What Is The Endocannabinoid System and Why Should You Care About It?

Chapter 1 from 2018 Edition:

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

To keep your mind healthy, your joints strong, your mood calm, and your digestive system comfortable, your body was given an amazing tool. That tool is called the endocannabinoid system. Researchers discovered its existence only as recently as 1988, when they were investigating how cannabinoids found in the marijuana plant (Cannabis sativa) affect the body.

The interesting thing about this system is that you don’t need marijuana to activate it. It’s a perfectly natural pathway that has served humankind and other mammals for millennia. Your body makes its own cannabinoids that work through this same system. These cannabinoids that your body makes are called endocannabinoids. There are also hemp-based cannabinoids (phytocannabinoids)—such as cannabidiol (CBD)—that work through the endocannabinoid system. These phytocannabinoids can even increase levels of your natural cannabinoids. CBD, unlike marijuana, works on the endocannabinoid system without making you high because it does not contain enough tetrahydrocannabinol (THC). That’s the component of marijuana responsible for its psychoactive effects.

Even though your body makes endocannabinoids, many aspects of modern life can lead to an endocannabinoid deficiency (more on this later). That’s when hemp-based CBD oil can be especially effective.

 

Your Body’s Locks and Keys

Cells throughout your body have receptors. These receptors act like locks. They need certain substances that act like keys to open or close the receptor locks. Depending on the cell’s location in the body and receptor involved, this can open or close different doors to health or disease depending upon whether the substance acting like a receptor key is beneficial or harmful and whether it locks or unlocks the receptor. Substances that bind to receptors to act like keys include drugs, hormones, and neurotransmitters (chemicals released from nerve cells).

In 1988, scientists Allyn Howlett and William Devane at the St. Louis University School of Medicine discovered that brains in mammals have receptors that react to cannabis-derived compounds.¹ These receptors are known as cannabinoid receptors. They’re the most abundant form of neurotransmitter receptor in the brain. These cannabinoid receptors respond to endocannabinoids. Plant-derived cannabinoids such as CBD from hemp and THC from marijuana also interact with these receptors.

CB1 and CB2 were the first two cannabinoid receptors discovered.¹ CB1 receptors are primarily located in the brain.¹ By contrast, CB2 receptors are located in the gastrointestinal (GI) tract, liver, spleen, endocrine glands, and the reproductive system.¹ The immune system and the peripheral nervous system also contain CB2 receptors.¹ The peripheral nervous system is the part of the nervous system located outside the brain and spinal cord.

 

The Endocannabinoid System’s Role in Your Health

There is a lot more for us to learn about the endocannabinoid system’s role in health. However, thousands of studies have now explored the many ways in which this system benefits us. The table below shows in which health concerns the endocannabinoid system plays a role.

 

