Downregulated, low, or reduced endocannabinoid tone (e-tone) and endocannabinoid signaling are also often referenced in the scientific literature as (clinical) endocannabinoid deficiency syndrome. Low e-tone and resulting clinical signs and symptoms have been found in large groups of diverse patient populations. Enhancing e-tone may represent a novel approach (M. Toczek et al., 2018).1
Enhancing e-tone may benefit patients with (not a complete list):
Alzheimer’s disease (C. Benito et al., 2007).2
Dravet syndrome (L. Anderson et al., 2022).3
Chronic orofacial pain (Y. Haviv et al., 2022).4
Anorexia nervosa (R. Collu et al., 2019).5
Chemotherapy-induced neuropathic pain (J. Guindon et al., 2016).6
Migraine (E. Russo, 2004).7
Fibromyalgia (E. Russo, 2004).8
Irritable bowel syndrome (E. Russo, 2004).9
Autism (ASD) (S. Schultz et al., 2021; A. Aran et al., 2018).10
Multiple sclerosis (F. Loría et al., 2010).11
Depression (D. Parolaro et al., 2010).12
Epilepsy (L. Anderson et al., 2022)13
Practical steps that may enhance e-tone
Physical exercise (PE) enhances ECS-based signaling (P. Sparling et al., 2003)14 and CB1 expression (T. Charytoniuk et al., 2020;15 G. Galdino et al., 2014).16 More specifically, anandamide (AEA) levels increase with PE (T. Charytoniuk et al., 2020).17
Lifestyle changes (e.g., meditation, nutraceuticals) and the consumption of several cannabis constituents increase e-tone (V. Brugnatelli et al., 2021).18
FAAH and MAGL inhibitors (M. Toczek et al., 2018).19 For instance, the FAAH inhibitor URB597 (aka KDS-4103) upregulates the tonic actions of anandamide associated with emotional processing (e.g., anxiolytic, antidepressant) and the modulation of pain (D. Piomelli et al., 2006).20
Endnotes:
1. Toczek M, Malinowska B. Enhanced endocannabinoid tone as a potential target of pharmacotherapy. Life Sci. 2018 Jul 1;204:20-45.
2. Benito C, Núñez E, Pazos MR, Tolón RM, Romero J. The endocannabinoid system and Alzheimer’s disease. Mol Neurobiol. 2007 Aug;36(1):75-81.
3. Anderson LL, Doohan PT, Hawkins NA, Bahceci D, Garai S, Thakur GA, Kearney JA, Arnold JC. The endocannabinoid system impacts seizures in a mouse model of Dravet syndrome. Neuropharmacology. 2022 Mar 1;205:108897.
4. Haviv Y, Georgiev O, Gaver-Bracha T, Hamad S, Nemirovski A, Hadar R, Sharav Y, Aframian DJ, Brotman Y, Tam J. Reduced Endocannabinoid Tone in Saliva of Chronic Orofacial Pain Patients. Molecules. 2022 Jul 21;27(14):4662.
5. Collu R, Scherma M, Piscitelli F, Giunti E, Satta V, Castelli MP, Verde R, Fratta W, Bisogno T, Fadda P. Impaired brain endocannabinoid tone in the activity-based model of anorexia nervosa. Int J Eat Disord. 2019 Nov;52(11):1251-1262.
6. Guindon J, Lai Y, Takacs SM, Bradshaw HB, Hohmann AG. Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacol Res. 2013 Jan;67(1):94-109.
7. 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? Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):31-9.
8. Ibid.
9. Ibid.
10. Schultz, Stephen, Georgianna G. Gould, Nicola Antonucci, Anna Lisa Brigida, and Dario Siniscalco. 2021. “Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?” Molecules 26, no. 7: 1845.
Aran, A., Eylon, M., Harel, M. et al. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism 10, 2 (2019).
11. Loría F, Petrosino S, Hernangómez M, Mestre L, Spagnolo A, Correa F, Di Marzo V, Docagne F, Guaza C. An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis. Neurobiol Dis. 2010 Jan;37(1):166-76.
12. Parolaro D, Realini N, Vigano D, Guidali C, Rubino T. The endocannabinoid system and psychiatric disorders. Exp Neurol. 2010 Jul;224(1):3-14.
13. Anderson LL, Doohan PT, Hawkins NA, Bahceci D, Garai S, Thakur GA, Kearney JA, Arnold JC. The endocannabinoid system impacts seizures in a mouse model of Dravet syndrome. Neuropharmacology. 2022 Mar 1;205:108897.
14. Sparling PB, Giuffrida A, Piomelli D, Rosskopf L, Dietrich A. Exercise activates the endocannabinoid system. Neuroreport. 2003 Dec 2;14(17):2209-11.
15. Charytoniuk T, Zywno H, Konstantynowicz-Nowicka K, Berk K, Bzdega W, Chabowski A. Can Physical Activity Support the Endocannabinoid System in the Preventive and Therapeutic Approach to Neurological Disorders? Int J Mol Sci. 2020 Jun 13;21(12):4221.
16. Galdino G, Romero T, Pinho da Silva JF, Aguiar D, de Paula AM, Cruz J, Parrella C, Piscitelli F, Duarte I, Di Marzo V, Perez A. Acute resistance exercise induces antinociception by activation of the endocannabinoid system in rats. Anesth Analg. 2014 Sep;119(3):702-715.
17. Charytoniuk T, Zywno H, Konstantynowicz-Nowicka K, Berk K, Bzdega W, Chabowski A. Can Physical Activity Support the Endocannabinoid System in the Preventive and Therapeutic Approach to Neurological Disorders? Int J Mol Sci. 2020 Jun 13;21(12):4221.
18. Brugnatelli V, Facco E, Zanette G. Lifestyle Interventions Improving Cannabinoid Tone During COVID-19 Lockdowns May Enhance Compliance With Preventive Regulations and Decrease Psychophysical Health Complications. Front Psychiatry. 2021 Jul 16;12:565633.
19. Ibid.
20. Piomelli D, Tarzia G, Duranti A, Tontini A, Mor M, Compton TR, Dasse O, Monaghan EP, Parrott JA, Putman D. Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev. 2006 Spring;12(1):21-38.
