Clinical endocannabinoid deficiency: when does it happen and why?

This article was republished with permission from The Cannigma. Read the original article.

Modern medicine has become quite advanced when it comes to treating our medical needs, but meanwhile still has a ways to go with many conditions remaining a mystery, both in their cause and their potential treatments. Disorders like fibromyalgia and irritable bowel syndrome are strong examples of this. There are no lab tests to determine if you have these conditions and the mechanisms that cause them to remain a mystery. Still, they share common symptomatology of increased sensitivity to pain. 

While the cause of these conditions has been mysterious up until now, hypotheses have emerged that these (and other) conditions may be caused by a disorder called Clinical Endocannabinoid Deficiency (CED). Could CED be the cause of many poorly understood conditions? According to Dr. Ethan Russo, it just might be. In his seminal 2016 article “Clinical Endocannabinoid Deficiency Reconsidered,” Russo lays out the theory behind CED.

What is clinical endocannabinoid deficiency?

To understand clinical endocannabinoid deficiency, you first need to understand that all humans and mammals have something called an endocannabinoid system. This natural system is responsible for maintaining internal homeostasis (or balance) and controls some of our body's most important functions. Your endocannabinoid system regulates things like sleep, mood, pain, immune response, memory, and hunger. It plays a big role in keeping your body well functioning. 

Endocannabinoid Receptor
This system contains three basic parts — cannabinoid receptors, endocannabinoids (natural internal chemicals which bind with cannabinoid receptors), and enzymes (which clear endocannabinoids from your system).

This system contains three basic parts — cannabinoid receptors, endocannabinoids (natural internal chemicals which bind with cannabinoid receptors), and enzymes (which clear endocannabinoids from your system). When endocannabinoids bind with these receptors, it stimulates those important functions — such as reducing pain, improving mood, or sparking hunger. 

According to Russo, all humans have an underlying endocannabinoid tone. This means we all have a general level of endocannabinoids and receptors present in our system, and a general level of efficiency for endocannabinoid production and metabolism.  

The theory behind CED is that some people might have deficiencies when it comes to endocannabinoid tone which could lead to less activation of the endocannabinoid system. This might be related to genetic differences in some, or it might be an acquired deficiency resulting from injury or disease. CED might manifest in many ways, including significantly low or high levels of endocannabinoids, significantly low or high levels of metabolites, too many or not enough endocannabinoid receptors, or even desensitization of those receptors. 

First proposed by Russo in 2001, this hypothesis was originally supported by the fact that cannabis seems to help with many difficult to treat conditions — and cannabinoids (some of the active chemicals in cannabis) are able to stimulate the endocannabinoid system in the same way endocannabinoids do. 

Still, very little hard evidence for the theory had been documented. But more recently, additional evidence (documented in Russo's article) has emerged in favor of the theory, showing physical indications of ECS dysfunction in several conditions. For example, statistically significant differences in endocannabinoid levels have been found in the cerebrospinal fluid of migraine sufferers, and imaging studies have shown lowered ECS function in patients with PTSD. 

Conditions associated with clinical endocannabinoid deficiency

The endocannabinoid system is a key system in the human body, responsible for maintaining internal homeostasis and balance. So what happens when this system is dysregulated? 

Well, if endocannabinoid function were to decrease, it would likely lower the pain threshold and disrupt digestion, mood, and sleep, among other functions. This is exactly what we see in the conditions suspected to originate with CED, such as migraine, fibromyalgia, and irritable bowel syndrome (IBS).

“These disorders actually have a lot in common in that they're all what are called diagnoses of exclusion, which is a way of saying that there are no specific tests for them, you can't scan for them, you can't do blood tests for them, but they all involve a sort of hypersensitivity to pain,” Dr. Russo said on the Cannabis Enigma podcast. “In the case of migraine, it's headaches, but also painful stimuli such as noise and bright light. For irritable bowel it's an acute awareness of the gut and phenomena that normally don't hurt are quite painful to people with that condition. And with fibromyalgia, you've got a generalized often increase in pain sensitivity on certain muscles or fibrous tissues may hurt to a great extent, but examining the tissue reveals no specific problem to explain it.”

These three conditions also include a higher likelihood of anxiety, depression, sleep disorders, and headaches. While this profile of symptomatology is the starting point for considering these conditions, there is compelling evidence for each suggesting it's a possible connection to CED. 