	Table 1: The Many Ways the Endocannabinoid System Regulates Health
Gut Health	• The endocannabinoid system is involved in regulating visceral pain and irritable bowel syndrome.2,3 • Endocannabinoids also help ensure we don’t get constipated or develop diarrhea.3 • The endocannabinoid system helps regulate intestinal permeability, meaning it can support the health of people with leaky gut.4 • The phytocannabinoid CBD may have a role to play in supporting the health of people with ulcerative colitis.5
Brain Function and Mental Health	• Endocannabinoids play a role in the gut-brain axis, the communication that occurs between the gut and the brain.6 • The endocannabinoid system is involved in regulating anxiety, posttraumatic stress disorder, depression, bipolar disorder, and schizophrenia.7
Pain	• CB2 receptors stimulate opioid receptors to cause pain relief in a non-addictive manner.8 • CB2 receptors may be involved in blocking the effect of painful stimuli in inflammatory processes of the nervous system.9 • The endocannabinoid system may be the reason why stress can lead to abdominal pain.3 • The pain-relieving effects of acetaminophen may be because one of its metabolites indirectly activates CB1 receptors.10 • The endocannabinoid system also is involved in the regulation of endometriosis-associated pain.11
Joint Health	• In rat studies of animals with osteoarthritis, transdermal or oral CBD improved joint health, reduced joint inflammation and swelling, and improved the ability of the animals to bear their own weight. CBD administered in advance of inducing osteoarthritis in animals blocked the development of joint pain and nerve damage.12,13 • Researchers have found cannabinoid receptors on human articular cartilage from patients with symptomatic osteoarthritis.14
Stress	• CBD’s role in promoting a calm mood is related to its effects on the serotonin receptor and the ability to control blood flow in regions of the brain involved in anxiety.15 • A number of clinical studies have shown CBD has a calming effect on people who have to give a public speech.16-19
Sleep	• Low-dose CBD can be stimulating and lead to wakefulness. However, higher doses of CBD can encourage restful sleep.20 • CBD may reduce stress and improve the quality and quantity of sleep.21 • CBD may be beneficial in REM sleep behavior disorder (a condition where people kick, move, or act out dreams in their sleep) and to feel less sleepy during the day.22
Women’s Health	• The endocannabinoid system plays an important role in fertility.23 • The endocannabinoid system is present within ovaries.24 • CBD may reduce discomfort in women with endometriosis.25 • Menopausal health and breast health may also be regulated by the endocannabinoid system.26,27
Men’s Health	• CBD may play a role in prostate health.28,29
Urinary Tract Health	• Cannabinoid receptors are present in the lower urinary tract and areas involved in urinary tract control.30 • Phytocannabinoids may support the health of the bladder, urethra, and prostate.30
Epilepsy	• CBD, administered together with anti-seizure medication, can support the health of people with seizures.31-34
Immunity	• The endocannabinoid system can be involved in both enhancing and suppressing immunity.35 • The endocannabinoid system is involved in the body’s response to respiratory syncytial virus (RSV), the primary cause of severe bronchiolitis and pneumonia in children.36-38 • CBD can support a healthy immune response in the liver.39 • All five major cannabinoids—cannabidiol, cannabichromene, cannabigerol, THC, and cannabinol—help control a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of bacteria.40
Inflammation	• Cannabinoids play a role in the recruitment of immune cells to the location of intestinal inflammation.41 • Cannabidiol also has been shown to block the production of pro-inflammatory proteins known as cytokines.42 • CBD has reduced markers of inflammation in a number of cell culture and animal studies.43-46 • Cannabinoids ability to support a healthy inflammatory response are not associated with the adverse effects produced by NSAIDs.47
ADHD/Autism	• Researchers have observed low levels of certain endocannabinoids in children with autism spectrum disorder (ASD).48 • Problems with endocannabinoid function are thought to play a role in the social challenges that occur in kids with ASD.49 • In adults with ADHD, CBD may help reduce hyperactivity, impulsivity, and ability to control behavior. However, more studies are needed in this group of people.50

 

Getting To Know The Endocannabinoids

There are two main endocannabinoids produced in the body: anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These activate CB1, CB2, and other receptors in the endocannabinoid system, serving as the “keys” that fit into the receptor “locks” (more on this later). Each of these endocannabinoids play an important role in health. AEA is involved in the perception of pain, emotional health, and energy metabolism (the body’s generation of energy from nutrients).⁵¹ It is nicknamed “the bliss molecule” since it’s involved in mood.

Like AEA, 2-AG is found throughout the body including the brain, cardiovascular system, and intestines.^52,1 2-AG may even be involved in orgasms during sex, indicating that AEA isn’t the only bliss molecule.⁵³

Another key player in the endocannabinoid system are enzymes that break down the endocannabinoids. For example, the enzyme fatty acid amide hydrolase—FAAH for short—breaks down AEA.⁵⁴  Some substances like CBD can increase levels of AEA by blocking FAAH actions.⁵⁵ Blocking FAAH may help support pain management and neurodegenerative health and relieve occasional anxiety.⁵⁴

 

Endocannabinoid Deficiency

Certain factors can cause what’s known as endocannabinoid deficiency. This happens when the body doesn’t make enough endocannabinoids to maintain optimal health or there are a reduced number of cannabinoid receptors. For example, early life stress leads to changes in AEA and 2-AG tissue levels within the amygdala and hippocampus regions of the brain.⁵⁶ Stress in early childhood can also reduce the number of CB1 receptors in all brain regions later in life.⁵⁶ These changes can lead to an inability to cope with stress as time goes on.⁵⁶

Endocannabinoid deficiency can also result due to genetic reasons or because of disease or injury.¹ Researchers have proposed that endocannabinoid deficiency may be the cause of migraines, fibromyalagia, and irritable bowel syndrome.¹ It may also play a role in autism spectrum disorder.¹

 

A Balancing Act

The goal is not always to increase endocannabinoid levels. Instead, sometimes lowering endocannabinoid levels is what is needed for optimal health. We must always strive for a balanced endocannabinoid system. For example, lower AEA was associated with the improvement in migraines that occur when patients with these headaches participate in aerobic exercise.⁵⁷ In addition, weight loss and improved mood after aerobic exercise training are linked to lower plasma AEA in healthy people.⁵⁸ In addition, high 2-AG levels are linked to excessive hunger in sleep-deprived people.⁵⁹ 

