The field of medicine continues to struggle with ailments that have subjective complaints, but no verifiable objective data and they remain treatment resistant. Foremost among these ailments are migraines, fibromyalgia, and irritable bowel syndrome (IBS). The commonality of symptoms with hyperalgesia (pain) and central sensitization with common pathological findings suggest that the endocannabinoid system, our system of regulation and balance, might be involved. When endocannabinoid tone becomes deficient or even just unbalanced, pathological conditions may result.
What is Clinical Endocannabinoid Deficiency (CED)
Everyone has an underlying “endocannabinoid tone” or the overall functioning of the endocannabinoid system (ECS). This refers to the density of receptors, the number of endocannabinoids present as well as the state of the corresponding metabolic enzymes associated with the ECS. A deficiency refers to a lack of receptors or number of endogenous cannabinoids in the ECS that lead to a dysregulation of the system and then on to disease. Dysregulation of endocannabinoid tone is known as clinical endocannabinoid deficiency syndrome or CED. Dysregulation can also occur with a disruption in the enzyme levels.
The CED theory was first introduced by Dr. Ethan Russo in 2001 who proposed that a dysregulation in ECS tone could lead to the development of migraines, fibromyalgia, irritable bowel syndrome (IBS) and other related pathologies and that cannabinoids play a role in blocking the pain in such disorders.
Syndromes of CED may be congenital or acquired. Inadequate endocannabinoids may be produced, or degradation may be too rapid. Infants may be born with this syndrome or it may be lifestyle or infection related.
The ECS at a Glance
As an overview, the ECS is a complex network of signaling molecules that communicate in the central nervous system, brain, peripheral cells, and immune system to regulate and coordinate activities in the human body. The ECS consists of endocannabinoids such as anandamide (AEA) and 2-AG, the cannabinoid receptors CB1 and CB2, other peripheral cannabinoid receptors and the enzymes that break the endocannabinoids down. FAAH is the enzyme that breaks AEA down and MAGL breaks down 2-AG. Phytocannabinoids such as CBD and THC can interact with this system and indirectly regulate it. THC and CBD both interact with the cannabinoid receptors in various fashions as well as influence each other in regulation of the ECS.
The roles of the ECS have been summarized as “relax, eat, sleep, forget and protect.” It modulates embryonic development, neural plasticity, neuroprotection, immunity, inflammation, cellular death, carcinogenesis, pain, emotional memory, and hunger, feeding and metabolism.
CED and Associated Disorders
Migraines
Migraine is the third most common ailment in the world affecting 12% of the population and is the 6th most disabling illness in the world. Migraines are a neurological disorder with symptoms of pain, nausea, vomiting, dizziness and sensitivity to light and sound. Attacks may last between 4-72 hours.
Serotonin is said to mediate this disorder. Both the natural endocannabinoid AEA and phytocannabinoids act on these serotonin receptors with a reduction in headache occurrences seen in headache sufferers treated with whole hemp extract.
The migraine symptoms of light sensitivity and avoidance suggest an overactive sensory pain threshold, just the kind of homeostatic imbalance that the ECS tends to correct in the central nervous system.
The importance of dopamine metabolism in headaches has been elaborated elsewhere. THC has been shown to modulate dopamine imbalance in headache. AEA stimulates nitric oxide when it inhibits dopamine release from the synapses. Nitric oxide causes vasodilation of the blood vessels, possibly restoring balance. Migraines, it should be noted, cause vasodilation and vasoconstriction at various points in the attack. Regulation of the system is more important than control. Opiates and cannabinoids use the same nitric oxide coupling pathway. However, opioids can precipitate a migraine attack and are not good for pain control in migraines.
THC and CBD have anti-inflammatory powers. Central nervous system endorphins (the body’s’ natural pain killer) are depleted during a migraine attack. The anti-inflammatories help with the inflammation which causes pain.
Cannabinoid agonists prevent a glutamate release via a ‘reduction without blockade’ of the NMDA system. The NMDA receptor is a glutamate receptor and interacts with multiple cellular proteins. Glutamate is an excitatory neurotransmitter. A trigeminovascular (trigeminal nerve + vascular) system has been implicated as important to the pain, inflammation and vascular effects of migraine linked through the NMDA/glutamate system. THC and CBD also act as neuroprotective antioxidants against glutamate toxicity and cell death mediated via NMDA receptors independent of cannabinoid receptors. Their antioxidant ability exceeds the antioxidant capacity of both vitamins C and E.
