The endocannabinoid system (ECS) is a major communication network that involves lipid-based signaling molecules (endocannabinoids), their receptors, and the enzymes that metabolize them.
The ECS helps modulate activity of the brain and immune cells, but also touches nearly every organ system in the body. Unstudied until the 1990s, this intricate body system may be the key to maintaining the balance of all others.
DISCOVERY OF THE ECS
If it weren’t for the fascination with the psychoactive properties of the cannabis plant, scientists might have never discovered the ECS
The story began in 1964 when an Israeli researcher by the name of Dr. Raphael Mechoulam isolated delta-9 tetrahydrocannabinol (THC) from cannabis.
It took nearly three more decades to determine the mechanism underlying THC. In 1990, researchers identified a receptor in the brain that’s activated by THC. They named it the cannabinoid 1 (CB1) receptor. Then in 1993, they detected a second cannabinoid receptor (CB2).
After these cannabinoid receptors were discovered, researchers quickly identified two compounds produced by the human body that bind to the receptors. They called them endocannabinoids. Together with their receptors and metabolic enzymes, endocannabinoids create a complex communication network throughout the brain and the body.
ENDOCANNABINOID RECEPTORS
CB1 receptors are concentrated in the brain, where they may influence motivation, reward, and memory processing. CB1 receptors are also abundant in the sympathetic nerve terminals of the peripheral nervous system, where they may modulate the stress response.
Although they’re most prominent in the nervous system, CB1 receptors have also been detected in the enteric nervous system, intestinal mucosa, adipose tissue, liver, skeletal muscle, bone, skin, eye, cardiovascular system, and reproductive system.
CB1 receptors are mostly found in cell surface membranes, but they’re also present in the mitochondrial membranes, where they may regulate the essential task of cellular energy production.
CB2 receptors are best known for their presence on immune cells, where they may modulate inflammation. They’ve also been found in the peripheral nervous system and the gastrointestinal tract.
Other receptors that have been found to interact with endocannabinoids include ion channels and nuclear receptors, like transient receptor potential vanilloid 1 (TRPV1) and peroxisome proliferator-activated receptor gamma (PPAR-gamma).
ENDOCANNABINOIDS
Endocannabinoids are eicosanoid molecules derived from fatty acids in cell membranes. They’re synthesized on demand and diffuse into the space between cells, where they act like neurotransmitters.
The two most studied endocannabinoids are derived from arachidonic acid. The first has been given the name anandamide, after the Sanskrit word for “bliss.” Anandamide activates CB1 receptors, but is almost inactive at CB2 sites.
The second endocannabinoid is 2-arachidonoylglycerol (2-AG), which activates both CB1 and CB2 receptors.
For many years, these two arachidonic acid–derived compounds were the only known endocannabinoids. Then in 2017, a team of researchers at the University of Illinois discovered a biosynthetic pathway in humans that produces endocannabinoids from omega-3 fatty acids.
There are now four endocannabinoid molecules known to be derived from omega-3 fatty acids: DHA ethanolamide, EPA ethanolamide, DHA glycerol, and EPA glycerol.
There is also a class of “endocannabinoid-like molecules” that form when omega-3s combine with neurotransmitters, such as serotonin and dopamine. The physiologic effects of these omega-3-derived molecules are still being explored.
ENDOCANNABINOID SIGNALING
Endocannabinoids act as retrograde neurotransmitters, meaning they’re released from postsynaptic neurons or cells and travel back to act on presynaptic neurons or cells. When they bind to receptors on the presynaptic neuron, they may inhibit neurotransmitter release.
For example, the release of 2-AG in the brain can activate CB1 receptors and suppress the release of glutamine or gamma-aminobutyric acid (GABA) from presynaptic cells. This is a system of modulation and regulation.
Endocannabinoids are then cleared from the synaptic space or broken down by enzymatic degradation. Two of the main enzymes that degrade endocannabinoids are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These enzymes have gained attention as targets for research to prolong the action of endocannabinoids.
HEALTH IMPLICATIONS
The ECS is a modulatory system that may help all other systems respond to stress and changing environments. It may support both emotional and physical stress-coping mechanisms. Disruption of the ECS may result in maladaptive responses, such as fear, stress, sleep disturbance, or physical symptoms.
In the gut, endocannabinoid signaling may influence a number of functions. It also plays an integral role in the gut-brain axis, mediating interactions between the nervous and gastrointestinal systems. Endocannabinoids may influence appetite and metabolism.
Numerous pain pathways depend on the ECS, where it may modulate the physical sensation of pain as well as the emotional responses. Recent evidence has found that endocannabinoids and their receptors may also modulate immune function, reproductive health, cardiovascular health, and bone health.
STRESS AND THE ECS
Responding to stress is one of the most important functions of the ECS. Acute stress leads to alterations in both anandamide and 2-AG. Anandamide initially drops to allow activation of the hypothalamic-pituitary-adrenal (HPA) axis, and 2-AG then rises to resolve the stress response.
The interactions between the ECS and other aspects of the physiologic response are complex, but one thing is for sure. The HPA axis doesn’t work in isolation, and we may need healthy endocannabinoid function for an appropriate stress response.
SLEEP AND THE ECS
Circulating endocannabinoids are dynamic and appear to follow a circadian rhythm. A study published in 2015 found that 2-AG levels peaked in the afternoon and hit a low level in the middle of the night, during sleep.
