by Sara Gottfried, MD and Elnaz Karimian-Azari, PhD
The endocannabinoid system is a fascinating network involved in regulating many physiological, homeostatic, and cognitive functions—including appetite, immune function, pain, metabolism and energy balance, stress response, anxiety, mood, fertility, pregnancy, pre- and postnatal development, memory, and neurogenesis, as well as the well-known pharmacological effects of cannabis.1,2 In our developing understanding of network medicine, it’s important as clinicians to understand that the endocannabinoid system plays a role far beyond getting high and impacts conditions we see every day, including obesity, prediabetes and diabetes, and cardiovascular disease.
In the emerging view of the vast role of the endocannabinoid system in network medicine, we as practitioners need to be aware of the components and myriad actions of the endocannabinoid system, and evidence-based ways to optimize endocannabinoid function. As with many of the issues that we face in Functional Medicine, there is often a fundamental issue of dysregulated signaling—in this case, too much or too little “tone” of the endocannabinoid system.3,4 Your patients with clinical endocannabinoid deficiency may show up in your office with migraine, fibromyalgia, and irritable bowel, and our aim is to help these patients and others return to homeostasis.
There is a long history of scientists gaining insight into human physiology by studying how plants interact with our bodies. Cannabis is a prime example. By isolating and mapping the chemical structure of bioactive compounds in the Cannabis sativa plant, researchers discovered a new biological system within our bodies known as the endocannabinoid system.
The endocannabinoid system is an important physiological system involved in regulating and balancing numerous functions and processes in the human body, including but not limited to stress responses, pain sensations, mood and memory, and immunomodulatory functions like attenuating inflammation.1,2
A prolonged alteration or imbalance in the endocannabinoid system—such as clinical endocannabinoid deficiency (CED)—may negatively impact many aspects of health.3,4 Since the endocannabinoid system drives homeostasis, nourishing its functions is essential for maintaining health of mind and body. In this article, we will explore lifestyle approaches and targeted bioactives, phytocannabinoids and terpenes as well as endocannabinoid-like lipid mediators, which may improve endocannabinoid system function.
Endocannabinoid system: components
The endocannabinoid system performs multiple functions in our body, and the goal of this system is to maintain a stable internal environment, AKA our internal homeostatic regulator. The endocannabinoid system consists of three main components:
- A widespread network of cannabinoid receptors throughout the body including cannabinoid receptor type 1 and type 2 (CB1 and CB2)
- Endogenous cannabinoids or endocannabinoids (eCBs) such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG)
- Various endocannabinoid metabolic enzymes including fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)3
The classic concept of the endocannabinoid system has extended with the discovery of other receptors such as the family of peroxisome proliferator-activated receptors (PPARs) and the endocannabinoid-like mediators such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA, the ethanolamide of palmitic acid, and OEA, the ethanolamide of oleic acid, are classified as endocannabinoid-like molecules, because they are synthesized and metabolized by the same class of enzymes as AEA, but only in part share the same mechanism of action.5
eCBs are produced on demand
The eCBs are produced and released on demand from phospholipid precursors in response to a stimulus and/or need, making the endocannabinoid system capable of adapting quickly to changing conditions. Their release activates cannabinoid receptors, leading to a variety of physiologic processes involved in maintaining homeostasis.2 CB1 receptors are primarily localized in the central nervous system, and their activation results in robust suppression of neurotransmitter release into synapses; CB2 receptors, on the other hand, are mostly located in immune cells and, when activated, can modulate immune cell migration and cytokine release.6,7 However, these receptors are present in several other cell types. For example, the CB1 receptor is also present at lower concentration in a variety of peripheral tissues including sensory nerve endings where its activation impacts pain sensation.1,2
eCBs in action: Hunger
Our bodies make eCBs in response to several physiological and pathophysiological factors, and their activation leads to different biological processes. For example, when we are hungry and presented with food (prior to consumption), circulating AEA levels increase, stimulating appetite and food intake.8
eCBs in action: Exercise
The levels of eCBs in our body increase in response to positive stimuli such as exercise and social interactions.8,9 It has been shown that moderate-intensity exercise (but not low- or high-intensity exercise) can significantly impact circulating endocannabinoid levels.10 For example in healthy cyclists following a 90-minute exercise period, a positive correlation was observed between circulating AEA and brain-derived neurotrophic factor (BDNF) levels.11 Preclinical studies have shown that the effects of exercise on spatial memory and BDNF expression depend on CB1 receptor signaling.8 Together, these data suggest that, at least in part, the effect of exercise on cognitive function and mood could be mediated by the endocannabinoid system.
eCBs in action: Stress
The function of eCB signaling during stress is to buffer the stress response and dampen negative emotions.6 Exposure to acute stress induces bidirectional changes in eCB levels—reducing AEA levels and leading to the activation of the hypothalamic-pituitary-adrenal (HPA) axis and stress-related behaviors; in contrast, the increase in 2-AG levels in response to stress contributes to the suppression of the HPA axis, therefore, restoring homeostasis.6 However, impairment in the endocannabinoid system as a result of chronic stress may correlate with dysregulated stress-related behaviors like anxiety and depression.6
eCBs in action: Inflammation
Another pathophysiological condition under which eCB signaling is altered is inflammation.8 An increase in circulating eCB concentrations has been observed in patients with cirrhosis, endotoxic shock, chronic hepatitis C infection, congestive heart failure, and atherosclerosis.8 eCBs are extensively involved in regulating the immune response by activating CB2 receptors, which are mainly expressed in human lymphocytes (B and T cells), macrophages, and, to a lesser extent, neutrophils.12
CB2 receptor activation is associated with a reduction in proinflammatory cytokine release and enhancement of anti-inflammatory cytokines.7,8 Therefore, eCB signaling may function as a feedback system to dampen inflammation, and dysregulation in the crosstalk between the immune system and endocannabinoid system has the potential to negatively influence the body’s immune response.13
What if the endocannabinoid system is out of balance?