Irritable bowel syndrome (IBS) 

Irritable bowel syndrome, also known as IBS or spastic colon, is characterized by gastrointestinal pain, spasm, discomfort, and altered bowel movements (usually predominantly characterized by diarrhea, constipation, or alternation between the two). While sometimes triggered by specific foods or behavior like overeating, it is also tied to anxiety. IBS is common in the western world, affecting about 10-15% of the population. Still, there are no physical signs tied to this disorder that might indicate a cause. 

But it may be that CED is at the root of this condition. More recently, it's been discovered that the GI tract is intimately related to the ECS, with the ECS modulating functions like GI propulsion, secretion, and inflammation in the gut. This suggests both that CED could be involved in IBS, and that cannabinoids might be an effective treatment for the condition. 

In fact, cannabis has long been used for GI problems. It was one of the first effective treatments in the 19th century for diarrhea associated with cholera, and modern research has supported its effectiveness for this use. Today, many IBS patients use cannabis to alleviate their symptoms and claim that it is effective. Still, there has been very little clinical research to determine whether these anecdotal claims hold up to scrutiny. 

But there is also additional evidence to tie IBS to CED. One study looking at muscle fibers from colonoscopic biopsies found that one endocannabinoid, anandamide, affected how colon muscles contract. The authors of this study suggested that the ECS was particularly important when the gut was suffering from disease or inflammation. 

Another study found increased TRPV1 nerve fibers in IBS sufferers, which could contribute to hypersensitivity and pain in IBS. Since certain cannabinoids such as the endocannabinoid anandamide or the phytocannabinoid CBD may desensitize TRPV1, this also relates to ECS function and further supports the idea that IBS may be a sign of CED. 

In addition, genetic differences in endocannabinoid metabolism were observed in patients with diarrhea associated IBS. Stimulating the CB1 receptors using cannabinoids like THC has been shown to slow colonic transit time and increase colonic compliance in these patients. 

THC has also been shown to alter the gut microbiome in obese mice — restoring it to a gut microbiome similar to healthy mice. 


Migraine is a common headache syndrome that affects about 15% of Americans and three times more women than men. Associated with nausea, sensitivity to light and sound, and hormonal and environmental triggers, migraine headaches are painful and difficult to live with.

So why do scientists like Russo believe migraines might be connected to CED imbalance?

migraines and weed
Modern surveys have shown that cannabis can significantly reduce migraine frequency.
Photo by: Gina Coleman/Weedmaps

Well, for one thing, migraine sufferers seem to respond to cannabis treatments. It's been used historically as a migraine treatment, and modern surveys have shown that cannabis can significantly reduce migraine frequency. In one survey 85.1% of those who used cannabis for migraines had decreased migraine frequency, diminishing from 10.4 to 4.6 attacks per month on average. 

Migraine sufferers' response to light and sound is also a clue. It suggests an overactive sensory experience in the central nervous system. This is exactly the sort of thing that the ECS would usually correct. In addition, the endocannabinoid anandamide is capable of producing serotonin receptor responses that are consistent with the profiles of drugs that have been effective at reducing migraine activity. 

And research is now showing that anandamide plays an important inhibitory role in activating the trigeminovascular system — a system in the human body whose activation and sensitization occur during migraine headaches. It could be that reduced levels of natural anandamide would lead to migraines by allowing for activation of the trigeminovascular system.

In fact, this is exactly what researchers are finding. In a study that Russo calls “perhaps the strongest evidence of the existence of CED in migraine or any disorder,” scientists from the University of Perugia in Italy looked at the anandamide levels in migraine sufferers and found that anandamide levels (along with other endocannabinoids) were significantly lower than in controls. 

Other studies found that anandamide caused dose-dependent vascular phenomena related to those seen in migraine sufferers — inducing vasoconstriction in one study and vasodilation in another. Since both vasoconstriction and vasodilation are present in migraine, this could indicate anandamide plays an important role in this aspect of the condition. 

Scientists have also found high levels of fatty acid amidohydrolase, or FAAH, in the platelets of migraine sufferers. These enzymes are responsible for breaking down anandamide and clearing it from the system, so high levels of this could mean less anandamide is active in migraine sufferers' systems — leading to decreased pain thresholds. 

In addition, scientists have found genetic links between migraine and the ECS, such as a genetic effect altering trigeminovascular activation in migraine sufferers, and another tying migraine to photophobia, nausea, and disability. 