Sleep restriction has been shown to disrupt the normal rhythm of the ECS. Sleep deprivation is perceived by the body as a stressor and subsequently leads to larger spikes of 2-AG or anandamide during daytime hours.
EXERCISE AND THE ECS
Exercise can create a decreased sensitivity to pain, known as hypoalgesia. Although this is often attributed to endorphin release, researchers at the University of Wisconsin in 2018 found that the endocannabinoid 2-AG played a bigger role than the opioid system in exercise-induced hypoalgesia.
Exercise can also lead to a feeling of bliss and calm, known as the “runner’s high.” Most people give endorphins credit for this, but numerous studies show that levels of anandamide and 2-AG increase in response to exercise and may contribute to its mood-supportive effects.
DIETARY FATS AND THE ECS
Because endocannabinoids are derived from the fatty acids in cell membranes, dietary fats may have a profound effect on the ECS. As mentioned earlier, there are known endocannabinoids derived from the omega-6 arachidonic acid as well as the omega-3s DHA and EPA.
There are also compounds molecularly similar to endocannabinoids that are derived from oleic acid (N-oleoylethanolamine, or OEA) and palmitic acid (N-palmitoyl-ethanolamine, or PEA). OEA activates a number of different cellular receptors, including CB1. PEA competes with anandamide for the enzyme that degrades them both.
Scientists have not yet determined the precise effects that different dietary fats have on endocannabinoid function, but most researchers recommend eating a balance of healthy fats that includes oleic acid from olive oil and omega-3 fatty acids from fish, nuts, and seeds.
PLANT FOODS AND THE ECS
Many phytochemicals that are naturally occurring in plant foods interact with the ECS. Some we call phytocannabinoids because they bind to cannabinoid receptors. Others potentiate the action of endocannabinoids—either by competing for enzymatic degradation or inhibiting reuptake.
Foods that contain phytocannabinoid compounds include Brassica vegetables (broccoli, cauliflower, kale, and Brussels sprouts), Apiaceae vegetables (carrots, celery, parsley, and ginseng), and spices (black pepper and clove).
Brassica vegetables contain diindolylmethane (DIM), which activates CB2 receptors. Apiaceae vegetables contain falcarinol, which blocks CB1 receptors. Some spices contain beta-caryophyllene (BCP), which activates CB2 receptors. Based on animal and in vitro studies, these foods could theoretically shift the balance of receptor activation away from CB1 and toward CB2.
Foods that contain compounds that potentiate the effects of endocannabinoids include black pepper, soybeans, chickpeas, and fava beans. For example, genistein and daidzein in soy slow down the enzymatic breakdown of endocannabinoids.
Most of the research on food compounds and the ECS has not been conducted in humans. Still, the evidence suggests that diets rich in vegetables and spices likely support healthy endocannabinoid function. This lends support for plant-based diets, such as the Mediterranean or traditional Indian diets.
HERBS AND THE ECS
Cannabis sativa dominates as the most well-known and extensively researched plant in relation to the ECS. Marijuana and hemp come from the same cannabis genus and species, but they’ve been cultivated for different purposes and contain different levels of active compounds.
Marijuana is rich in THC, which activates both CB1 and CB2 receptors. Hemp extracts can be rich in CBD, which binds to cannabinoid receptors but modulates them in ways that are less understood. Both marijuana and hemp also contain at least 100 other phytocannabinoid compounds.
Echinacea (Echinacea purpurea and Echinacea angustifolia) contains alkylamides that can bind to CB2 receptors more strongly than endogenous cannabinoids. Because CB2 receptors are most abundant on immune cells, this may be part of the mechanism to explain echinacea’s immune-modulating effects.
Magnolia bark (Magnolia officinalis) contains at least two phytocannabinoids: magnolol and honokiol. Magnolol activates CB2 receptors, while honokiol activates CB1. Also, a major metabolite of magnolol strongly activates CB2 receptors. These actions may partially explain magnolia’s long-time traditional use to support sleep, mood, and immune function.
Peruvian maca root (Lepidium meyenii) contains macamide, which inhibits the reuptake of anandamide, potentiating its ability to act on CB1 receptors. Maca has traditionally been used as an adaptogenic herb to support healthy hormonal function, mood, memory, and energy. Supporting the ECS may also be one of its many mechanisms.
It’s also likely that countless other herbal extracts interact with the ECS by acting on endocannabinoid-related receptors.
For example, one of the receptors activated by endocannabinoids and CBD is a TRP-channel receptor called TRPV1. Capsaicin in cayenne chili pepper (Capsicum annuum) also strongly activates TRPV1 receptors. Other herbal compounds that activate TRP-channel receptors include gingerol in ginger, cinnamaldehyde in cinnamon, and eugenol in cloves.
THE ECS IN EVERYDAY PRACTICE
The ECS has been present in humans since the beginning of time, yet we’re only on the cusp of unraveling its complexities.
Consequently, in the everyday practice of integrative medicine, the ECS is easily overlooked. We focus on supporting the HPA axis and inflammatory pathways and other systems, but what we may not notice is that the ECS is overseeing them all.
As we recommend herbs, foods, exercise, sleep, and stress-management techniques, we are no doubt activating the ECS. Although we have much more to learn about how this complex system works, its subtle yet powerful network of molecules and receptors likely plays a major role in why integrative practices work.
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