Is there evidence of an endocannabinoid deficiency?

Various faults can occur in the endocannabinoid system, each causing a unique set of symptoms. Evidence of endocannabinoid deficiency is often lacking, but poor ECS function is good science to cause special conditions. And the deficit is based on causation and not just correlation.

Raphael Mechoulam discovered anandamide in 1992 and 2-AG a few years later. (1, 2) After the discovery of endocannabinoids, scientists began to study their role in health and disease. Finally, endocannabinoids are crucial in almost all human diseases. (3) In 2001, evidence of ECS deficiency was vague and based primarily on correlation. (4) A twenty-year leap and quantifiable results in peer-reviewed journals now provide good evidence for clinical endocannabinoid deficiency.

Find evidence of endocannabinoid deficiency

• 2001 – Ethan Russo, MD first establishes the role of clinical endocannabinoid deficiency (cECD) in headache. (4)
• 2003 – An Italian study analyzed endocannabinoid levels in blood samples from women with migraines. (5)
• 2004 and 2008 – Russo nails his theory on endocannabinoid deficiency. (6)
• 2007-2008 – Additional Italian studies documented endocannabinoid levels in migraineurs. (7, 8) One study collected CSF from the spines of three dozen participants, including twenty controls. (9)
• 2009 – Daniele Piomelli led a study on endocannabinoid levels in the spinal fluid of psychosis patients. The team discovered an inverse correlation between anandamide and psychosis. (10)
• 2009 – Researchers at the University of Manchester have elucidated genetic defects in CB1 receptors that can cause migraines. (11)
• 2012 – Chronic use of painkillers caused deficiencies in the endocannabididiome, which were detected in blood samples (platelets). (8, 12)
• 2013 – Researchers discovered a gene responsible for CB1 expression in irritable bowel syndrome, providing some evidence of endocannabinoid deficiency in the condition. (13)

The old theory reconsidered

• 2016 – Russo revises his hypothesis on cECD. (14)
• 2019 – Endocannabinoid levels analyzed by blood (serum) samples were deficient in children with autism spectrum disorder. (fifteen)
• 2020-2022 – Multiple studies identify endocannabididiome deficiency after Covid-19 infection.
• 2022 – The Max Plank Institute has teamed up with Harvard Medical School and discovered another root cause of poor 2-AG function. (16)
• 2022 – Endocannabinoid levels were not disturbed at rest in veterans with PTSD, bearing in mind that endocannabinoids often act on demand during stress. (17)

Testing of endocannabinoids in human tissue

• blood samples (Platelets, plasma, or serum) – Slightly invasive to patients and a quick collection method, but not a long-term repository for endocannabinoids. Good for testing on-demand features.
• cerebrospinal fluid — powerful results for researchers and a long-term repository of endocannabinoids, but collection is highly invasive for patients.
• PET (positron emission tomography) picture test — Boston Children’s Hospital developed an imaging test to detect MAG-1, which chews 2-AG, in brown tissue. The image test requires a radioactive ligand and has only been tested in mice for MAG-1. But the study provides early evidence that endocannabinoid deficiency plays a role in mammalian metabolic disorders. (18)

Diet and routine prior to supplementation

Is Cannabis Really Essential? Perhaps phytocannabinoids are required for proper health. But an endocannabinoid system can function properly without cannabis. However, fats are vital in our diet. And endocannabinoids are made from phospholipids, or omega-3 fatty acids, found in food.

Genetics or inflammation after physical injury can quickly deplete the endocannabinoid system. In these circumstances, supplementing the ECS with certain cannabis strains may provide benefits. Remember, THC isn’t always the answer. Either way, proper diet and routine will help prevent endocannabinoid deficiencies caused by poor life choices.

Let us know what you think about possible ECS deficiencies. Do you think there is enough evidence to diagnose patients with cECD?

