Endocannabinoid System Dysfunction

Chronic medical conditions can stress the endocannabinoid system to the point of dysfunction leaving the person with the chronic illness and struggling to get back to homeostasis-balance. However, dysfunction within the endocannabinoid system itself can cause chronic medical conditions. Underactivity and overactivity of the endocannabinoid system has been linked to disease states and has been the focus of research around the world. Understanding how the dysfunction of the endocannabinoid system can cause disease or result from disease is crucial to the use of cannabis as medicine.

Endocannabinoid Deficiency Syndrome

A deficiency of endocannabinoids-the compounds that are made on demand in our brains and bodies to maintain homeostasis-can lead to diseases. Research has confirmed that underlying endocannabinoid deficiencies indeed play a role in a growing list of medical conditions.

Endocannabinoid system dysfunction has been found in the following medical conditions:

  • Anxiety and depression1
  • Autoimmune diseases2
  • Cardiovascular disease3
  • Complex regional pain syndrome4
  • Eating disorders5
  • Failure to thrive in newborns7
  • Fibromyalgia/myofascial pain syndrome8
  • Huntington’s disease9
  • Irritable bowel syndrome10
  • Insomnia
  • Migraine headaches11
  • Multiple sclerosis12
  • Muscle Spasms
  • Nausea and motion sickness13
  • Parkinson’s disease14
  • Schizophrenia15

***You can supplement an endocannabinoid deficiency with cannabinoids from medical marijuana just as you would supplement a vitamin D deficiency with vitamin D tablets!!***

Endocannabinoid Overactivity

At the other end of the spectrum, there can be overactivity causing dysregulation of the endocannabinoid system.  An example of this is the role of the endocannabinoid system in appetite, digestion, and energy metabolism.

Overactivity of the endocannabinoid system may be associated with obesity and type 2 diabetes.16 Studies found that overweight/obese individuals and those with type 2 diabetes have abnormally elevated blood levels of endocannabinoids, which may be due to lower levels of enzymes that are needed to break down the endocannabinoids.  Preliminary studies showed that overweight/obese people do not make enough of these enzymes, resulting in the endocannabinoids hanging around longer at the receptor, continuing to activate them.17  This results in increased hunger, which increases body weight, which then increases endocannabinoid levels, which then increases hunger, and so on, creating a vicious cycle of endocannabinoid dysfunction.

Cannabis is Medicine, written by Dr. Bonnie Goldstein, is a must read if you are interested in learning more about the endocannabinoid system and how medical cannabis and CBD are healing everything from anxiety to chronic pain. 

If you are suffering from a chronic, difficult-to-treat condition, and have not found relief from conventional medicine, then call Blue Calm Doctors and schedule a consultation today! Click here


1Ashton CH, Moore PB. “Endocannabinoid system dysfunction in mood and related disorders”. Acta Psychiatr Scand. 2011 Oct;124(4):250-61. doi: 10.1111/j.1600-0447.2011.01687.x. Epub 2011 Mar 9. PMID: 21916860. Yin AQ, Wang F, Zhang X. “Integrating endocannabinoid signaling in the regulation of anxiety and depression”. Acta Pharmacol Sin. 2019 Mar;40(3):336-341. doi:10.1038/s41401-018-0051-5. Epub 2018 Jul 12. PMID: 30002489; PMCID: PMC6460364.

2Centonze D, Bari M, Rossi S, Prosperetti C, Furlan R, Fezza F, De Chiara V, Battistini L, Bernardi G, Bernardini S, Martino G, Maccarrone M. “The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis”. Brain. 2007 Oct;130(Pt 10):2543-53. doi: 10.1093/brain/awm160. Epub 2007 Jul 11. PMID: 17626034. Sipe JC, Arbour N, Gerber A, Beutler E. “Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders”. J Leukoc Biol. 2005 Jul;78(1):231-8. doi: 10.1189/jlb.0205111. Epub 2005 Apr 21. PMID: 15845647. Cabral GA, Griffin-Thomas L. “Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation”. Expert Rev Mol Med. 2009 Jan 20;11:e3. doi: 10.1017/S1462399409000957. PMID: 19152719; PMCID: PMC2768535.