 

Beyond Cannabinoid Receptors

Earlier, we discussed the cannabinoid receptors CB1 and CB2. However, endocannabinoids, CBD, and other hemp-derived cannabinoids interact with other receptors, too. Here are some of these other receptors:

• G-protein coupled receptors (GP- CRs: GPR18, GPR55 and GPR119)– GPR18 is expressed primarily in immune cells while GPR55 is expressed in several brain areas as well as in some neurons with larger diameters.⁶⁰ GPR55 may also be expressed in the immune system as well as in immune-regulating cells located in the brain and spinal cord known as microglia.⁶⁰ GPR55 can also be activated in the bone.⁶⁰
• Type 1 vanilloid receptors (TRPV₁)– These receptors may be involved in some of the beneficial effects of cannabinoids. For example, scientists have found TRPV₁ receptors in neurons that play a role in pain management.⁶¹
• Serotonin receptor (5-HT1A) – Scientists have shown that endocannabinoids and plant-derived cannabinoids can affect the serotonin receptor subtype 5-HT1A. Serotonin is known as the “feel-good” neurotransmitter. Optimal levels of this neurotransmitter lead to a sense of well-being and happiness. The mood-boosting effects of CBD are due in part to activation of the 5-HT1A receptor.⁶²
• Other cannabinoid receptors– Cannabinoids may interact with other receptors. These other receptors may be involved in some of the pain-relieving effects linked to cannabinoids.^63,64

 

The Pain-Killing Endocannabinoid Lookalike

There is a substance known as palmitoylethanolamide (PEA). It’s not an endocannabinoid but it works on the endocannabinoid system by helping the body make better use of the endocannabinoid AEA.⁶⁵ PEA is best known for its role in pain management. PEA is a natural painkiller.⁶⁵ Your body makes it when it’s in pain. PEA is also found in some foods including egg yolks, peanuts, and soybeans. However, it’s not found in cannabis.

There’s now a lot of evidence to indicate PEA reduces neuroinflammation, a process that’s linked to pain.⁶⁵ It does this in part by blocking mast cells and regulating glial cells in the central nervous system.⁶⁵ If you have hay fever then you’re all too familiar with what overactivated mast cells can do. They release inflammatory substances such as histamine. Glial cells play a role in the health of your neurons.

Researchers reviewed the results of 12 clinical trials to find out whether PEA could reduce pain.⁶⁵ The researchers concluded that PEA supplementation was better at progressively decreasing pain intensity compared with control. According to these scientists, “These results confirm that PEA might represent an exciting, new therapeutic strategy to manage chronic and neuropathic pain associated with neuroinflammation.”

 

The Remarkable Cannabinoid System

Cannabinoids—both the endocannabinoids made in your body and hemp-based cannabinoids like CBD—play a role in virtually every area of health. Well-being and happiness, pain management, a healthy digestive system, a good night’s rest, a strong immune system, reproductive health, and healthy joints are all dependent upon this system. Taking steps to keep your endocannabinoid system healthy is therefore critical to optimal health.

Read Chapter 2: CBD’s Mechanisms in the Body: How This Amazing Cannabinoid Keeps You Healthy

The statements mentioned in this content have not been evaluated by the FDA, and are not intended to prevent, diagnosis, or treat any disease. Always work with your personal healthcare provider.

 

References:

