The Endocannabinoid Theory: Applications for Cannabinoid Therapy

The endocannabinoid theory of disease began with the discovery of the endocannabinoid system. Unlike the central nervous system, the respiratory system, and other essential systems which have been investigated for centuries, researchers only stumbled onto the existence of the endocannabinoid system less than 30 years ago.


As one of the newest physiological revelations, it\’s also the least understood. But a growing chorus of voices has hypothesized how clinical endocannabinoid deficiency could help understand chronic subjective pain syndromes such as irritable bowel syndrome, fibromyalgia, and migraine.


What do these conditions have in common? Many of these conditions are difficult to diagnose and even more difficult to treat, yet they often respond well to medical cannabis therapy. It\’s not uncommon to read reports of patients who have exhausted all other pharmaceutical and therapeutic solutions, who eventually settle on cannabis. These patients detail how cannabinoids help alleviate the physical and mental symptoms when nothing else has worked.


Cannabis\’ ability to relieve the symptoms of treatment-resistant conditions like those mentioned above is perhaps why patients tout it as the next miracle \”cure-all\” capable of treating any and all diseases. More likely, it\’s not so much a miracle but rather evidence of the existence of clinical endocannabinoid deficiency.


The Recent Discovery of the Endocannabinoid System


Cannabis earned the attention of modern medicine at the turn of the 20th century. Over the proceeding century, researchers carefully identified and synthesized the primary compounds, called cannabinoids. At last count, the literature identifies more than 150 cannabinoids, with more uncovered every year.


Studies began hinting at the existence of a cannabinoid receptor by the 1970s. But it wasn\’t until more than a decade later that Allyn Howlett and his laboratory demonstrated proof of these mysterious receptors. In 1990, researchers successfully cloned (and therefore confirmed) the existence of the CB1 receptor. By 1993 came the discovery of the CB2 receptor. Within only a few years, researchers added two endogenous cannabinoids (internally produced, as opposed to \’phyto\’ or plant-produced cannabinoids) into the equation.


Thus, by the mid-1990s, researchers had uncovered the structure of the endocannabinoid system —a network of receptors and endogenous chemical messengers spread throughout the body. Since then, scientists have pieced together enough information to grasp how this system manages mood, memory, pain, inflammation, reproduction, and much more.


In Detail: The Components of the Endocannabinoid System


Remarkably, researchers only stumbled onto this system because of investigations into cannabis and cannabinoids. But, how do the CB1 and CB2 receptors and chemical messengers work together to promote balanced physiological function?


As per a summary by Bradley E. Alger, Ph.D., published in Cerebrum, \”CB1 is densely located in the neocortex, hippocampus, basal ganglia, amygdala, striatum, cerebellum, and hypothalamus. These major brain regions mediate a wide variety of high-order behavioral functions, including learning and memory, executive function decision making, sensory and motor responsiveness, and emotional reactions, as well as feeding and other homeostatic processes.\”


The CB2 receptors are mainly outside the central nervous system, concentrated on immune cells. Although not as clearly understood as CB1 receptors, the \”likely roles of these [CB2] receptors, including modulation of cytokine release and of immune cell migration,\” and occur mainly in the immune cells.


The two main endocannabinoids are anandamide, which regulates brain reward circuitry, and 2-arachidonoyl glycerol (2AG), a CB1 agonist with neuromodulatory effects. Anandamide and 2AG may be the primary endocannabinoids, but we now know about other less direct neurotransmitters, which work within the endocannabinoid system as well.


Phytocannabinoids, just like endocannabinoids, can be full or partial receptor agonists and receptor antagonists, engaged in a well-choreographed dance to maintain homeostasis. As the study of cannabinoid therapy has unfolded, it has become clear how these compounds can help regulate an imbalanced endocannabinoid system.


The Endocannabinoid Deficiency of Disease, a New Theory

Endocannabinoids, such as anandamide and 2-AG, are responsible for regulating mood, memory, pain, appetite, and many other critical functions. However, what happens when the endocannabinoid system is in a state of dysfunction, throwing it off rather than returning it into balance?


