Clinical Endocannabinoid Deficiency Syndrome
By Stacey Marie Kerr, MD
a fine balance
Neurotransmitters carry messages throughout the central nervous system, and when these messengers are deficient the effects are catastrophic. If acetylcholine is deficient, we see Alzheimer’s Disease. If dopamine is deficient, we see Parkinsonian syndromes, and if serotonin and norepinephrine are deficient we diagnose depression. Clearly, the healthy functioning of neurotransmitters is essential to our well-being.
neurotransmitters in the endocannabinoid system
Anandamide and arachidonoylglycerol (2-AG) are neurotransmitters that carry messages throughout the endocannabinoid system (ECS). They are modulators, serving to maintain homeostasis throughout the body. When systems get out of balance, these neurotransmitters go to work to bring us back to a state of health.
The ECS has CB1 receptors in the brain with a greater density than most of the other neurotransmitter systems, and CB2 receptors are found throughout the GI tract, liver, spleen, immune system and peripheral nervous system.
With this prevalence of the ECS, if anandamide and 2-AG are deficient in their activities, we would expect to see health problems like lowered pain thresholds, problems with digestion, problems with sleep, and an increase in mood disorders. Research on the proper functioning of the ECS could give us new opportunities to address some health problems that have, so far, been difficult to both diagnose and treat.
The three most studied conditions linked to Clinical Endocannabinoid Deficiency (CED) are migraines, fibromyalgia, and Irritable Bowel Syndrome. These three have much in common. All of them cause an increased sensitivity to pain and all must be diagnosed subjectively by a process of exclusion, there being no objective tissue or lab findings for any one of them. All are associated with a higher incidence of anxiety and/or depression. And they often overlap, with patients presenting with some combination of the three quite often. 
Migraine is a public health issue that affects 14% of Americans, costing $20 billion each year and affecting women three times more often than men.  A migraine attack, often brought on by environmental and hormonal stressors, presents with a throbbing headache associated with nausea, photophobia, phonophobia (aversion to loud noises), and other associated symptoms.
Currently, several types of pharmaceuticals are used to treat migraines. Pain relievers like ibuprofen, aspirin, caffeine, and acetaminophen may help mild migraines but regular use of these can cause problematic side effects that include bleeding stomach ulcers and new headaches caused by medication over-use.
Triptans like Imitrex are injectables that block blood vessels to the brain, aborting the onset of migraines if taken early enough. Ergotamine combined with caffeine can be used if the migraine lasts more than 48 hours, but this combination can also exacerbate the nausea and vomiting that often occurs. Narcotics, steroids, and anti-nausea medicines are prescribed for persistent painful migraines.
Pharmaceuticals are sometimes helpful in preventing migraine headaches. Blood pressure medications, anti-depressants, anti-seizure medications, and Botox have all been used with varying rates of success. Some of these are quite effective, but each has its own set of possible side effects.
cannabis for migraine: if it worked for queen victoria...
For 4000 years cannabis was used to treat migraines; it was prescribed extensively in Western medicine between 1842 and 1942. Queen Victoria used it, and patients still use cannabis to prevent and treat migraine headaches. A survey of 120 adults who used cannabis for migraine prophylaxis reported that 85% of these patients had at least decreased migraine frequency with almost 40% noting significant positive effects – prevention of, reduced frequency, or aborted headaches – all using presumable high-THC cannabis.  What is the science to support these observations?
the ecs and migraine physiology
The trigeminovascular system (see image below) is considered by many to be at the root of migraine pathophysiology, both through neurons and blood vessels. CB1 receptors are dense in the trigeminovascular system and research on endocannabinoids in these areas indicates an important role of the ECS in migraine episodes. The endocannabinoid anandamide inhibits the trigeminovascular system as part of its modulating functions, and analyzation of cerebrospinal fluid in chronic migraineurs revealed significantly lower levels of circulating anandamide in those patients. 
Inflammation, serotonin, dopamine and depleted beta-endorphins in the central nervous system contribute to migraine syndromes, all of which are modulated by the ECS.  In addition, the CB1 gene has been linked to migraines through a mapped genetic effect that alters trigeminovasular activation. 
All this lends credence to the link between migraines and dysfunction of the Endocannabinoid System.
Anyone with fibromyalgia knows the frustration of diagnosing and treating this disabling condition. Fibromyalgia is the most common diagnosis in American rheumatology practices.  Patients with fibromyalgia have painful trigger points that are severe enough to limit lifestyle and quality of life. Over time, these painful areas intensify pain perception in the brain leading to disturbances in sleep, dysfunction of the nervous system, and depression. Unfortunately, the depression of fibromyalgia does not respond well to commonly used anti-depressant medication.