Sources

1. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain component that binds to the cannabinoid receptor. Science. 1992;258(5090):1946-1949. doi:10.1126/science.1470919
2. Mechoulam, R., Ben-Shabat, S., Hanus, L., et al. Identification of an endogenous 2-monoglyceride present in the canine gut that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83-90. doi:10.1016/0006-2952(95)00109-d
3. de Melo Reis RA, Isaac AR, Freitas HR, et al. Quality of life and a monitoring endocannabinoid system. Front neurosci. 2021;15:747229. Published October 28, 2021. doi:10.3389/fnins.2021.747229
4. Russo EB. Hemp for headaches: an in-depth historical and scientific review of cannabis in migraine treatment. J. Cannabis Ther. 2001;1:21-921. 1b.) Russo EB. Handbook of psychotropic herbs: a scientific analysis of herbal remedies for psychiatric disorders. Haworth Press: Binghamton, NY, 2001
5. Cupini LM, Bari M, Battista N, Argiro G, Agro AF, Calabresi P and Maccarrone, MI (2003) Abnormal breakdown of endocannabinoids in women with migraine. Cephalalgia 23: 684-685.
6. Russo EB. Clinical endocannabinoid deficiency (CECD): Can this concept explain the therapeutic utility of cannabis in migraine, fibromyalgia, irritable bowel syndrome, and other treatment-resistant disorders? Neuroendocrinol Lett. 2004;25:31-39
7. Cupini LM, Costa C, Sarchielli P, et al. Depletion of endocannabinoids in chronic migraine headaches and drug overuse headaches. Neurobiol Dis. 2008;30(2):186-189. doi:10.1016/j.nbd.2008.01.003
8. Rossi C, Pini LA, Cupini ML, et al. Endocannabinoids in platelets of patients with chronic migraine and patients with drug-overuse headache: relationship to serotonin levels. Eur J Clin Pharmacol. 2008;64:1-8
9. Sarchielli P, Pini LA, Coppola F, et al. Endocannabinoids in chronic migraine: CSF findings suggest systemic failure [published correction appears in Neuropsychopharmacology. 2007 Jun;32(6):1432]. Neuropsychopharmacology. 2007;32(6):1384-1390. doi:10.1038/sj.npp.1301246
10. Köthe D, Giuffrida A, Schreiber D, et al. Anandamide elevation in cerebrospinal fluid in early prodromal stages of psychosis [published correction appears in Br J Psychiatry. 2011 Jun; 198(6):495]. Br J Psychiatry. 2009;194(4):371-372. doi:10.1192/bjp.bp.108.053843
11. Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor 1 gene predispose to migraine. Neurosci Lett. 2009;461:116-120
12. Perrotta A, Arce-Leal N, Tassorelli C, et al. Acute reduction in anandamide hydrolase (FAAH) activity is coupled with a reduction in nociceptive pathways, facilitating relief in medication-overuse headache patients after withdrawal treatment. Headache. 2012;52:1350-1361
13. Camilleri M, Kolar GJ, Vazquez-Roque MI, et al. Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative characteristics. Am J Physiol Gastrointest Liver Physiol. 2013;304:G553-G560
14. Russo EB. Clinical endocannabinoid deficiency reconsidered: Current research supports the theory in migraine, fibromyalgia, irritable bowel and other treatment-resistant syndromes. Cannabis Cannabinoid Res. 2016;1(1):154-165. Published July 1, 2016. doi:10.1089/can.2016.0009
15. Aran, A., Eylon, M., Harel, M. et al. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism 10, 2 (2019). https://doi.org/10.1186/s13229-019-0256-6
16. Davies AK, Alecu JE, Ziegler M et al. AP-4-mediated axonal transport controls endocannabinoid production in neurons. Nat Commun 13, 1058 (2022).
17. Leen NA, de Weijer AD, van Rooij SJH, Kennis M, Baas JMP, Geuze E. The role of the endocannabinoids 2-AG and anandamide in clinical symptoms and treatment outcomes in veterans with PTSD. Chronic Stress (Thousand Oaks). 2022;6:24705470221107290. Published June 9, 2022. doi:10.1177/24705470221107290
18. Cheng R, Fujinaga M, Yang J, et al. A novel monoacylglycerol lipase-targeted 18F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network [published online ahead of print, 2022 May 5]. Acta Pharmacol Sin. 2022;10.1038/s41401-022-00912-8. doi: 10.1038/s41401-022-00912-8

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