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  • Writer's pictureTravis Cesarone

How facial pain and migraines affects endocannabinoids in saliva

A new study looked at endocannabinoid levels in the saliva of patients suffering from chronic facial pain. Individuals tested in the study experienced pain from two headache types and three different varieties of neuropathic pain.

The Faculty of Medine and Dental Medicine from The Hebrew University of Jerusalem in Israel tested 83 individuals with orofacial pain, including 11 cases of temporomandibular disorder (TMD) and 43 migraineurs. Still, only 5 had Tension-Type Headaches (TTH.) The study analyzed 11 participants with Posttraumatic Neuropathy, and 11 more had Trigeminal Neuralgia. But only 7 individuals tested had Burning Mouth Syndrome (BMS.)

The study characterized the remaining 4.8% of patients with orofacial pain (OFP) as “others.” Forty-three pain-free controls also partook for a total of 126 study participants.

Neuropathic pain affects 2-AG

Pain in the face affects the tone of different endocannabinoids in saliva, depending on the type of pain. Headache pain reduced endocannabinoids in the NAPE family, including anandamide. Neuropathic pain, on the other hand, affected the full CB1 and CB2 agonist — 2-AG.

2-AG levels moderately declined in individuals with neuropathic pain from Post Traumatic Neuropathy (PTN.) In comparison, pain caused by Trigeminal Neuralgia caused a significant drop in 2-AG levels. (1) Whole-plant CBG extracts are often better suited for protecting 2-AG. (2)

Endocannabinoids and headache pain

Anandamide levels exclusively increased with pain from Burning Mouth Syndrome. Too few patients with BMS or TTH participated in the study to conduct good results, though.

Regardless, migraine and tension headaches reduce anandamide and the endocannabinoid’s lipid relatives, OEA and PEA. Pain from headaches and migraines also caused a significant drop in arachidonic acid, an inflammatory byproduct of endocannabinoid metabolism. (1)

This author hypothesizes that a drop in arachidonic acid alongside anandamide implies endocannabinoid protection is not a solitary key to migraine therapy. Reducing endocannabinoid oxidation during migraine must occur through nitric oxide mediation.

Cause or correlation: Migraines and anandamide

Two primary theories exist to explain migraine. The first is a depleted endocannabinoid system, validated after participants agreed to an invasive spinal tap in 2007. (3) The second is a defective mouth microbiome that metabolizes nitrate-rich foods into the inflammatory agent known as nitric oxide. (4) The two theories might, however, be interconnected.

Our hearts require nitric oxide for proper function, but the inflammatory gas requires constant maintenance. Anandamide happens to be an endogenous mediator that prevents uncontrolled nitric oxide proliferation. But anandamide also regulates the microbiome.

Microbiota run rampant with depleted anandamide levels. (5) This new research (1) on salivary endocannabinoid tone in patients with facial pain supports the idea that mouth microbiome and anandamide tone correlate in migraineurs.


Various mechanisms drive endocannabinoid degradation, such as pain signals and reactive oxygen species. Anandamide and 2-AG further function through different metabolic pathways and compensate for each other during unique ailments. Neuropathic pain degrades 2-AG, and headache conditions cause a drop in anandamide, for example.


  1. Heiliczer, S.; Wilensky, A.; Gaver, T.; Georgiev, O.; Hamad, S.; Nemirovski, A.; Hadar, R.; Sharav, Y.; Aframian, D.J.; Tam, J.; Haviv, Y. Salivary Endocannabinoid Profiles in Chronic Orofacial Pain and Headache Disorders: An Observational Study Using a Novel Tool for Diagnosis and Management. Int. J. Mol. Sci. 202223, 13017.

  2. De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-1494. doi:10.1111/j.1476-5381.2010.01166.x

  3. 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

  4. Gonzalez A, Hyde E, Sangwan N, Gilbert JA, Viirre E, Knight R. Correction for Gonzalez et al., “Migraines Are Correlated with Higher Levels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort”. mSystems. 2017;2(2):e00023-17. Published 2017 Apr 11. doi:10.1128/mSystems.00023-17

  5. Russo EB. Cannabis Therapeutics and the Future of Neurology. Front Integr Neurosci. 2018;12:51. Published 2018 Oct 18. doi:10.3389/fnint.2018.00051

  6. Kozak KR, Marnett LJ. Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids. 2002;66(2-3):211-220. doi:10.1054/plef.2001.0359

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