The ECS helps keep your body in balance, so it only makes sense for everything to get thrown off when the ECS isn’t doing what it’s supposed to do.

Clinical endocannabinoid deficiency (CED) is only a theory so far, and it’s based on the idea that maybe low levels of endocannabinoids manifest in certain disorders, similar to how neurotransmitter deficiencies are associated with many brain disorders.

Let’s look at what the studies show so far, the diseases implicated in endocannabinoid deficiencies, and how this affects medicine.

What is Clinical Endocannabinoid Deficiency (CED)?

To understand CED, you have to know the basics behind the endocannabinoid system (ECS).

The ECS regulates the following systems:

• Sleep and circadian rhythm
• Mood and stress
• Nervous system
• Immune system
• Reproductive system and fertility
• Digestive System and appetite
• Hormones
• Arterial and respiratory system
• Skin health
• Pain
• Appetite
• Inflammation, including neuroinflammation
• Motor control
• Temperature regulation
• Memory
• Pleasure/reward

Crucial? You bet.

Endocannabinoids anandamide (AEA, or the bliss molecule) and 2-arachidonoylglycerol (2-AG) act on the cannabinoid receptors CB1 and CB2, which then send signals to specific parts of the body, telling them to take an action of some sort. Certain enzymes break down the endocannabinoids.

The theory is that a shortage of these endocannabinoids causes problems, as one would suspect. It doesn’t take a scientist to figure that out. These deficiencies could be caused by genetic or congenital defects, injury, or other diseases.

The problem is narrowing down what specific issues come up and what to do about them. Because the ECS does so much, it’s hard — almost impossible — to tweak one area without affecting the others.

Researchers have found many diseases that are possibly linked through an endocannabinoid deficiency, but migraines, irritable bowel syndrome (IBS), and fibromyalgia are the greatest evidence that it exists so far. These three, until now, appeared to have no cause and are, therefore, hard to diagnose. In fact, they tend to be written off as psychosomatic (“all in your head”). Medications and other treatments are hit-and-miss, usually resulting in a lifetime of care that really doesn’t do much.

We’ll look at the health problems that might be caused by low endocannabinoid levels, or possible symptoms, so to speak, of CED.

CED & Disease

If CED proves to be the underlying cause in even some of these issues, the door for new treatments will fly open. As we mentioned, it’s a matter of finding ways to fix one problem without causing more problems somewhere else. Still, researchers are finding ways to do this, which we’ll also discuss.

CED & Migraines, IBS, & Fibromyalgia

Migraines, IBS, and fibromyalgia might tend to go underdiagnosed and untreated, but why link them together beyond that? What do these three have in common that sets them apart?

They all share the following pathophysiological trends: (abnormal physical changes that happen because of a disease):

• Lack of characteristic tissue pathology or laboratory findings

• Diagnoses based on exclusion, after ruling out everything else

• Anxiety and depression are common

• Often labeled psychosomatic

• Comorbidity among the three diseases is high

• Patients with one are at high risk of developing one or both of the others

CED & Melancholic Depression

This type can be more severe than general depression, though the symptoms are similar.

People with melancholic depression tend to move and speak slower, show little emotion, lose weight, sleep poorly but have increased wakefulness, feel extra sensitive to stress, and have trouble concentrating and remembering things. This usually accompanies strong feelings of guilt and thoughts of suicide.

Blocking the CB1 receptor causes a phenotypic state similar to melancholic depression — specifically, decreased appetite, increased anxiety and stress, wakefulness, and arousal — suggesting the ECS could play a role in the cause of it. There’s a possible further connection since some antidepressants increase endocannabinoid activity while chronic stress down-regulates it.

CED & Stress

More and more research is showing just how crucial of a role the ECS plays in regulating stress by acting as a buffer to its effects. Changes in the system seem to affect aspects of the stress response.

In 2014, a study compared mice exposed to chronic stress with CB1 knock-out mice (the CB1 receptor was inactivated).

The mice under stress developed symptoms of depression, and the knock-out (KO) mice exhibited the same symptoms with or without added stress. KO mice had decreased 5-HTT levels under non-stressful situations, similar to the mice under stress. This study reveals a link between stress, depression, and the ECS.

CED & PTSD

In many studies, PTSD sufferers show reduced AEA and increased CB1 availability. There also seems to be a link between increased CB1 receptor availability in the amygdala, abnormal threat processing, and increased hyperarousal.

In fact, it’s almost a given that endocannabinoid levels in PTSD patients will be off. Previous attempts to study cannabinoid levels in blood samples of those with PTSD and those without it have been inconsistent. However, hair samples are proving to be a reliable way to assess these differences, and researchers are finding a significant difference in levels. Because of this, the ECS could be a target for treating PTSD.

CED & Huntington’s Disease

Reduced CB1 availability seems to be widespread in Huntington’s disease, which seems to repress its transcription. Huntington’s also causes a decrease in GABA, which might be linked to the ECS since it usually helps modulate GABA.

Other Possible Problems From CED

While finding new treatments for any or all of the above would be fantastic, there are other areas the CED might impact. The following all remain treatment-resistant and show unexplained symptoms.

