopamine |
| OAE | Virodhamine (O-arachidonoyl ethanolamine) |
| AGE | 2-arachidonyl glyceryl ether (noladin ether) |
| Pregnenolone | Pregnenolone (a steroid described as a signalling-specific inhibitor of the CB1 receptor) |
| LPI | Lysophosphatidylinositol (an endogenous agonist of the GPR55 receptor) |
Anorexia and cachexia
I have seen how serious illnesses can severely affect a patient's eating patterns. Anorexia (an abnormal loss of appetite) and cachexia (involuntary loss of body weight, including muscle mass and fat) are non-specific symptoms often seen in cases of autoimmune diseases, serious infections and tumours.
In some situations, individuals dependent on psychoactive substances may also experience these symptoms. When not addressed over time, these conditions can lead to serious physical complications, sometimes requiring artificial nutritional support for recovery.
Which cannabinoids produce a psychoactive effect?
Impact on muscle mass and nutrient deficiency
Cachexia is associated with notable reductions in muscle mass and general declines in physical strength. Many individuals living with the condition may report feelings of fatigue, diminished physical capacity and reduced overall well-being. Symptoms such as nausea, anxiety and low mood are often observed alongside these physical changes.
Based on observations from scientific research, disruptions in the body's energy balance have been linked to potential deficiencies in key nutrients such as calcium, vitamin D and phosphate. These imbalances may contribute to broader complications affecting bone and dental health.
Cognitive function and immune response can also be affected, although individual experiences vary. Continued research suggests that improvements in overall immune health may be possible following appropriate management and recovery strategies.
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Role of the endocannabinoid system
I have observed that the endocannabinoid system (ECS) is an area of interest in scientific studies related to hunger and physiological balance. One receptor, known as GPR55, has attracted attention for its involvement in regulating intracellular calcium levels in cells and neurons through cannabinoid interactions.
Researchers are investigating how this mechanism may relate to changes in the body's energy demands during illness. Anandamide, one of the body's endocannabinoids, has been studied for its interactions with CB1 receptors, with some research exploring possible associations with appetite signalling.
I have also seen studies suggesting a potential connection between the endocannabinoid system and energy metabolism, although further research is needed to clarify these findings.
The endocannabinoid system (ECS)
Personal perspective
Working within the CBD industry for several years, I have closely followed developments around the human endocannabinoid system, particularly the role of 2-AG and anandamide. It is well-established that these two endocannabinoids interact naturally with CB1 and CB2 receptors to support the body's internal balance.
In my experience, a growing understanding of 2-AG and anandamide among consumers and practitioners alike is reshaping conversations around cannabinoids. I find it encouraging to see more emphasis placed on the body's own cannabinoid production rather than focusing solely on external sources, as this reflects a more complete view of the endocannabinoid system’s role in human physiology.
Frequently asked questions
What are 2-AG and anandamide?
2-Arachidonoylglycerol (2-AG) and anandamide (arachidonoylethanolamide) are naturally occurring endocannabinoids in the human body. They are lipid-based neurotransmitters that bind to cannabinoid receptors.
How are 2-AG and anandamide synthesised in the body?
2-AG is mainly synthesised through the enzymatic cleavage of diacylglycerol by diacylglycerol lipase. Anandamide is primarily produced from N-arachidonoyl phosphatidylethanolamine (NAPE) through the action of specific phospholipase enzymes.
What are the main functions of 2-AG and anandamide?
2-AG and anandamide play a part in influencing a range of natural bodily functions, such as mood, appetite and memory. These compounds serve as signalling agents within the endocannabinoid system.
How do 2-AG and anandamide interact with cannabinoid receptors?
Both 2-AG and anandamide bind to cannabinoid receptors, primarily CB1 and CB2 receptors. 2-AG is considered a full agonist at these receptors, while anandamide acts as a partial agonist.
Which endocannabinoid is more abundant in the brain?
2-AG is significantly more abundant in the brain compared to anandamide. A 1997 study in rats reported brain levels about 170 times higher than those of anandamide, and later reviews describe brain anandamide levels as roughly 10 to 100 times lower than those of 2-AG.
How are 2-AG and anandamide broken down?
2-AG is primarily degraded by the enzyme monoacylglycerol lipase (MAGL). Anandamide is mainly broken down by fatty acid amide hydrolase (FAAH).
Do 2-AG and anandamide have different physiological roles?
Yes, 2-AG has been studied for its involvement in immune and inflammatory processes, while anandamide has been explored in relation to mood and emotional regulation. Their differing interactions with cannabinoid receptors have been observed to contribute to variations in receptor activity.
Are 2-AG and anandamide found in foods?
Both 2-AG and anandamide are not typically present in foods, but certain food sources contain compounds that may influence their levels in the body. For example, chocolate contains compounds structurally similar to anandamide.
How are new cannabinoids being discovered and classified?
