Clinical endocannabinoid deficiency (CECD) is a proposed spectrum disorder that has been implicated in a range of illnesses, including fibromyalgia, migraine and irritable bowel syndrome. So far, very little research has been conducted on this speculative disorder, but if it is found to exist, it could be responsible for these very common conditions as well as many related ones.
Clinical endocannabinoid deficiency (CECD) was a term coined only recently, in 2004, by Dr Ethan Russo. Until the field of research expands, this condition remains mostly a theory, but with very solid grounding. Essentially, Ethan Russo bases his theory on the idea that there are many brain disorders which arise out of a neurotransmitter deficiency, and that many other conditions may arise similarly out of a deficiency in endocannabinoids.
As it stands, Russo shows that there is some evidence suggesting that endocannabinoid deficiency is linked with migraines, fibromyalgia and irritable bowel syndrome. In this article, we explore the complex associations between endocannabinoid deficiency and some of these common pathologies. Overall, it is a complex notion that underlying many of these pathologies is possibly endocannabinoid deficiency as a cause, and there is still much research to be done in the area.
Migraine, serotonin and the blood plasma platelets
Migraines are one of the three conditions that feature common clinical and biochemical patterns that may point to underlying CECD. Migraines are thought to be influenced by endocannabinoid function, as areas suspected to be involved with generation of migraines are also affected by cannabinoid activity. Furthermore, the endocannabinoid, anandamide, with its role in pain modulation and serotonin transmission, is believed to positively affect sufferers of the condition.
The biochemistry of migraine is highly complex and poorly understood, but it is known that high levels of serotonin are present during attacks. THC and its endogenous ligand, anandamide, have been shown to inhibit serotonin in high doses (although low doses may increase its production), particularly in the platelets of the blood plasma. The platelets contain the body’s highest reserves of serotonin, which are also present in the enteric nervous system as well as throughout the brain. Serotonin release from the platelets is thought to be crucial to generation of migraines, and migraine is often thought to be a disease of the blood on this basis.
The effect of THC on the release of serotonin and the consequent relief from migraine are what ultimately point towards the possibility of underlying endocannabinoid deficiency. According to the research presented, anandamide deficiency may lead to increased release of serotonin, finally resulting in a migraine. With sufficient anandamide circulating through the blood and brain, serotonin release may be inhibited, therefore alleviating symptoms of migraine.
Fibromyalgia and serotonin deficiency
Fibromyalgia, a pain disorder which is widely considered to be neuropsychiatric in nature, and which modern medicine has very few treatment options. According to a 2014 survey by the National Pain Report, over 30% of fibromyalgia sufferers use medical cannabis as treatment, whether self-medicated or by prescription. Of those who reported having used medicinal cannabis, 62% reported significant improvement after treatment. This kind of self-report does not prove that cannabis is an effective treatment for Fibromyalgia, but indicates the need for randomized controlled trials testing this hypothesis.
In another study which documented the effect of nabilone on fibromyalgia sufferers, subjects experienced significant improvement of symptoms when administered the cannabinoid. Another study demonstrated that quality of life was markedly improved in fibromyalgia sufferers that self-administered oral or smoked cannabis.
The most recent study conducted on this matter took place in 2018. Twenty-six patients were studied and treated with medical cannabis over 10-12 months. Researchers reported a significant improvement in every aspect of their survey for patients, finding that even 50% of those studied stopped taking any other medications for their fibromyalgia symptoms.
Serotonin levels in the platelets are also known to be affected in fibromyalgia, although it is thought that deficiency of serotonin, rather than over-abundance, is responsible for the sufferer’s aberrant perception of pain. This disparity is not fully understood, and is somewhat surprising given the high degree of comorbidity between the diseases,
In one study, up to 63% of primary fibromyalgia sufferers also reported symptoms of migraine, in another, 22.2% of primary migraine sufferers were also found to have fibromyalgia. This disparity may be partly explained by gender differences, as none of the male migraine sufferers reported symptoms of fibromyalgia, and the latter disease is overwhelmingly experienced by women, who comprise 90% of sufferers.