3Montecucco F, Di Marzo V. “At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction”. Trends Pharmacol Sci. 2012 Jun;33(6):331-40. doi: 10.1016/ Epub 2012 Apr 13. PMID: 22503477. Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Bátkai S, Kunos G. “Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations”. Hypertension. 2008 Oct;52(4):601-7. doi: 10.1161/HYPERTENSIONAHA.105.063651. Epub 2008 Sep 8. PMID: 18779440; PMCID: PMC2568884. Pacher P, Steffens S. “The emerging role of the endocannabinoid system in cardiovascular disease”. Semin Immunopathol. 2009 Jun;31(1):63-77. doi: 10.1007/s00281-009-0145-8. Epub 2009 Apr 9. PMID: 19357846; PMCID: PMC2791499.

4Kaufmann I, Hauer D, Huge V, Vogeser M, Campolongo P, Chouker A, Thiel M, Schelling G. “Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report”. Eur Surg Res. 2009;43(4):325-9. doi: 10.1159/000235870. Epub 2009 Sep 2. PMID: 19729930.

5Monteleone P, Matias I, Martiadis V, De Petrocellis L, Maj M, Di Marzo V. “Blood levels of the endocannabinoid anandamide are increased in anorexia nervosa and in binge-eating disorder, but not in bulimia nervosa”. Neuropsychopharmacology. 2005 Jun;30(6):1216-21. doi: 10.1038/sj.npp.1300695. PMID: 15841111.

6Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ. “The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy”. J Pharmacol Exp Ther. 2003 Oct;307(1):129-37. doi: 10.1124/jpet.103.051920. Epub 2003 Sep 3. PMID: 12954810. Ludányi A, Eross L, Czirják S, Vajda J, Halász P, Watanabe M, Palkovits M, Maglóczky Z, Freund TF, Katona I. “Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus”. J Neurosci. 2008 Mar 19;28(12):2976-90. doi: 10.1523/JNEUROSCI.4465-07.2008. PMID: 18354002; PMCID: PMC6670708.

7Fride E, Bregman T, Kirkham TC. “Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood”. Exp Biol Med (Maywood). 2005 Apr;230(4):225-34. doi: 10.1177/153537020523000401. PMID: 15792943.

8Kaufmann I, Schelling G, Eisner C, Richter HP, Krauseneck T, Vogeser M, Hauer D, Campolongo P, Chouker A, Beyer A, Thiel M. “Anandamide and neutrophil function in patients with fibromyalgia”. Psychoneuroendocrinology. 2008 Jun;33(5):676-85. doi: 10.1016/j.psyneuen.2008.02.009. Epub 2008 Apr 18. PMID: 18395993. Fede C, Albertin G, Petrelli L, Sfriso MM, Biz C, De Caro R, Stecco C. “Expression of the endocannabinoid receptors in human fascial tissue”. Eur J Histochem. 2016 Jun 28;60(2):2643. doi: 10.4081/ejh.2016.2643. PMID: 27349320; PMCID: PMC4933831.

9Sepers MD, Smith-Dijak A, LeDue J, Kolodziejczyk K, Mackie K, Raymond LA. “Endocannabinoid-Specific Impairment in Synaptic Plasticity in Striatum of Huntington’s Disease Mouse Model”. J Neurosci. 2018 Jan 17;38(3):544-554. doi: 10.1523/JNEUROSCI.1739-17.2017. Epub 2017 Nov 30. Erratum in: J Neurosci. 2018 Aug 15;38(33):7364. PMID: 29192125; PMCID: PMC5777109.

10Storr MA, Yüce B, Andrews CN, Sharkey KA. “The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome”. Neurogastroenterol Motil. 2008 Aug;20(8):857-68. doi: 10.1111/j.1365-2982.2008.01175.x. PMID: 18710476. Pesce M, D’Alessandro A, Borrelli O, Gigli S, Seguella L, Cuomo R, Esposito G, Sarnelli G. “Endocannabinoid-related compounds in gastrointestinal diseases”. J Cell Mol Med. 2018 Feb;22(2):706-715. doi: 10.1111/jcmm.13359. Epub 2017 Oct 9. PMID: 28990365; PMCID: PMC5783846.

