The endocannabinoid system (ECS) is probably the most important physiological system most of us never learned about in our training! Although its existence was speculated in the 1960s, it wasn’t discovered in humans until the 1990s. In fact, the ECS is found in living organisms throughout the animal kingdom, with the possible exception of insects.(1)
The ECS interacts with every known biological system in the body, including the immune, endocrine, cardiovascular, and neurological systems. It supports a multiplicity of functions that are crucial to homeostasis. Fundamentally, the ECS is the master regulator of physiological homeostasis behind all biological processes.
Anandamide is one of two major endogenous cannabinoids, or endocannabinoids, that are ligands for receptor sites in the ECS. This article will provide a brief overview of the ECS with specific focus on the effects of anandamide.
- A Brief Overview of the Endocannabinoid System (ECS)
- Endocannabinoids and Retrograde Signaling
- Endocannabinoids and the Skin
- The Role of Anandamide
- Effects Beyond Cannabinoid Receptors
- Epigenetic effects
- In Summary
A Brief Overview of the Endocannabinoid System (ECS)
The ECS consists of cannabinoid receptor sites; endocannabinoids; and enzymes for the biosynthesis and metabolism of the endocannabinoids. The term endocannabinoid refers to cannabinoids that are made by the body, in contrast to phytocannabinoids, which are manufactured by plants. Both our endogenous cannabinoids and phytocannabinoids can interact with cannabinoid receptors.
The ECS modulates an enormous range of physiological processes and functions, including neurogenesis and neuroprotection; inflammatory and immune responses; cell growth and proliferation; lipid metabolism; glucose metabolism; smooth muscle contractility; mood; cognition and memory; reproduction; nociception; and appetite. As the master neuromodulator of homeostasis, it responds to external input (such as pain and stress), as well as monitoring energy metabolism and intracellular flow of biological information.(2,3)
The two major cannabinoid receptors are known as CB1 and CB2. CB1is the most numerous G-protein-coupled receptor expressed in the brain and spine. It is also expressed in adipocytes, hepatocytes, and musculoskeletal tissue. CB2 is mostly located in the peripheral nervous system, organs, and immune system, but is also expressed in activated microglia in the central nervous system, in bone, and in the gastrointestinal tract.(4)
Humans have more receptor sites for endocannabinoids than for ligands of all the other biological systems combined, a testament to both the complexity and reach of the ECS.
Endocannabinoids and Retrograde Signaling
The two most studied endocannabinoids are arachidonyl ethanolamide (abbreviated AEA), which is also called anandamide, and 2-arachidonoyl glycerol (2-AG). Our bodies manufacture these endocannabinoids from essential fatty acids derived from cell membrane phospholipids. In contrast to every other known receptor-based system, anandamide and 2-AG are not synthesized in advance and stored in presynaptic vesicles. Instead, because of their intrinsic role in moment-to-moment homeostasis, they are manufactured within seconds “on demand,” in response to neuronal activation.
The ECS is uniquely designed to be protective by operating through retrograde signaling or transmission.(5)
Usually, central nervous system (CNS) neurotransmitters are synthesized and stored presynaptically, then released into the synapse where they initiate their effects via postsynaptic neurons. This is known as forward or anterograde transmission. The ECS works in the opposite direction using retrograde transmission. With retrograde transmission, postsynaptic neurons that are, for example, stimulated by excitatory neurotransmitters, will trigger the on-demand production of endocannabinoids that will be released into the synapse. From there, the endocannabinoids will travel “backwards” and bind to receptors on the axon terminal of the presynaptic neuron. This means receptors on the receiving end of a flood of excitatory neurotransmission are able to send a signal backwards to presynaptic neurons, to get help with reducing this hyperstimulation. In this way, it is thought the ECS supports homeostasis and neuroprotection by muting the kind of excessive neuronal activity that can be present in acute anxiety, as well as with seizures, and pain syndromes.(6,7)
In keeping with their on-demand, essential role, endocannabinoids have a short half-life, and are catabolized quickly by the enzymes fatty acid amide hydrolase (FAAH), in the case of anandamide, and monoacylglycerol lipase (MAGL) in the case of 2-AG. Even though both endocannabinoids have similar chemical structures, they are synthesized and broken down by different enzyme pathways. In addition, their levels are regulated separately within cells, tissues, and organs, suggesting they likely have different and complementary physiological functions.(8)
Endocannabinoids and the Skin
Given that the skin is a neuroimmunoendocrine organ, it is no surprise that it directly interacts with the ECS. Skin cells produce endocannabinoids. CB1 and CB2 receptors are found in dermal layers all the way to the subcutaneous tissue. The ECS plays a major role in skin homeostasis including barrier formation; skin cell regeneration; and regulation of the inflammatory and immune responses. Evidence suggests that ECS dysregulation contributes to the development of acne vulgaris, atopic dermatitis, contact dermatitis, psoriasis, itching, pigmentation disorders, abnormal hair growth, and the cutaneous signs of scleroderma.(9,10,11) Endocannabinoids can also have an analgesic effect in the skin.(12)
The Role of Anandamide
Anandamide was the first endocannabinoid neurotransmitter to be identified. It was given the nick name “bliss molecule” in part because of its positive effects on mood. Anandamide is rapidly synthesized in response to factors such as pain, stress, anxiety, and appetite. It also contributes to “runner’s high,” via interaction with the endorphin and opioid receptor systems. Its ability to bind to CB1 and CB2 receptors means it is involved in multiple physiological functions and processes of the ECS.
