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The School of UnLearning: Wellness

Four-twenty 411: Endocannabinoidome

Endocannabinoidome: Interconnectedness of the endocannabinoid system and the microbiota and their role in modulating the gut, inflammation, mental health, and pain

I have a vivid memory from a medical school lecture wherein the Dean poetically explained that evolutionarily, we are merely a tube. Our whole body develops around this tube of mouth to anus, as increasingly complex tissue types grow and lay down into layers we know as our skin, soft tissues, nervous, immune, and reproductive systems. He stood on stage and gestured with his hand, the intimate act of eating, is to invite something to become part of self. We are literally composed of what we eat.

And so, it is the immense job of the intestinal barrier to decide what is self versus non-self. Our microbiota (the everchanging balance of our body’s own bacteria, fungi and viruses) has an intimate relationship with our endocannabinoid system (ECS), and has immense downstream activity regarding the gut, inflammation, our mental state and how we experience pain.

This intimate relationship is often called the ”gut-brain connection,” and the signaling between the ECS and gut is believed to be bi-directional. The enteric nervous system is this bi-directional highway network of nerves and the main road within it is the vagus nerve. There is a structural and chemical relationship between your brain and belly. What you think and feel affects your gut; the population density and distribution of your microbiome affects your mood, perception of pain and sleep cycle.

The ECS is a vast network of chemical signals and cellular receptors that are densely packed throughout our brain and body., The receptors located in your central nervous system, CB1, are extremely abundant and act as the master conductors in modulating your sleep-wake cycle, libido, thermoregulation, ability to forget traumatic events, perception of pain and appetite. Your immune system plays host the second highest concentration of CB2 receptors, modulating intestinal inflammation, peristalsis and perception of pain in the bowel.

These cannabinoid receptors allow humans to experience the effects of the cannabis plant when consumed (smoking, vaping, eating, suppository) and are also prevalent in other plants including black pepper, clove, ginsing, echinacea and kava. But the only reason you have those receptors is because your body makes its own (endogenous) cannabinoids called anadamide (ANA) and 2-arachiodonoyl glycerol (2-AG). ANA is named for the Sanskrit word bliss, anada, and the compound fits like a key perfectly into the receptors of CB 1,2. ANA is an endocannabinoid; endogenous meaning it came from self. All cannabinoids help bring your body back into balance and set the stage for self-healing on the cellular level.

All cannabinoids help bring your body back into balance and set the stage for self-healing on the cellular level.

Inflammation, is a reflection of imbalance within the body, and, on a cellular level, can lead to chronic pain, fatigue, anxiety, brain fog, poor sleep and digestion. The ECS is responsible, in part, for protecting the gut from inflammation. Higher levels of endogenous cannabinoids are found patients with ulcerative colitis, diverticulitis and celiac disease. This increased ECS activity in chronic intestinal inflammatory states, is evidence the body is trying to safeguard itself from inflammatory damage. Excess or prolonged states of inflammation can change the intestinal barrier strength/permeability. We know CB1 and 2 receptors are expressed in the intestinal barrier and in response to acute inflammation, the expression of CB1 is increased. CB1 regulates intestinal secretory IgA, one of the tagging compounds for your immune system to be able to label something as self or non-self. CB2 receptors appears to be more active when the gut barrier needs repair, decreasing inflammatory cytokines, thereby decreasing the inflammation and perceived pain. Certain probiotics (Lactobacillus acidophillus) activate the CB2 receptor. This relationship between the CB2 receptor, gut permeability and inflammation may help explain why probiotics help with mood and mental health.

Peristalsis, how the gut moves digested materials through the bowel with wave like contractions, can be increased or decreased with ECS activation, depending on what is needed for the individual to regain homeostasis or health. In some cases, peristalsis is slowed by activation of the CB1 receptors. ANA or 2-AG act as a key to the CB1 receptor on the surface of the cell, causing an intracellular activation of acetylcholine (ACH). ACH is released and slows the smooth muscle contractions which cause the bowel to move which can lead to a lessening of nausea, slowing the gastric emptying time and even decreasing stomach acid. There are also compounds that act to decrease CB1 activity which may be useful in cases of gastroparesis or hypomobility of the bowel.

This constant flux of the ECS, as it is informed by the enteric nervous system, can affect your mood and mental health too. In the most basic essence, our nervous system can be split up into two parts: the parasympathetic and sympathetic. The parasympathetic portion is responsible for rest, digest and procreation. The sympathetic portion governs our fight or flight response. I like to refer to the parasympathetic as classical music and sympathetic as heavy metal. Most of my patients have heavy metal blasting and classical music turned way down. The balance of these two systems is called the autonomic tone. Our bodies are dynamic and constantly in flux, seeking homeostasis.

Our bodies are dynamic and constantly in flux, seeking homeostasis.

What’s going on inside a body with too much heavy metal blasting (i.e., constant state of fight or flight)? I refer to this as the neurochemical soup in which you live. So, a heavy metal dominant environment is laden with epinephrine, norepinephrine and cortisol. These are stress hormones, and, in small amounts, they help us accomplish extraordinary tasks, like running from a bear or keeping your child safe. However, when you are in a constant state of fear, anxiety or stress these hormones, in excess, can lead to cardiovascular disease, hypertension, poor sleep and stubborn belly fat.

When and how can we make the classical music get louder? When you rest, practice meditation, experience joy, have loving connections and eat non-toxic/non-inflammatory foods your body switches into a parasympathetic dominant state. Serotonin and GABA are the key players in this neurochemical soup. Disease states consistent with lower levels of these hormones are depression, anxiety and elevated inflammatory markers.

You create the world around and within you. What you invite into self, whether it be probiotics, cannabinoids or positive self-affirmations has a profound effect on your health and state of homeostasis.  Be well, stay mindful, nourish your mind, body and spirit. With deep reverence to the complexities that is your endocannabinoidome: ECS, enteric nervous system and gut microbiome.


As a Doctor of Osteopathy, General Practitioner trained in Whole Foods Plant Based Medicine. Dr. Hartridge brings a different perspective to Primary Care as a CBD and Cannabis Expert. You can find her on Instagram @drcarolinehartridge

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