Supporting your Endocannabinoid System:

How Drugs and Natural Products Affect the Endocannabinoid System.

Published in

Randy’s Club

11 min readJun 28, 2016

by Tyler Strause and Linda Strause, Ph.D.

When your body is healthy and your endocannabinoid system (ECS) is operating optimally, the overall activity of the ECS is generally low. The ECS operates in concert with our central nervous system (CNS) to modulate and maintain homeostasis in the body. Baseline ECS activity may change during an immune response or increased CNS activity caused by stress or physiological dysfunction.

A look at the research reveals that several classes of drugs currently prescribed by doctors all upregulate the ECS; these include analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. In addition, other complementary and alternative medicine (CAM) therapies, such as massage and body manipulation, acupuncture, dietary supplements, and herbal medicines, also upregulate the ECS. Unfortunately the link between these therapies and the ECS has not been proven by controlled clinical trials. None the less data suggests that the ECS is impacted by a wide range of medical interventions including both conventional and alternative therapies.

Our basic understanding of the ECS includes the cannabinoid receptors, their associated ligands, and their metabolic enzymes. From this understanding, a new theory has developed suggesting the possibility of a Clinical Endocannabinoid Deficiency Syndrome (CEDS) first proposed by Dr. Ethan Russo (1,2). This article aims to discuss ways to support the ECS by increasing the availability or activity of endocannabinoids and their corresponding receptors.

Endocannabinoid System (ECS)

The ECS is responsible for the modulation of homeostasis in the body. The ECS is more widely expressed in the body than all other neuromodulatory systems combined. The ECS is mostly expressed in cells of the immune system and CNS, but is also present in fat, liver, and muscle cells, and skeletal tissue. Cannabinoids act as neuromodulators for a variety of processes, including appetite, motor learning, pain sensation and other cognitive and physical processes.

The primary cannabinoid receptor, CB1, is the most abundantly expressed G-protein-coupled receptor in the body. G-protein-coupled receptors act like an inbox for messages that inform cells about the presence or absence of life-sustaining light or nutrients in their environment, or they convey information sent by other cells.

CB2, the second most common ECS receptor, is principally involved in modulating the body’s immune response. It may have some involvement with the CNS where it is thought to play a critical role in controlling inflammation in the brain.

The two main endocannabinoids produced by the body are N-arachidonylethanolamide, (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). Both AEA and 2-AG are produced on demand by cells and work to maintain homeostasis, breaking down after they are utilized by either the CB1 or CB2 receptors. For example, human breast milk contains endogenous cannabinoids including high levels of 2-AG; 2-AG is known to have a calming effect. In fact, one study found that rats given a cannabinoid blocker stopped nursing and died (3). This suggests that endocannabinoids may play a role in feeding and perhaps even the mother-child bond. This basic understanding of the ECS has been expanded to include related enzymes and receptors which can enhance the effects of AEA and 2-AG by way of the “entourage effect”, where compounds inhibit the breakdown of endocannabinoids thus increasing their activity. Endogenous entourage compounds include N-palmityl ethanolamide (PEA), N-oleoyl ethanolamide (SEA), and cis-9-octadecenoamide (oleamide, OEA,).

Clinical Endocannabinoid Deficiency Syndrome (CEDS)

The role of the ECS in maintaining homeostasis, or a stable equilibrium, within the body can be summarized as “relax, eat, sleep, forget, and protect.” The ECS modulates everything from embryological development, to neural plasticity and neuroprotection. It also supports the immune system and promotes a healthy inflammatory response. The ECS is involved in cellular processes from apoptosis and carcinogenesis, the regulation of pain, hunger, satiety, feeding, and metabolism, to our emotional memory.

Disorders that have become associated with the ECS are numerous and, when taken together, represent the Clinical Endocannabinoid Deficiency Syndrome (CEDS). The CEDS is caused by the bodies inability to produce or utilize endocannabinoids. CEDS describes a dysfunction in the ECS which contributes to a generalized breakdown in the body’s ability to maintain a stable equilibrium, known as homeostasis. This can lead to a variety of illnesses including migraines, fibromyalgia, irritable bowel syndrome, and even depressive illnesses such as bipolar disorder and schizophrenia. Other conditions which may in part be caused by CEDS include multiple sclerosis, Huntington’s, Parkinson’s, anorexia and even chronic motion sickness.

There are three ways to address CEDS. First, you can increase the amount of endocannabinoids produced by the body. Second, you can decrease the rate at which endocannabinoids are degraded. Third, you can increase the number of receptors and improve their function. So far there have not been any controlled clinical trials involving drugs that treat CEDS. This lack of human clinical trials forces us to rely on preclinical approaches that allow for a systematic review of the available research to better understand CEDS and possible interventions. Possible interventions for CEDS include already approved pharmaceutical drugs, CAM therapies, and unapproved investigational new drugs. See Table 1 for a summary of interventions, mechanism of action and effects of some of these products.