Ethan B. Russo, a leading cannabis researcher, first hypothesized about clinical endocannabinoid deficiency in 2008 and revisited it in 2016. The clinical endocannabinoid theory of disease holds that \”numerous common subjective pain syndromes that lack objective signs and remain treatment resistant\” are caused by a deficiency in cannabinoid production and abundance. Importantly, Russo notes, these very same conditions are also responsive to cannabinoid treatment.


As Russo summarizes, the endocannabinoid deficiency theory developed after researchers identified several neurological conditions that come from a deficiency in neurotransmitters. A few examples include acetylcholine (Alzheimer\’s disease), dopamine (Parkinson\’s\’ disease), and serotonin and norepinephrine (depression). The endocannabinoid theory postulates that an endocannabinoid deficiency could trigger conditions related to endocannabinoid function like pain, fatigue, mood disorders, and more.


Both Russo\’s 2008 and 2016 papers highlight irritable bowel syndrome, fibromyalgia, and migraines as chronic, psychosomatic conditions, with evidence of differences in endocannabinoid tone. According to Russo, these conditions have the most clinical backing.


As a telling example, scientific analysis has demonstrated a genetic polymorphism of the CB1 receptor among patients with IBS. Not only does the polymorphism affect endocannabinoid tone, it also creates more severe cases. The authors of \”Irritable bowel syndrome: a dysfunction of the endocannabinoid system?\” confirm that \”the endocannabinoid system, including their receptors and metabolic pathways, may be involved in the pathophysiology of IBS and it is now multifold evidence from genetic studies, clinical trials, and basic science that supports this notion.\”


Beyond these three conditions, could endocannabinoid deficiency cause other common psychosomatic conditions? Preliminary research suggests that motion sickness, multiple sclerosis, Huntington\’s disease, Parkinson\’s disease, and post-traumatic stress disorder may also be attributed to endocannabinoid malfunction.


The Potential of Cannabinoid Therapy for Clinical Endocannabinoid Deficiency


Interestingly, all of these conditions have several common overlapping symptoms, like depression, pain, and fatigue. In Russo\’s analysis of IBS, migraine, and fibromyalgia, many patients qualify for several comorbidities. Under the modern pharmacological approach, treatment plans include single active ingredients targeting a single symptom. But cannabinoids seem to provide a more holistic treatment option.


Russo\’s 2016 review states that patients with these challenging conditions often turn to cannabis as a last resort. When it comes to IBS, conventional treatment includes anticholinergics, opioids, and antidepressants, but their effectiveness is \”suboptimal.\” Although there has thus far been only limited clinical study of cannabinoids for inflammatory bowel conditions, consistently surveys find patients are already relying on it. Patients report pain relief, diarrhea relief, and improvements to appetite.

Small studies of cannabis for migraines have demonstrated marvellous results. As Russo details, one study in 2016 reported 85.1 percent of participants had decreased migraine frequency, 39.7 percent felt positive effects, and 19.8 percent said it prevented the onset.

Finally, fibromyalgia patients have long reported benefits from the use of cannabis. As an example, a study of 28 patients with fibromyalgia showed a statistically significant reduction in pain and stiffness two hours after cannabis consumption. They also reported an \”enhancement of relaxation, and an increase in somnolence and feeling of well being,\” on top of other mental health effects.


Cannabis: The Key to the Endocannabinoid System


Medical cannabis advocates often describe it as a miracle because it seems capable (at least according to patients) of treating a wide variety of conditions. How can one plant treat so many people with such powerful reported results?


Cannabis isn\’t a cure-all, but its effectiveness for many seemingly unrelated conditions is telling. According to Russo and others, effective cannabinoid treatment could instead highlight a clinical endocannabinoid deficiency, connecting all these conditions together. Not only did cannabis help lead to the discovery of the endocannabinoid system, but it may also now hold the key to unlocking the treatment of common painful conditions, from migraines to IBS to fibromyalgia and more.

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