The connection between hyperalgesia (increased sensitivity to pain) and the endocannabinoid system is supported by studies that injected cannabinoid antagonists into mice. When the CB1 receptors were blocked this way, the mice experienced significant pain, which was relieved by the injection of synthetic cannabinoids. This and other studies support the use and study of cannabinoid agonists for chronic pain conditions like fibromyalgia and migraines.  Presumably, if the endocannabinoid system was working as it should, chronic pain and hyperalgesia would not develop. Supplementing a deficient endocannabinoid system with phytocannabinoids could help patients with fibromyalgia regain some quality of life.
This presumption was strengthened by the National Pain Report of 2014, conducted by the National Pain Foundation. They surveyed 1339 people with fibromyalgia and had them compare cannabis to the three medications currently approved by the FDA for their condition.  The survey results are below:
Irritable Bowel Syndrome
Irritable Bowel Syndrome (IBS) is as debilitating as fibromyalgia and migraines, as evidenced by the numerous graphic advertisements seen regularly on TV with patients afraid to get very far from a bathroom. It, like the other conditions discussed here, is a diagnosis of exclusion with no objective tissue or lab findings to rely upon. People with IBS have fluctuating symptoms of GI pain, spasms, distention, and bouts of diarrhea with occasional constipation. The unpredictable nature of these symptoms can be triggered by infection or changes in diet, which may explain the common correlation with anxiety. It is the most common referral diagnosis for American gastroenterologists. [1, 3]
Gastrointestinal propulsion, secretion and inflammation are all modulated by the ECS. If all is working well, the ECS does a good job of keeping the system pain free and regular. Conventional treatment attempts with pharmaceuticals for IBS have been disappointing. Two agents have actually been taken off the market after being approved, one for a high risk of ischemic colitis (injury to the colon from inadequate blood supply) and another for cardiovascular adverse effects. 
Studies on the use of cannabinoids in the treatment of IBS have not yet been performed, but cannabis does have a long history of effectively treating cholera, intestinal colic and other gastrointestinal disorders. There are many anecdotal reports of its efficacy with IBS so well-designed studies are certainly warranted.
Three questions are posed in Dr. Russo’s review of CED, published in 2004:
1) Are there as yet unelucidated biochemical explanation for these disorders?
2) Might endocannabinoid deficiency explain their pathophysiology?
3) Are the symptoms alleviated by clinical cannabis?”
Considering these three questions, there are other difficult health problems that could be a result of CED. For many years most of these have been considered psychological in origin, but this may change as we learn more. Premature ejaculation, phantom limb pain, glaucoma, hyperemesis gravidarum (excessive vomiting during pregnancy), infantile colic, cystic fibrosis, and intractable depression are simply a few conditions that may be caused by dysfunction of the endocannabinoid system.  Clinical Endocannabinoid Deficiency is not yet provable, and neither do we know what might cause these neuromodulators to be dysfunctional. However, as we gain more knowledge of the ECS and develop more directed methods of affecting the endocannabinoid system we may find interventions to help thousands of patients who have not yet found relief. Ideally we would be able to measure the amount of active endocannabinoids in an individual and adjust specifics according to each individual patient’s needs. There is hope that frustration and pain could be a thing of the past for many who now suffer from migraines, fibromyalgia, IBS, and many other difficult-to-treat conditions.
1. Russo; Cannabis and Cannabinoid Research 2016, 1.1. http://online.liebertpub.com/doi/10.1089/can.2016.0009
2. Sarchielli P, Pini LA, Coppola F, et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007;32:1384–1390.
3. Russo E. Clinical Endocannabinoid Deficiency (CECD): Can This Concept Explain Therapeutic Benefits of Cannabis in Migraine, Fibromyalgia, Irritable Bowel Syndrome and Other Treatment-Resistant Conditions? Neuroendocrinology Letters. Nos.1/2, Feb-Apr Vol.25, 2004
4. National Pain Report. Marijuana rated most effective for treating fibromyalgia. National Pain Report, 2014. Available at: http://nationalpainreport.com/marijuana-rated-most-effective-for-treating-fibromyalgia-8823638.html
5. Smith, Wagner; Clinical Endocannabinoid Deficiency Revisited; Neuroendocrinology Letters 2014;35(3):198-201
6. Fichna J, Wood JT, Papanastasiou M, Vadivel SK, Oprocha P, et al. (2013) Endocannabinoid and Cannabinoid-Like Fatty Acid Amide Levels Correlate with Pain-Related Symptoms in Patients with IBS-D and IBS-C: A Pilot Study. PLoS ONE 8(12): e85073. doi:10.1371/journal.pone.0085073
7. Di Carlo G, Izzo AA. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin Investig Drugs 2003;12:39–49.