Clinical Endocannabinoid Deficiency

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Clinical Endocannabinoid Deficiency Could Explain Why You’re Sick

Dr. Ethan Russo is one of the world’s foremost experts in cannabis research.

Not only is he a board-certified neurologist, psychopharmacology researcher, and an accomplished author in many scientific journals, he’s also the former Senior Medical Advisor to GW Pharmaceuticals – a global leader in the development of cannabis-based medicines. Today, he serves as the Medical Director at Phytecs, a biotechnology company that specializes in developing cutting edge therapies targeting endocannabinoid dysregulation associated with inflammatory and metabolic diseases from eczema to cancer.

Yet even with his years of experience and decades of advancements in cannabis research, he still has one theory that has remained unproven for well over 15 years.

You see back in 2001, Dr. Russo introduced the theory of clinical endocannabinoid deficiency (CED).

The theory of CED was based on the concept that because many brain disorders are associated with neurotransmitter deficiencies, like deficiencies in acetylcholine in Alzheimer’s disease, dopamine in Parkinson’s disease, and serotonin and norepinephrine in depression, then deficiencies in endocannabinoid levels should be associated with certain disorders and diseases as well – especially since the endocannabinoid system’s (ECS) receptor density is far greater than many of the others.

Its base hypothesis is that all humans have an underlying endocannabinoid tone. That means that the number and state of cannabinoid receptors and the levels of endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) all stay within a normal range in all humans.

But under certain conditions, endocannabinoid tone becomes deficient and can lead to diseases with symptoms like chronic pain, along with derangements of digestion, mood, and sleep.

This theory lends itself well to common pain syndromes that are mostly considered subjective and are resistant to treatment. Some of the most common include migraine, fibromyalgia, and irritable bowel syndrome.

If proven true, this theory could help explain why patterns of symptoms can be mediated by the endocannabinoid system and also why cannabinoid treatments can provide symptomatic relief for some of these conditions.

Unfortunately, when the theory was put forth back in 2001, objective proof and formal clinical trial data were almost non-existent.

However, in one of his most recent articles published in 2016 in the journal Cannabis and Cannabinoid Research, Dr. Russo reviewed the latest research on CED in Irritable Bowel Syndrome, Migraine, and Fibromyalgia, and was able to conclude that we are now much closer to proving his theory than ever before.

Irritable Bowel Syndrome and CED

Irritable bowel syndrome (IBS) is a very common disorder that affects the large intestine (colon) and is known to cause symptoms such as abdominal pain, cramping, distention, gas, diarrhea and constipation. It is often considered a life-long condition and its attacks can be triggered by anything from anxiety, to certain foods, to even antibiotics.

IBS is particularly difficult for physicians to treat because of its fluctuating and often subjective symptoms. Treatment options can include anticholinergics, opioids, antidepressants and others affecting a myriad of neurotransmitter systems. Unfortunately, most drug treatments are suboptimal, at best.

However, the ECS has been identified as a key modulator of gastrointestinal (GI) tract function. Recent studies have shown that the ECS can modulate GI propulsion, secretion, and inflammation in the gut and is an important contributor to overall gut health. This makes cannabinoids excellent treatment candidates for IBS and also points to the existence of CED in IBS.

Migraine and CED

Migraine is a very common condition that is characterized as a moderate or severe headache. It can be felt as a throbbing pain on one side of the head and symptoms can include nausea, vomiting and increased sensitivity to light or sound. Migraines can happen frequently or occasionally.

As discussed in our previous article, there is no cure for this condition and current treatments are inadequate. Treatments may include avoidance of migraine triggers, medications, physical therapies and behavioral therapies. When a patient has a migraine, over-the-counter pain relievers and prescription medications are usually taken however side effects often limit the use of medications.

But according to Dr. Russo’s article, perhaps the strongest evidence of the existence of CED in migraine or any disorder comes from an Italian study published in 2007. Researchers assayed cerebrospinal fluid (CSF) AEA levels in 15 chronic migraineurs versus 20 controls and the results showed a phenomenal statistically significant difference. According to Dr. Russo:

Reduced AEA levels in the CSF of CM [chronic migraine] patients support the hypothesis of the failure of this endogenous CB [cannabinoid] system in CM.

In this instance, the existence of CED was clearly demonstrated in relation to chronic migraine.


Fibromyalgia is a chronic disorder characterized by widespread pain all over the body. Symptoms can include musculoskeletal pain and tenderness in localized areas, and the condition is often accompanied by fatigue, sleep, memory and mood issues. It is also noteworthy for its characteristic “trigger points” that are often severe enough to limit physical activity.

Many researchers believe that fibromyalgia affects the way your brain processes pain signals. They’ve also discovered that fibromyalgia, like migraine, is associated with secondary hyperalgesia – or a heightened sensitivity to pain – in areas adjacent to the affected parts as well.

But similar to IBS and Migraine, drug treatment for Fibromyalgia is not known to be effective. Pain medicines, sleeping pills, and antidepressants are often prescribed to help ease pain, boost mood, and improve sleep but none of these treatments are particularly effective.

Interestingly, hyperalgesia has also been observed in association with central endocannabinoid hypofunction (inadequate functioning) in the spinal cord and that endocannabinoids reduced associated hyperalgesia. This makes the ECS a prime target for treatment and CED a rational explanation for the disorder. Not surprisingly, cannabis or cannabinoids have been frequently utilized by fibromyalgia patients to treat its myriad of symptoms and a limited number of clinical trials have produced evidence for decreased pain, improved sleep, and other benefits to cannabinoid treatment.

Understanding CED could have huge implications for the future of medicine

Other disorders that may be linked to CED include neonatal failure to thrive, cystic fibrosis, causalgia, brachial plexopathy, phantom limb pain, infantile colic, glaucoma, dysmenorrhea, hyperemesis gravidarum, unexplained fetal wastage (repetitive miscarriages), post-traumatic stress disorder (PTSD), bipolar disease, and possibly many others. All of these conditions have complicated pathophysiological features and remain treatment resistant.

However, the results from cannabis studies so far have opened up the door for further investigation into CED and disease. These results certainly support an urgent need for more definitive randomized controlled trials of well-formulated and standardized cannabis-based medicines.

Dr. Russo believes, based on the evidence discussed, that this is long overdue and that additional investigations in a similar vein to assess endocannabinoid levels in the serum or spinal fluid of migraine, IBS, and fibromyalgia versus controls would be illuminating. He also hopes that advancements in scanning techniques (fMRI, PET) will soon allow for real-time direct assessments of endocannabinoid levels in living patients as well. Genomics could also play a huge part in exploring the gene functions that underlie the CED-related conditions discussed above.

Although cannabis research is still in its infancy, science has made great strides in uncovering the relationship between man and plant. Proof of this theory could bring us one step closer to healing the conditions that modern medicine can’t.

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Tags: Alzheimer’s Disease, Anxiety, Bipolar Disorder, Cannabidiol, CBD, CBD research, Depression, Fibromyalgia, Glaucoma, IBS, Inflammation, Migraine, Nausea, Parkinson’s Disease, PTSD

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