1. Smith SC, Wagner MS. Clinical endocannabinoid deficiency (CECD) revisited: Can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinology Letters. 2014;35(3):198-201.
2. Sakin YS, Dogrul A, Ilkaya F, et al. The effect of FAAH, MAGL, and Dual FAAH/MAGL inhibition on inflammatory and colorectal distension-induced visceralpain models in Rodents. Neurogastroenterol Motil. 2015 Jul;27(7):936-44.
3. Sharkey KA, Wiley JW. The Role of theEndocannabinoid System in the Brain-Gut  Gastroenterology. 2016 Aug;151(2):252-66.
4. Cani PD, Plovier H, Van Hul M, et al. Endocannabinoids–at the crossroads between the gut microbiota and host metabolism. Nat Rev Endocrinol. 2016 Mar;12(3):133-43.
5. Irving PM, Iqbal T, Nwokolo C, et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm Bowel Dis. 2018 Mar 19;24(4):714-24.
6. DiPatrizio NV. Endocannabinoids in the Gut. Cannabis Cannabinoid Res. 2016 Feb;1(1):67-77.
7. Rubino T, Zamberletti E, Parolaro D. Endocannabinoids and Mental Disorders. Handb Exp Pharmacol.2015;231:261-83.
8. Ibrahim MM, Porreca F, Lai J, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3093-8.
9. Manzanares J, Julian MD, Carrascosa A. Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes. Curr Neuropharmacol. 2006 Jul; 4(3): 239-57.
10. Klinger-Gratz PP, Ralvenius WT, Neumann E, et al. Acetaminophen Relieves InflammatoryPain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla. J Neurosci. 2018 Jan 10;38(2):322-34.
11. Sanchez AM, Cioffi R, Viganò P, et al. Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis. Reprod Sci. 2016 Aug;23(8):1071-9.
12. Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. 2017 Dec;158(12):2442-51.
13. Costa B, Colleoni M, Conti S, et al. Oral anti-inflammatory activity ofcannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol. 2004 Mar;369(3):294-9.
14. Dunn SL, Wilkinson JM, Crawford A, et al. Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies. CannabisCannabinoid Res. 2016 Jan 1;1(1):3-15.
15. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011 Jan;25(1):121-30.
16. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016 Fall;20(4):16-005.
17. Soares VP, Campos AC. Evidences for the Anti-panic Actions of Cannabidiol. Curr Neuropharmacol. 2017;15(2):291-9.
18. Linares IM, Zuardi-AW, Pereira LC, et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry. 2019 Jan-Feb;41(1):9-14.
19. Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiolreduces the anxiety induced by simulated public speaking in treatment-naïve socialphobia patients. Neuropsychopharmacology. 2011 May;36(6):1219-26.
20. Carlini EA, Cunha JM. Hypnoticand antiepileptic effects of cannabidiol. J Clin Pharmacol. 1981 Aug-Sep;21(S1):417S-27S.
21. Shannon S, Opila-Lehman J. Effectiveness of Cannabidiol Oil for Pediatric Anxiety and Insomnia as Part of Posttraumatic Stress Disorder: A Case Report. Perm J. 2016 Fall;20(4):16-005.
22. Babson KA, Sottile J, Morabito D. Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep. 2017 Apr;19(4):23.
23. Walker OS, Holloway AC, Raha S. The role of the endocannabinoid system in female reproductive tissues. J Ovarian Res. 2019:12:3.
24. El-Talatini MR, Taylor AH, Elson JC, et al. Localisationand function of the endocannabinoid system in the human ovary. PLoS One. 2009;4(2):e4579.
25. Armour M, Sinclair J, Chalmers KJ, Smith CA. Self-management strategies amongst Australian women with endometriosis: a national online survey. BMC Complement Altern Med. 2019 Jan;19:17.
26. Abdulnour J, Yasari S, Rabasa-Lhoret R, et al. Circulatingendocannabinoids in insulin sensitive vs. insulin resistant obese postmenopausal women. A MONET group study. Obesity (Silver Spring). 2014 Jan;22(1):211-6.
27. Kisková T, Mungenast F, Suváková M, et al. Future Aspects for Cannabinoids in Breast Cancer Therapy. Int J Mol Sci. 2019 Apr;20(7):1673.
28. Fraguas-Sánchez AI,Fernández-Carballido A, Torres-Suárez AI. Phyto-, endo- and synthetic cannabinoids: promising chemotherapeutic agents in the treatment of breast and prostate  Expert Opin Investig Drugs. 2016 Nov;25(11):1311-23.
29. Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015 Apr;33(4):1599-608.
30. Ruggieri MR Sr. Cannabinoids: potential targets for bladder dysfunction. Handb Exp Pharmacol. 2011;(202):425-51.
31. Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-20.
32. Devinsky O, Patel AD, Cross JH, et al. Effectof Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. N Engl J Med. 2018 May 17;378(20):1888-97.
33. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in Patients with Seizures Associated with Lennox-Gastaut Syndrome (GWPCARE4): a randomized double-blind,placebo-controlled phase 3 trial. 2018 Mar 17;391(10125):1085-96.