Fibromyalgia is a condition characterized by pain throughout the body, which is aggravated by exertion. Associated with painful 'trigger points' (which produce intense pain), depression, anxiety, and sleep disorders, researchers haven't been able to pinpoint physical signs to diagnose this mysterious but common condition. As a matter of fact, there is no specific test to diagnose this condition. Still many believe that sensitization of the central nervous system could be at the root of the condition. 

Russo points to a few different pieces of evidence that fibromyalgia is related to CED. For one, like the other potential CED conditions, it is associated with increased sensitivity to pain. This sensitivity has been observed in cases with decreased endocannabinoid function in the spinal cord — and it's been noted that endocannabinoids actually reduce pain sensitivity. So, reduced endocannabinoid functioning is a good guess as to why fibromyalgia patients experience this heightened sense of pain. 

The cannabinoids in cannabis are also known to reduce pain sensitivity and are often used by fibromyalgia patients to treat their condition. Studies on fibromyalgia patients using cannabis found that those who were able to tolerate THC's secondary side effects had significant reductions in pain and stiffness, enhanced relaxation and sleep, and increased feelings of well-being. Still, more rigorous controlled studies need to be conducted to validate these results. 

Additionally, since Russo's review, one study looked at endocannabinoid levels in fibromyalgia patients and found elevated levels of certain endocannabinoids. The authors of this study report that the elevated levels indicate some sort of metabolic asymmetry is going on. This adds further support for the theory that fibromyalgia may be due to an imbalance in the endocannabinoid system. 

Other conditions that may be related to CED

In addition to fibromyalgia, IBS, and migraine headaches, there are other conditions that Russo suggests may be related to CED. CED has been implicated in conditions such as motion sickness, multiple sclerosis (MS), diabetic neuropathy, Huntington's disease, Parkinson's disease, schizophrenia, anorexia, anxiety, autism, neonatal failure to thrive, cystic fibrosis, causalgia, brachial plexopathy, phantom limb pain, infantile colic, glaucoma, dysmenorrhea, hyperemesis gravidarum, repetitive miscarriages, post-traumatic stress disorder (PTSD), bipolar disease, and more. 

For example, nausea from motion sickness is correlated with reductions in anandamide. Impaired ECS functioning has been linked to MS, Huntington's disease, anxiety, PTSD, and major depression. Higher levels of anandamide were found in patients with Parkinson's disease and schizophrenia. 

In addition, the ECS is responsible for fear extinction mechanisms that allow people to recover from traumatic experiences. In patients with PTSD, it's hypothesized that their lower levels of anandamide might impede this process. 

In autism, genes associated with the disorder also regulate ECS function. In addition, new research suggests that children with autism have lower levels of endocannabinoids circulating through their system. 

In all of these conditions, while the causes are somewhat mysterious, we can see that there are clear disruptions in endocannabinoid functioning. 

Treating clinical endocannabinoid deficiency

If you believe you have CED, it's best to talk to a doctor who specializes in cannabinoid medicine. Testing for CED is pretty rare, but you can ask your doctor about it to see if they can offer you this test. While testing for endocannabinoid levels used to be fairly invasive, there are tests now that measure endocannabinoid levels in saliva. Your doctor may be able to help you take this test or recommend a specialist who can. More commonly, your doctor will work with you to find the best option based on your conditions and symptoms. Either way, it's helpful to have some expert advice. 

medical cannabis
Cannabinoids like THC and CBD (particularly whole-plant cannabis extracts) may be helpful for some cases as a way to stimulate the endocannabinoid system.
Photo by: Gina Coleman/Weedmaps

Russo suggests that cannabinoids like THC and CBD (particularly whole-plant cannabis extracts) may be helpful for some cases as a way to stimulate the endocannabinoid system. While CED may be harmful, an excess of cannabinoids can also cause problems, so a doctor can help you to decide whether cannabis is the right treatment for you — and if it is, what cannabis options to try.

Lifestyle changes like diet and exercise can also improve endocannabinoid function. In particular, low-impact aerobic exercise regimens have shown promise for stimulating endocannabinoid function. According to Russo, including more supplements like probiotics and prebiotics may help not only IBS but the whole spectrum of CED conditions.  

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The information contained in this site is provided for informational purposes only, and should not be construed as medical or legal advice. This page was last updated on June 22, 2021.