In one Italian study on a group of women migraine sufferers, an increased level of the enzyme FAAH that breaks down AEA was found in the migraine sufferers but not in the control group. The number of receptors was not decreased in either group, again indicating the role of the ECS in migraine sufferers.
An observational trial in Colorado reported that among 120 adults with migraine whom cannabis prophylaxis was recommended, the frequency of headache significantly diminished from 10.4 to 4.6 attacks per month. Overall, 85.1 % had decreased migraine frequency with 39.7% reporting positive effects such as prevention of or reduced headache frequency or aborted headache. The mixture of cannabis used had a high THC content.
The unique attributes of cannabis and its entourage of synergistic effects on the serotonergic, dopaminergic, opioid, anti-inflammatory and NMDA mechanisms of migraine both acutely and prophylactically make it an ideal drug for migraines.
Fibromyalgia
This condition without a cause is one of the most frequent rheumatic diseases diagnosed in the US today. No chemical or organ dysfunction can be found for this battery of symptoms of increased pain sensitivity, disturbed sleep, and prevalence of secondary depression. It is a disorder of central sensitization consistent with neuropathic pain at the root of the syndrome.
A reaction to adverse stimuli with overwhelming and all-encompassing pain suggests a massive firing of sensory neurons presumably aggravated by a misstep in the serotonin system and the NMDA receptors. Other neurotransmitters in the central analgesia symptoms may be involved as well.
Fibromyalgia is considered a stress-related disorder with elevated cortisol levels and a disturbed circadian rhythm. It is also common in those with autoimmune disorders. However, no precipitating factors were found in 72% of patients studied by one researcher- a disturbing yet common trend.
Studies have shown that pain can be blocked by AEA and researchers have recommended sub-psychoactive doses of cannabinoids for treatment of fibromyalgia. It is clear from mouse studies that the endocannabinoid system regulates pain thresholds and in the absence of such regulation such as in CED, pain and related chronic pain conditions can coexist. Studies where the CB1 receptor was knocked out caused a situation of significantly increased pain suggesting a role for the endocannabinoids and cannabinoids in regulating pain thresholds.
Herbal cannabis users showed a significantly higher reduction in pain and stiffness, greater feelings of relaxation and an increase in feelings of well being in a study of 28 fibromyalgia patients and matched controls.
Irritable Bowel Syndrome
Irritable bowel syndrome or IBS is another catch all diagnosis that is often used when doctors do not have a distinct diagnosis for their patient’s symptoms of alternating diarrhea and constipation, gastrointestinal pain (g.i.) and spasms, distension and other g.i. complaints. Despite this lack of specificity, it remains one of the most frequent reasons for a referral to a gastroenterologist.
The concept of visceral hypersensitivity was introduced early on with a symphony of neuroactive and pro-inflammatory chemicals involved that led to pain and discomfort in the g.i. tract. It was found that this hypersensitivity involved receptors called vanilloid receptors which are a sort of cannabinoid receptor. It is worth mentioning here that both AEA and CBD are agonists at the vanilloid receptor, an agonist being a substance that causes a reaction when binding to a receptor.
The enteric nervous system expresses the CB1 receptor and stimulation of it depresses gastrointestinal motility. Observed effects included a delay in gastric emptying (helpful in cases of diarrhea), some decrease in peptic acid secretion and inhibition of motility through the affecting of neurotransmitter release. These effects are mediated at the brain level as well as the gut level. CB1 receptors are also in the central nervous system and brain. The brain and the gut thus demonstrate communication.
Chronic intestinal inflammation results in an increase or sensitization of cannabinoid receptors. While CBD has little effect on intestinal motility it does increase the action of THC in slowing down the transit of a meal.
Anecdotal evidence shows support for many patients turning to cannabis for treatment alternatives, especially since there are no viable drugs on the market that seem to capture and control the problems associated with IBS.
To summarize, g.i. propulsion, secretion and inflammation in the gut are all modulated by the ECS which provides a rationale for using cannabis as treatment for IBS. Much more research is needed in this area, particularly in the area of human clinical trials.