11Sarchielli P, Pini LA, Coppola F, Rossi C, Baldi A, Mancini ML, Calabresi P. “Endocannabinoids in chronic migraine: CSF findings suggest a system failure”. Neuropsychopharmacology. 2007 Jun;32(6):1384-90. doi: 10.1038/sj.npp.1301246. Epub 2006 Nov 22. Erratum in: Neuropsychopharmacology. 2007 Jun;32(6):1432. PMID: 17119542. Volfe Z, Dvilansky A, Nathan I. “Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients”. Int J Clin Pharmacol Res. 1985;5(4):243-6. PMID: 2997048.

12Chiurchiù V, van der Stelt M, Centonze D, Maccarrone M. “The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases”. Prog Neurobiol. 2018 Jan;160:82-100. doi: 10.1016/j.pneurobio.2017.10.007. Epub 2017 Oct 31. PMID: 29097192. Di Filippo M, Pini LA, Pelliccioli GP, Calabresi P, Sarchielli P. “Abnormalities in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis”. J Neurol Neurosurg Psychiatry. 2008 Nov;79(11):1224-9. doi: 10.1136/jnnp.2007.139071. Epub 2008 Jun 5. PMID: 18535023.

13Sticht MA, Rock EM, Limebeer CL, Parker LA. “Endocannabinoid Mechanisms Influencing Nausea”. Int Rev Neurobiol. 2015;125:127-62. doi: 10.1016/bs.irn.2015.09.001. Epub 2015 Nov 6. PMID: 26638766. Choukèr A, Kaufmann I, Kreth S, Hauer D, Feuerecker M, Thieme D, Vogeser M, Thiel M, Schelling G. “Motion sickness, stress and the endocannabinoid system”. PLoS One. 2010 May 21;5(5):e10752. doi: 10.1371/journal.pone.0010752. PMID: 20505775; PMCID: PMC2873996.

14Di Filippo M, Picconi B, Tozzi A, Ghiglieri V, Rossi A, Calabresi P. “The endocannabinoid system in Parkinson’s disease”. Curr Pharm Des. 2008;14(23):2337-47. doi: 10.2174/138161208785740072. PMID: 18781984. Basavarajappa BS, Shivakumar M, Joshi V, Subbanna S. “Endocannabinoid system in neurodegenerative disorders”. J Neurochem. 2017 Sep;142(5):624-648. doi: 10.1111/jnc.14098. Epub 2017 Jul 5. PMID: 28608560; PMCID: PMC5669051.

15Koethe D, Pahlisch F, Hellmich M, Rohleder C, Mueller JK, Meyer-Lindenberg A, Torrey EF, Piomelli D, Leweke FM. “Familial abnormalities of endocannabinoid signaling in schizophrenia”. World J Biol Psychiatry. 2019 Feb;20(2):117-125. doi: 10.1080/15622975.2018.1449966. Epub 2018 Mar 22. PMID: 29521179. Leweke FM, Mueller JK, Lange B, Fritze S, Topor CE, Koethe D, Rohleder C. Role of the “Endocannabinoid System in the Pathophysiology of Schizophrenia: Implications for Pharmacological Intervention”. CNS Drugs. 2018 Jul;32(7):605-619. doi: 10.1007/s40263-018-0539-z. PMID: 30022465.

16Di Marzo V. “The endocannabinoid system in obesity and type 2 diabetes”. Diabetologia. 2008 Aug;51(8):1356-67. doi: 10.1007/s00125-008-1048-2. Epub 2008 Jun 18. PMID: 18563385.

17Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V. “Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia”. J Clin Endocrinol Metab. 2006 Aug;91(8):3171-80. doi: 10.1210/jc.2005-2679. Epub 2006 May 9. PMID: 16684820.

Leave a Comment

Your email address will not be published.