• Cystic fibrosis
• Causalgia
• Phantom limb pain
• Brachial plexopathy
• Neonatal failure to thrive
• Infantile colic
• Glaucoma
• Dysmenorrhea
• Hyperemesis gravidarum
• Bipolar disease
• Repetitive miscarriage

Is There a Solution to CED?

While finding the right balance could be difficult, research shows that it might not take much of a bump to get the ECS working right. Instead of a complete overhaul, a small nudge could provide amazing results.

There are, potentially, a number of ways to increase endocannabinoid levels — specifically AEA — though more research is needed before we come to any conclusions.

• MGL and FAAH-inhibitors

• CB1 or CB2 agonists or partial agonists

• Inhibiting endocannabinoid transport

• Modulating ECS function through allosteric sites

• Glucocorticoid hormones

• Lifestyle changes, such as low-impact aerobic exercise and diet

FAAH (fatty acid amide hydrolase) is an enzyme that breaks down AEA, and MGL (monoacylglycerol lipase) breaks down 2-AG. Slow down this process, and you have more available endocannabinoids.

Phytocannabinoid Wannabes

Cannabinoids aren’t quite exclusive to cannabis, though it sure seems so. It’s certainly the best place to find them. Most plants don’t contain arachidonic acid, an essential ingredient in binding to receptors. However, some plant compounds like to pretend they’re cannabinoids. Here are some examples of plant ‘ingredients’ that exhibit cannabinoid-like behavior.

1. N-alkylamides (Alkamides)

Echinacea contains certain alkamides that can interact with CB2 receptors, slow down AEA reuptake, and show similar effects as AEA.

2. Falcarinol

The common plant Daucus carota (carrots) contains falcarinol, which binds to both receptors. This goes through an alkylation reaction with CB1, resulting in a strong inverse agonistic effect.

3. Salvinorin A

The research goes back and forth on salvinorin A, the main active molecule in Salvia divinorum, a dissociative hallucinogenic plant. In some studies, it did not show binding to CB1 activity, but whole leaves from the plant did. Other studies showed it interacted with CB1 and k-opioid receptor dimers, suggesting a possible connection between the two.

4. Yangonin

Yangonin is a major component of kavalactone, the active compound in Piper methysticum, or kava. We’ve known it has GABAB receptor activity, but current research shows it binds to CB1 receptors — it’s unclear whether the activity is antagonistic or agonistic.

5. Beta-Caryophyllene

Beta-caryophyllene is a terpene common in cannabis, but it’s plenty abundant elsewhere, too — hops, black pepper, and cloves, to name a few. It’s possibly the only terpene that interacts with CB receptors. In this case, it’s a full agonist of CB2.

References Used

1. Russo, E. B. (2016). Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis and cannabinoid research, 1(1), 154-165 [1].
2. Hill, M. N., & Gorzalka, B. B. (2005). Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behavioural pharmacology, 16(5-6), 333-352.
3. Morena, M., Patel, S., Bains, J. S., & Hill, M. N. (2016). Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology, 41(1), 80-102 [3].
4. Burokas, A., Martín‐García, E., Gutiérrez‐Cuesta, J., Rojas, S., Herance, J. R., Gispert, J. D., … & Maldonado, R. (2014). Relationships between serotonergic and cannabinoid system in depressive‐like behavior: a PET study with [11C]‐DASB. Journal of Neurochemistry, 130(1), 126-135 [4].
5. Neumeister, A., Seidel, J., Ragen, B. J., & Pietrzak, R. H. (2015). Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder. Psychoneuroendocrinology, 51, 577-584.
6. Wilker, S., Pfeiffer, A., Elbert, T., Ovuga, E., Karabatsiakis, A., Krumbholz, A., … & Kolassa, I. T. (2016). Endocannabinoid concentrations in hair are associated with PTSD symptom severity. Psychoneuroendocrinology, 67, 198-206 [6].
7. Van Laere, K., Casteels, C., Dhollander, I., Goffin, K., Grachev, I., Bormans, G., & Vandenberghe, W. (2010). Widespread decrease of type 1 cannabinoid receptor availability in Huntington disease in vivo. Journal of Nuclear Medicine, 51(9), 1413-1417.
8. Allen, K. L., Waldvogel, H. J., Glass, M., & Faull, R. L. M. (2009). Cannabinoid (CB1), GABAA and GABAB receptor subunit changes in the globus pallidus in Huntington’s disease. Journal of chemical neuroanatomy, 37(4), 266-281 [8].
9. Hill, M. N., Campolongo, P., Yehuda, R., & Patel, S. (2018). Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder. Neuropsychopharmacology, 43(1), 80-102.
10. Vemuri, V. K., & Makriyannis, A. (2015). Medicinal chemistry of cannabinoids. Clinical Pharmacology & Therapeutics, 97(6), 553-558.
11. Russo, E. B. (2016). Beyond cannabis: Plants and the endocannabinoid system. Trends in pharmacological sciences, 37(7), 594-605.
12. Capasso, R., Borrelli, F., Cascio, M. G., Aviello, G., Huben, K., Zjawiony, J. K., … & Izzo, A. A. (2008). Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis‐induced hypermotility: cross‐talk between κ‐opioid and cannabinoid CB1 receptors. British journal of pharmacology, 155(5), 681-689.