How Do You Correct CED?
Correcting CED may be accomplished by 3 different mechanism:
- Stimulating endocannabinoid biosynthesis
- Decreasing endocannabinoid breakdown
- Increasing or decreasing receptor density or function
Complementary Methods to Treat CED
While there are pharmacological drugs used in combination with cannabinoids that may be beneficial, most of these are beneficial when used in short-term settings but counterproductive when used long term under chronic conditions. These drugs include nonsteroidal anti-inflammatories, acetaminophen, corticosteroids, opiates, anti-depressants, and anti-epileptics.
Stress Management and CED
Stress challenges the body’s sense of balance or homeostasis. While some stress is inevitable in our lives, both acute and chronic stress are common causes of disruption to ECS tone. Chronic stress reduced AEA levels throughout the brains of stressed rodents. Basically, chronic stress impairs the ECS system via decreased levels of AEA and 2-AG. Stress management may reverse the effects of chronic stress through ECS signaling although there are few clinical studies available to prove this theory.
Numerous effective stress reduction methods exist including massage, yoga, meditation, deep breathing exercises and social support. For example, a human trial of osteopathic manipulative treatment showed an increase in endocannabinoid levels by 168% over pretreatment levels.
Toxin Exposure and CED
Some endocrine disruptors used in pesticides such as chlorpyrifos and diazinon alter normal ECS function. Thus, choosing organic foods may lower one’s exposure to these pesticides. Plastic water bottles and food containers have added chemicals called phthalates that have been shown to block cannabinoid receptors in animal models. Avoiding plastics may be beneficial to your ECS.
Exercise and CED
Exercise has been linked to higher endocannabinoid levels in people, too. The infamous “runner’s high” may be an example of activation of the ECS. Forced exercise may have the opposite effect according to human and animal studies. So basically, if you are having fun doing your exercise then you are having a beneficial effect on your ECS tone. So, enjoy what you are doing!
Probiotics and Prebiotics and CED
Many researchers believe that the ECS is the key to the gut-brain communication system. Researchers have demonstrated that probiotics such as lactobacillus acidophilus regulate the ECS in the colon. So, probiotic rich foods like yogurt, kefir, kombucha and kimchi and probiotic supplementation can provide targeted support for the ECS tone. Furthermore, preliminary evidence has shown a role for prebiotics in maintaining healthy ECS tone. Prebiotics are like food for probiotics, they are a type of fiber that feed the bacteria in the gut.
Alcohol and CED
Chronic consumption of alcohol impairs the ECS system by increasing levels of endocannabinoids which lead to a reduction in the number of receptors and thus the function of such receptors The downregulation of cannabinoid receptors is directly related to alcohol tolerance and it is therefore recommended that to keep a healthy ECS tone, alcohol should be consumed in moderation.
Diet and CED
While endocannabinoids are products of dietary polyunsaturated fatty acids, an imbalance in these fatty acids can lead to cannabinoid receptor dysfunction. A diet rich in omega 3 fatty acids has been shown to regulate the endocannabinoid signaling in dysregulated tissues such as the liver and fatty tissues. In a typical Western diet, the diet is high in omega-6 polyunsaturated fatty acids which causes an overstimulation of ECS that ultimately decreases insulin sensitivity in muscles and promotes fat accumulation in the fatty tissues. Decreasing omega-6 fatty acids and increasing omega-3 fatty acids will help regulate ECS tone positively.
Sources of omega-6 include nuts, seeds, meats, eggs, safflower and sunflower oils, corn and soybeans. Sources of omega-3 include fish, chia seeds, walnuts, flaxseeds, canola oil and flaxseed oil.
Herbs and CED
Cannabis extracts are ECS enhancers. CBD has substantial evidence of effectiveness in treating chronic pain, chemotherapy-induced nausea, and muscle spasticity in multiple sclerosis among other effects. Evidence suggests that whole plant cannabis extract that contains other phytocannabinoids, terpenes and flavonoids is superior to isolated compounds from the plant.
Hemp extract oil can be found here along with other full spectrum CBD products. Full spectrum products provide the entourage of effects that Dr. Russo talks about in his theory on endocannabinoid deficiency syndrome.
Treating CED is a multifaceted process utilizing lifestyle modification, diet changes, exercise, and herbal therapy.