Anxiety and stress
Baseline circulating concentrations of anandamide are inversely associated with anxiety and hypothalamic-pituitary-adrenal (HPA) axis reactivity, suggesting that high circulating levels may be protective against anxiety, and facilitate recovery from stress reactions.(13)
Central nervous system anandamide deficiency is predictive for the development of stress-induced anxiety and possibly for other stress-related conditions. Anandamide helps balance HPA axis activation, but chronic stress depletes the available pool of anandamide signaling, thereby diminishing the modulating effects of the ECS.(14,15)
During a stress response, anandamide inhibits the activity of the enzyme that synthesizes nitric oxide (NO). This suggests it may also help reduce stress reactivity by suppressing NO production in the hypothalamus and adrenal glands.(16)
Anandamide has been shown to play a key role in fear extinction. Extinction is the learned ability to dampen recall of adverse memories that, for example, lead to a conditioned fear response and hypervigilance. Extinction is applied in animal models to represent and quantify the experience of anxiety. Understanding how fear extinction works at a neuronal level has huge clinical relevance, as extinction therapy is the basis of psychological approaches to many anxiety and maladaptive fear disorders.(17) It is known that fear extinction in rodents is associated with increased levels or heightened signaling of anandamide (18) in the amygdala,(19) a brain region crucial for the emotional regulation of trauma and fear in humans as well.
Animal studies have shown that raising anandamide levels by inhibiting the catabolizing enzyme FAAH, actually reverses anxiety-based behaviors shown by mice after exposure to intense, acute stressors.(20,21)
A 2015 study that looked at both humans and mice with a genetic polymorphism that prevents biosynthesis of FAAH found that the resulting elevated anandamide levels were associated with enhanced mood and less fear and anxiety in the presence of a perceived threat.(22) Interestingly, researchers have found a consistent and strong correlation between the prevalence of the gene that inhibits FAAH production and the levels of happiness and well-being reported by people in different countries. In other words, the happier that people say they are, the more prevalent this genetic polymorphism is in the general population.(23)
Pleasure and pain
Anandamide is involved in oxytocin release, and may augment a sense of social reward and pleasure.(24) Anandamide decreases nociception and attenuates transmission of pain signals.(25,26)
The ECS plays a significant role in gastrointestinal health through a variety of mechanisms that involve both the gut-brain axis and the enteric nervous system.(27) High levels of anandamide and FAAH activity are found in the colon.(28)
Hormonal regulation and neonatal health
Anandamide plays a complex role infertility and hormonal regulation. Research suggests that a higher plasma level of anandamide is required at ovulation,(29) and a significantly lower level during implantation for a successful pregnancy to result.(30) Anandamide levels during birth are markedly higher in babies delivered vaginally than those delivered by cesarean section. This may protect the emerging infant against pain and inflammation.(31)
Anandamide was shown to be neuroprotective against induced lesions in the brains of neonatal rodents.(32) In another rodent study, rats that received poor rearing during the neonatal period exhibited a dysregulated neuroendocrine stress response, which was mitigated by raising anandamide levels.(33) Anandamide also interacts with the hypothalamic-pituitary-gonadal (HPG) axis in men. FAAH was shown to regulate important steps in biological pathways of sperm production.(34)
Effects Beyond Cannabinoid Receptors
Anandamide exerts some of its wide-ranging, modulatory effects independently of binding to cannabinoid receptor sites. By interacting with PPAR receptors, it may play a role in analgesic, neuroprotective, anti-inflammatory, anti-tumor, lipid metabolism, glucose regulation, gastrointestinal, and cardiovascular effects.(35)
Interaction with TRPV1 receptors contributes to its ability to dampen nociception and pain signaling, which could have positive implications in the treatment of neuropathic pain.(36,37)
Anandamide interacts with the GABAergic system to modulate acute blood pressure changes and heart rate.(38) It also attenuates pain sensation and transmission by modulating glutamatergic signaling.(39)
Several studies suggest that anandamide has an overall modulatory effect on brain reward pathways.(40,41)
Increasing evidence points to the role of anandamide as a natural repressor of gene transcription via mechanisms that lead to increased DNA methylation and reduced histone acetylation. Alterations in methylation are associated with many disease processes including cancer, suggesting that anandamide may have anti-cancer effects.(42)
A study of children on the autism spectrum found they had lower circulating levels of anandamide than children not on the autism spectrum.(43) This is particularly interesting as a possible link to the immune hypothesis of psychiatric disorders and neurodegenerative diseases.(44,45) Microglia found in the brain and spinal cord act as immune cells for the central nervous system. When activated, microglia create an inflammatory response, and also express endocannabinoid receptors. Anandamide blocks microglial activation to support neuroprotection by keeping the inflammatory reaction in check.(46)
Anandamide is one of two major endogenous cannabinoids, or endocannabinoids, that are ligands for receptor sites in the endocannabinoid system (ECS). Structurally, anandamide is a long-chain polyunsaturated fatty acid that is synthesized on-demand from cell membrane phospholipids. It is crucial for the constant modulation of fine-tuned adjustments that are required for homeostasis via its interactions with both the ECS and with a range of other receptor-based physiological systems. Its release through retrograde transmission allows it to dampen the excessive neuronal reactivity that can arise with acute anxiety, as well as with seizure disorders and certain pain syndromes. The ECS mediates an enormous range of physiological processes and functions in which anandamide likely plays a key role. This includes neurogenesis, immune activity, lipid metabolism, glucose metabolism, mood, cognition, reproduction, and nociception.
Anandamide helps balance HPA axis activation, but chronic stress depletes the available pool of anandamide signaling, which reduces the overall modulating capacity of the ECS. Part 2 of this article discusses the health implications of central anandamide deficiency, specific factors that deplete anandamide, and lifestyle considerations that enhance endocannabinoid biosynthesis.
Want to connect with other professionals in your field? Join the CBD CLINIC Professionals Facebook group and learn how other clinicians are incorporating CBD products into their practices!