Is there proof of an endocannabinoid deficiency?

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Various errors can occur in the endocannabinoid system, each causing a unique set of symptoms. Proof for any endocannabinoid deficiency is often lacking, but poor ECS function causes particular conditions according to good science. And the deficit is based on causation and not simply correlation.

Raphael Mechoulam discovered anandamide in 1992 and 2-AG a few years afterwards. (1, 2) Following the discovery of endocannabinoids, scientists began studying their role in health and disease. Conclusively, endocannabinoids are critical in almost all human illnesses. (3) In 2001, proof of an ECS deficiency was vague and primarily based on correlation. (4) Skipping ahead twenty years and quantifiable results in peer-reviewed journals now provide good evidence of Clinical Endocannabinoid Deficiency.

Finding proof of an endocannabinoid deficiency

  • 2001 — Ethan Russo, M.D. first hypothesizes the role of Clinical Endocannabinoid deficiency (cECD) in headaches. (4)
  • 2003 — An Italian study analyzed endocannabinoid levels in blood samples of women with migraine. (5)
  • 2004 and 2008 — Russo flushes out his theory on endocannabinoid deficiency. (6)
  • 2007-2008 — Further Italian studies documented endocannabinoid levels in migraine patients. (7, 8) One study collected cerebrospinal fluid from the spines of three dozen participants, including the twenty control subjects. (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 from Manchester University elucidated genetic deficiencies in CB1 receptors that can cause migraine. (11)
  • 2012 — Chronic consumption of pain medication caused deficiencies in the endocannabidiome detected in blood (platelet) samples. (8, 12)
  • 2013 — Researchers discovered a gene responsible for CB1 expression in Irritable Bowel Syndrome, providing some proof of an endocannabinoid deficiency in the condition. (13)

The old theory reconsidered

  • 2016 — Russo revisits his hypothesis on cECD. (14)
  • 2019 — Endocannabinoid levels, analyzed by blood (serum) samples, were deficient in children with Autism Spectrum Disorder. (15)
  • 2020-2022 — Several studies note a deficient endocannabidiome following Covid-19 infection.
  • 2022 — Max Plank Institute teamed up with Harvard Medical School and discovered one more root cause of poor 2-AG function. (16)
  • 2022 — Endocannabinoid levels were not disrupted in resting veterans with PTSD, remembering that endocannabinoids often function on-demand during stress. (17)

Testing endocannabinoids in human tissue

  • Blood samples (platelets, plasma, or serum) — mildly invasive for patients and a fast collection method, but not a long-term storage site for endocannabinoids. Good for testing on-demand functions.
  • Cerebrospinal fluid — strong results for researchers and a long-term storage site for endocannabinoids, but the collection is highly invasive for patients.
  • PET (Positron Emission Tomograph) image test — Boston Children’s Hospital developed an imaging test for the detection of MAG-l, which chews up 2-AG, in brown tissue. The image test requires a radioactive ligand and has only been tested for MAG-l in mice. But the study provides early proof that an endocannabinoid deficiency plays a role in mammalian metabolic disorders. (18)

Diet and routine before supplementation

Is cannabis genuinely essential? Perhaps phytocannabinoids are required for adequate health. But an endocannabinoid system can properly function without cannabis. Fats are crucial in our diet, though. And endocannabinoids are produced from phospholipids or dietary omega-3 fat.

Genetic predispositions or inflammation after a physical injury can rapidly degrade the endocannabinoid system. In these circumstances, supplementing the ECS with specific varieties of cannabis can provide benefits. Keep in mind that THC is not always the answer. In any case, proper diet and routine help to avoid endocannabinoid deficiencies caused by poor life choices.

Let us know your thoughts on the possibility of ECS deficiencies. Do you think there is enough proof to diagnose patients with cECD?


  1. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent 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 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 Surveillant Endocannabinoid System. Front Neurosci. 2021;15:747229. Published 2021 Oct 28. doi:10.3389/fnins.2021.747229
  4. Russo EB. Hemp for headache: 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 conditions. Haworth Press: Binghamton, NY, 2001
  5. Cupini LM, Bari M, Battista N, Argiro G, Agro AF, Calabresi P, and Maccarrone, MI (2003) Abnormal degradation of endocannabinoids in migrainous women. Cephalalgia 23:684–685.
  6. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett. 2004;25:31–39
  7. Cupini LM, Costa C, Sarchielli P, et al. Degradation of endocannabinoids in chronic migraine and medication overuse headache. 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 chronic migraine patients and medication-overuse headache patients: relation with 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 a system failure [published correction appears in Neuropsychopharmacology. 2007 Jun;32(6):1432]. Neuropsychopharmacology. 2007;32(6):1384-1390. doi:10.1038/sj.npp.1301246
  10. Koethe D, Giuffrida A, Schreiber D, et al. Anandamide elevation in cerebrospinal fluid in initial prodromal states 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 of anandamide-hydrolase (FAAH) activity is coupled with a reduction of nociceptive pathways facilitation in medication-overuse headache subjects 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 traits. 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 2016 Jul 1. 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).
  16. Davies, A.K., Alecu, J.E., 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 Outcome in Veterans with PTSD. Chronic Stress (Thousand Oaks). 2022;6:24705470221107290. Published 2022 Jun 9. 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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