34. Cunha JM, Carlini EA, Pereira AE, et al. Chronic administration of cannabidiol to healthy volunteers and epileptic patients. 1980;21(3):175-85.
35. Klein TW, Friedman H, Specter S. Marijuana, immunity and infection. J Neuroimmunol. 1998 Mar 15;83(1-2):102-15.
36. Kaplan BLF. Endocannabinoidengagement of CB₂regulates RSV-induced immunity. 2018 Jan 1;9(1):494-5.
37. Tahamtan A, Samieipoor Y, Nayeri FS, et al. Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice. 2018 Jan 1;9(1):217-30.
38. Tahamtan A, Tavakoli-Yaraki M, Shadab A, et al. The Role of Cannabinoid Receptor 1 in the Immunopathology of Respiratory Syncytial Virus. Viral Immunol. 2018 May;31(4):292-8.
39. Lowe HI, Toyang NJ, McLaughlin W. Potential ofCannabidiol for the Treatment of Viral  Pharmacognosy Res. 2017 Jan-Mar;9(1):116-8.
40. Appendino G, Gibbons S, Giana A, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.
41. Alhouayek M, Lambert DM, Delzenne NM, et al. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 2011 Aug;25(8):2711-21.
42. Schicho R, Bashashati M, Bawa M, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis.2011 Aug;17(8):1651-64.
43. Borrelli F, Aviello G, Romano B, et al. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl).2009 Nov;87(11):1111-21.
44. De Filippis D, Esposito G, Cirillo C, et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One. 2011;6(12):e28159.
45. Petrosino S,Verde R, Vaia M, et al. Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis. J Pharmacol Exp Ther. 2018 Jun;365(3):652-63.
46. Parker J, Atez F, Rossetti RG, et al. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol Int. 2008 May;28(7):631-5.
47. Zurier RB, Burstein SH. Cannabinoids, inflammation, and fibrosis. FASEB J. 2016 Nov;30(11):3682-9.
48. Karhson DS, Krasinska KM, Dallaire JA, et al. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism. 2018 Mar 12;9:18.
49. Wei D, Lee D, Cox CD, et al. Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci USA. 2015 Nov 10;112(45):14084-9.
50. Cooper RE, Williams E, Seegobin S, et al. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. Eur Neuropsychopharmacol. 2017 Aug;27(8):795-808.
51. Oliveira AB, Ribeiro RT, Mello MT, et al. AnandamideIs Related to Clinical and Cardiorespiratory Benefits of Aerobic Exercise Training in Migraine Patients: A Randomized Controlled Clinical Trial. Cannabis Cannabinoid Res. 2019 Dec 9;4(4):275-84.
52. Science Direct. 2-Arachidonoylglycerol. Comprehensive Natural Products II. 2010. https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/2-arachidonoylglycerol. Accessed January 20, 2020.
53. Fuss J, Bindila L, Wiedemann K, et al. Masturbation toOrgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans. J Sex Med. 2017 Nov;14(11):1372-9.
54. Maccarrone M, Finazzi-Agrò A. Anandamide hydrolase: a guardian angel of human reproduction? Cell. 2004 Jul. 25(7):353-7.
55. Fogaça MV, Campos AC, Coelho LD, et al. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. 2018 Jun;135:22-33.
56. Goldstein Ferber S, Trezza V, Weller A. Early life stress and development of the endocannabinoid system: A bidirectional process in programming future coping. Dev Psychobiol. 2019 Dec 18. [Epub ahead of print.]
57. Oliveira AB, Ribeiro RT, Mello MT, et al. AnandamideIs Related to Clinical and Cardiorespiratory Benefits of Aerobic Exercise Training in Migraine Patients: A Randomized Controlled Clinical Trial. Cannabis Cannabinoid Res. 2019 Dec 9;4(4):275-84.
58. Belitardo de Oliveira A, de Mello MT, Tufik S, Peres MFP. Weight loss and improved mood afteraerobic exercise training are linked to lower plasma anandamide in healthy people. Physiol Behav. 2019 Mar 15;201:191-7.
59. Hanlon EC, Tasali E, Leproult R, et al. Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol. 2016 Mar 1;39(3):653-64.
60. Miller RJ, Miller RE. Is cannabis an effective treatment for jointpain? Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):59-67.
61. O’Hearn S, Diaz P, Wan BA, et al. Modulating theendocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies. Ann Palliat Med. 2017 Dec;6(Suppl 2):S209-14.
62. Sartim AG, Guimarães FS, Joca SR. Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex-Possible involvement of 5-HT1A and CB1 receptors. Behav Brain Res. 2016 Apr 15;303:218-27.
63. Breivogel CS, Griffin G, Di Marzo V, Martin BR. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol. 2001 Jul;60(1):155-63.
64. Hájos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. 2001;106(1):1-4.
65. Paladini A, Fusco M, Cenacchi T, et al. Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis. Pain Physician. 2016;19:11-24.