Table 1: Summary of agents that affect the ECS

Pharmaceutical drugs

Pharmaceutical drugs that have been shown to interact with the ECS include pain relievers such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opiates, and glucocorticoids. Some NSAID pain relievers have been shown to inhibit a key enzyme responsible for breaking down endogenously produced cannabinoids enhancing the activity of those cannabinoids as well as the activity of natural and synthetic cannabinoids. In animal studies (4), combining NSAIDs with cannabinoids produces synergistic effects in which a low dose of a cannabinoid became fully activated following the administration of an NSAID pain reliever. By administering both ibuprofen and AEA researchers produced synergistic pain relieving effects which were shown to involve both CB1 and CB2 receptors. Moreover, in one study (5) a cannabinoid was found to reduce the number and severity of gastric lesions produced by NSAID pain relievers.

Obese individuals are known to have an overactive ECS which may suggest a breakdown in the ability to regulate hunger and metabolism. A drug called Rimonabant was developed to reverse this effect by blocking the CB1 receptor. It was approved for the treatment of obesity. It was ultimately taken off the market due to serious adverse effects including some suicides. Research is underway into second generation neutral CB1 antagonists which may minimize the side effects associated with depression and anxiety while providing potential efficacy in the treatment of obesity.

Another approved drug that has been shown to interact with the ECS is glucocorticoids. Research has shown that chronic administration enhances the activity of endocannabinoids and suggests that mania brought on by corticosteroids might involve the ECS and suggests that corticosteroids have a cannabimimetic component which could lead to the chronic down-regulation of the ECS which would be consistent with chronic stress (6)

Antidepressant drugs including selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs), were long thought to work by increasing the amount of the neurotransmitter serotonin. New evidence suggests that antidepressant drugs may upregulate the CB1 receptor resulting in improved mood and symptoms (7).

Other pharmaceutical drugs may also interact with the ECS in various ways but more research is needed to understand the processes involved. The fact that drugs that have been on the market for many years, including some OTC drugs, have cannabimimetic activity may be surprising but should not be considering the diversity and scope of the ECS in our bodies.

Complementary and Alternative Medicine therapies (CAM)

Other interventions that have been shown to affect the ECS fall into the broad category of CAM.

Polyunsaturated fatty acids (PUFAs) play an important role in many cellular and multicellular processes. These include promoting a healthy inflammatory response, supporting our immune system and enhancing neurotransmission. Two such PUFA, alpha-linolenic acid (an omega-3-fatty acid) and linoleic acid (an omega-6-fatty acid) are considered essential because they cannot be produced by the body and must be obtained from foods. Unfortunately, the typical western diet is often deficient in these essential fatty acids. This deficiency may hinder the activity of the ECS leading to increased inflammation, pain, and swelling. Taking a PUFA supplement containing omega-3 and omega-6 fatty acids, will ensure that adequate levels are present to ensure proper ECS signaling. Supplementation will also increase the number of entourage compounds promoting the “entourage effect” described earlier. Interestingly, a persistent deficit in the amount of PUFA’s has been shown to cause chronically elevated endocannabinoid levels in the brain, which hinders signaling by desensitizing endocannabinoid receptors to the effects of cannabinoids (8)

Overall, dietary PUFAs appear to help regulate the ECS. In cases of deficiency or excess, the result was a decrease the activity of the ECS. This dysregulation can be avoided by consuming enough essential fatty acids but not in excess.

Probiotics are symbiotic microorganisms that are beneficial to human health. They are produced during fermentation and are found in fermented foods like yogurt and kimchi. Prebiotics, like oligofructose, are carbohydrates that support probiotic organisms so that they can thrive in our gut. Probiotics seem to increase the expression of the CB2 receptor in the cells that line the gut which has been associated with having less pain (9) Probiotics also modulate CB1 receptor expression reducing the expression of CB1. This decrease was in turn associated with a decrease in the amount of fatty tissue.

Another supplement that has been shown to interact with the ECS in an indirect manner is a vitamin E derivative called α-tocopheryl phosphate (α-TP) (10) Some examples of foods rich in vitamin E are nuts, seeds, avocado, vegetable oils, and wheat germ. Some dark leafy greens and fish are also sources of vitamin E. α-TP is not known to bind directly to cannabinoid receptors but has been shown to modulate synaptic transmission suggesting an indirect role in the modulation of the ECS.

Plants also produce compounds known to interact with the ECS. The most popular being the cannabis plant which produces the classic cannabinoids, THC and CBD. Other plants such as the Copal tree, Wormwood and Khat, have also been shown to produce compounds which interact with the ECS. These plants produce terpenes and other ingredients that bind to either one or both of the two classic cannabinoid receptors, CB1, and CB2.