IBS and the link between the brain and gut
Irritable bowel syndrome (IBS) is a common gastroenteric condition that presents as bloating, abdominal cramps and diarrhoea. It has long been suspected that there is a link between IBS and neuropsychiatric dysfunction, as the condition is often comorbid with psychiatric conditions such as anxiety, depression and PTSD. Acute symptoms often arise in times of mental distress. However, as endocannabinoids are expressed in the enteric nervous system (ENS), as well as the areas of the brain affected by such psychiatric disorders, their effect may be independent.
Serotonin also plays a part in IBS, partially influencing gut motility (the peristaltic actions of the colon, which become “spastic” or uncontrolled during bouts of IBS), sensitivity and secretion of fluid. Interestingly, IBS-D (characterised by diarrhoea) sufferers have been shown to have increased blood serotonin levels, while sufferers of IBS-C (characterised by constipation) experience reduced levels of serotonin.
The effect of serotonin in IBS sufferers suggests a correlation with endocannabinoid deficiency, given that ingestion of cannabinoids affects blood levels of serotonin. With that being said, it is particularly difficult to pinpoint, as in certain cases serotonin levels deficient and in others serotonin levels are excessive.
Cannabinoid receptors in the enteric nervous system
It has been demonstrated that activation of the cannabinoid receptors in the enteric nervous system decreases hypersensitivity of the gut, as well as reducing gut motility and inflammation. Many sufferers of IBS use cannabis to alleviate their symptoms, although some report that symptoms worsened subsequent to commencing use; some even postulate cannabis as a trigger for IBS in certain individuals.
The overlap between instances of these conditions has led to the hypothesis that they are all expressions of the same underlying somatic disorder. Many sufferers of IBS also report symptoms of migraine, and up to 70% of fibromyalgia sufferers also present IBS symptoms. Many have all three, but it is not strictly necessary for all three to be present for an underlying condition such as CECD to be the cause, as many spectrum disorders manifest markedly different symptoms from patient to patient, and other related conditions may be involved.
Is an underlying condition responsible?
The idea that a dysfunctional endocannabinoid system is responsible for this postulated somatic disorder first arose within the last few years. In 2004, when the condition CECD was first proposed, researchers suggested that the high degree of comorbidity, along with the common feature of unusual cannabinoid receptor activity, pointed to an underlying disorder of the endocannabinoid system.
Many known conditions can be attributed to dysfunction of a specific neurotransmitter system: Alzheimer’s is caused by deficiency of the acetylcholine neurotransmitter, and Parkinson’s by age-related dopamine deficiency. It is therefore plausible to assume that deficiency of the cannabinoid neurotransmitters would also cause a specific disorder, or set of related disorders.
The relationship with the serotonin signalling system cannot be ignored when researching the possibility of CECD’s existence. Behavioural studies suggest that the effects of endocannabinoid signalling are mediated by regulation of the serotonin system. For example, THC has been shown to inhibit serotonin release from the platelets in migraine sufferers, as well as increasing synthesis of serotonin in the brain. 2-AG and cannabidiol have demonstrated similar effects. However, the independent effects of cannabinoids on the cannabinoid receptors are thought to be the underlying cause of CECD, despite this possibly fundamental relationship with serotonin signalling.
If the existence of CECD is proven, targeted therapies can be investigated, which would pinpoint the precise nature of the deficiency and determine the appropriate ration and dosage of supplemental exogenous cannabinoids. At present, treatment of these conditions is usually through ingestion of crude cannabis extract, or through smoking, which may involve wildly different cannabinoid ratios between cannabis strains. Due to the dose-dependent effect of many cannabinoids, relief of symptoms may not be adequate with some varieties.
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