Another broad class of compounds with reported ECS activity are called flavonoids. Flavonoids are in large part the chemicals which give things flavor, hence the name. One plant rich in flavonoids is red clover which contains biochanin. Others include soybeans, which contain genistein and camelia sinensis, which contains kaempferol. Theses and other flavonoids have been shown to inhibit the enzyme that breaks down cannabinoids.

Nature produced products that interact with the ECS in a variety of ways. Some natural products like Kava Kava, produce a cannabinoid-like compound called yangonin that has been shown to bind to cannabinoid receptors. Legumes, mushrooms, sunflowers, rhododendron, and liverworts have all been shown to produce cannabinoid-like compounds. Other plants produce like falcarinol. Falcarinol is a skin irritant produced by many plants that appear to have pro-inflammatory effects due to it’s ability to block the CB1 receptor which may affect the body’s ability to modulate inflammation in that area. Health supplements, such as echinacea, contain compounds which produce synergistic effects by directly bind to and inhibiting removal of endocannabinoids from the body. In addition to positive ECS effects, echinacea may also act against the action of THC possibly reducing some of its adverse effects. It has also been said that sniffing black pepper can reduce some of the side-effects of THC. This is because black pepper contains β-caryophyllene (BCP) which is a dietary cannabinoid found in food that has anti-inflammatory effects and has been reported to decrease adverse effects caused by THC.

Mind-body practices are another means by which we are able to affect the ECS. This is mostly mediated by the hypothalamic-pituitary-adrenocortical (HPA) axis. Interestingly, while chronic stress is known to increase cortisol levels and reduce 2-AG levels, with repeated stress, 2-AG levels increase or decrease depending on the nature of the stress and whether it be persistent or intermittent. This may help to explain how the bodies of individuals in high stress jobs like air traffic controllers or first responders, are able to adapt and manage their cortisol levels despite high levels of stress. It may also help explain why some people seem to be more naturally suited to high stress jobs than other.

Other alternative practices like acupuncture have also been shown to affect the ECS. Acupuncture has been shown to work by upregulating the expression of cannabinoid receptors and by increasing the levels of endocannabinoids in the skin. Still others like massage and body manipulation increased endocannabinoid levels while decreasing overall ECS activity.

Finally exercise, there’s lots of data showing that exercise induces analgesia and sedation. Despite decades of research attempting to show a neurochemical basis for these phenomena, the mechanism underlying these changes remained a mystery until researchers were able to show evidence that exercise of moderate intensity activates the endocannabinoid system, suggesting a new mechanism for exercise-induced analgesia (11)

Not everything that interacts with the ECS is going to help it. Alcohol has been shown to affect cannabinoid signaling in the body by dampening the effects of endocannabinoids and likely reducing cannabinoid receptor sensitivity. Nicotine has also been shown to have synergistic effects with natural cannabinoids like THC. The effects of nicotine on our nerves may reduce some of the effects of THC on memory suggesting that nicotine might also interact with the ECS albeit indirectly. Coffee is sometimes mixed with hash to increase its absorption and enhances the endocannabinoid system making it more sensitized. These effects vary by dosage and are less pronounced over time. Caffeine may also increase the effects of THC on short term memory.

Which brings us to cannabis itself. Cannabis is a poly-pharmaceutical plant medicine comprised of multiple active compounds including THC, CBD, and over 100 minor cannabinoids along with terpenes, flavonoids, and other therapeutically active compounds. How one responds to these cannabinoids appears to be dependent on dose yet varies significantly from individual to individual. Fundamentally THC mimics AEA and 2-AG acting as a natural supplement if taken when the body is deficient. THC may also increase ECS activity overall by stimulating directly cannabinoid receptors increasing the amount of cannabinoid receptors and their sensitivity. However, excess THC may have the opposite effect, suppressing the ECS and desensitizing its receptors. Cannabis is more than just THC. Synergies exist between THC and CBD such that when combined they further enhanced cannabinoid receptor expression in the brain and the overall survival of cells. Additionally, CBD counteracts some of the psychomimetic effects of THC reducing some of it’s side effects in humans.

Summary

There remain many unanswered questions about the ECS and ways natural cannabinoids and other drugs interact and affect it. Much of the data is preliminary and from animal models and some of it is contradictory and inconsistent. None the less many studies have been done looking at the effects of various interventions on the ECS including dietary supplements, mindfulness, acupuncture, massage, and manipulation. All of these interventions appear to be good methods of supporting the ECS. Drugs such as antidepressants, anti-anxiety drugs, and muscle relaxants are typically administered chronically which could have an adverse effect on the ECS over the long term. Other drugs like steroids, opioids and nicotine have serious side effects that make them inappropriate for upregulating the ECS. Cannabis is a clearly promising intervention that is in use in dozens of states now and is legal for adult use in four states. The opportunity to study these populations and the need to do more controlled clinical research remains a high priority.

References:

Supporting your Endocannabinoid System:

How Drugs and Natural Products Affect the Endocannabinoid System.

Written by Tyler Strause