An imbalance in eCB “tone”, which is a reflection of eCB levels in the brain and other parts of the body, how they are produced, how they are broken down, and how many CB receptors a person has, could be associated with various disorders.14
Too little eCB tone
CED has been suggested to contribute to the etiology of certain conditions such as pain and psychiatric disturbances, with the greatest evidence present for migraine, irritable bowel syndrome, and fibromyalgia.14
- Suboptimal functioning of the endocannabinoid system in the spinal cord was associated with increased pain sensitivity.15
- Several reports have demonstrated benefits of cannabinoid treatments for conditions with neuropathic pain states like fibromyalgia.14
- Another example of CED is the impact of posttraumatic stress disorder (PTSD) on the endocannabinoid system among survivors of the World Trade Center attacks. Serum 2-AG levels were observed to be significantly lower in victims with PTSD compared to those without PTSD, suggesting an inability of the body to reset a healthy eCB tone and resume homeostasis after a traumatic event for some individuals.16
Too much eCB tone
On the other hand, an overactive endocannabinoid system is associated with conditions like obesity, metabolic syndrome, and hepatic fibrosis.17
- Visceral fat accumulation and excess food intake lead to upregulation of eCB tone in both peripheral and central tissues, mainly by increasing eCBs levels and/or CB1 receptor overexpression.17 High eCB tone further contributes to fat accumulation and obesity by reducing energy expenditure and enhancing both food intake and lipogenesis.17
- Available data suggest that overstimulation of the endocannabinoid system has direct, harmful effects on insulin sensitivity and glucose metabolism in tissues like the liver, adipose tissue, and skeletal muscle.17
- The endocannabinoid system mediates proapoptotic effects in cancer cells exhibiting low CB receptor expression, while enhanced expression of CB1 and/or CB2 receptors in various tumor tissues may promote cell survival and cancer progression.18 For example, in colon cancer cells, activation of the CB2 receptor may contribute to cancer cell proliferation.19
Strategies to support the endocannabinoid system
Certain lifestyle choices and strategies employed in integrative or Functional Medicine may help support the endocannabinoid system functions. The following approaches have been suggested to naturally promote the body’s own homeostatic modulator:4
- Maintain ideal body weight
- Engage in regular aerobic exercise
- Follow an anti-inflammatory diet, such as a Mediterranean diet, with an emphasis on olive oil, fish, seeds, and nuts
- Eat organic food when possible and reduce exposure to endocrine-disrupting chemicals
- Control or eliminate alcohol, tobacco, and coffee consumption
Integrative and Functional Medicine approaches
- Stress management
- Massage and acupuncture
- Targeted therapies like pre- and probiotics
- Plant-derived bioactive therapies like cannabinoids (also known as “phytocannabinoids” and terpenes)
Plant-derived cannabinoids and endocannabinoid-like lipids
Several synthetic modulators of the endocannabinoid system (i.e., pharmaceutical agents) have been studied and used for a broad range of diseases; however, many have been are associated with serious, unexpected complexities.20 For example, rimonabant—a synthetic antagonist of the CB1 receptor used as an anorectic antiobesity drug in Europe in the early 2000s—was withdrawn from the market due to severe psychiatric adverse effects.21 There is an ongoing need to identify methods to enhance the endocannabinoid system without drugs or medical procedures. Nutritional therapies leveraging naturally occurring cannabinoids found in foods and plants such as PEA, phytocannabinoids, and terpenes appear to be promising candidates due to their high safety and low adverse effects profiles.17
Phytocannabinoids and terpenes
Phytocannabinoids, naturally occurring cannabinoids found in plants like cannabis, have the ability to modulate a variety of physiological systems influenced by the endocannabinoid system as well as support its overall functioning. Cannabis sativa is an herb containing hundreds of bioactive compounds including phytocannabinoids and terpenes.23 The most well-known phytocannabinoids in cannabis are ∆9-tetrahydrocannabinol (∆9-THC) from the marijuana species and cannabidiol (CBD) from the hemp species. Both phytocannabinoids have beneficial properties with clinical relevance; however, ∆9-THC induces psychoactive effects, while CBD does not.24
Phytocannabinoids within the cannabis plant have specific and complementary effects on the endocannabinoid system either by interacting with cannabinoid receptors or inhibiting enzymes that are involved in breaking down endocannabinoids.25 For instance, CBD exerts anti-inflammatory activity by suppressing FAAH activity, thereby increasing concentrations of the anti-inflammatory endocannabinoid AEA.26 Given the promising biochemical, physiologic, and preclinical data on CBD, several clinical studies have evaluated its effects in the treatment of conditions like movement disorders, psychosis, PTSD, anxiety, and sleep disorders.25-27
Terpenes are fragrant oils common to human diets and share a precursor with phytocannabinoids. They can be found in citrus fruit rinds, mango, thyme, black pepper, peppermint, and cannabis, to name just a few. 23,24 β-caryophyllene, one of the known terpenes found in numerous plants and spices such as pepper and cloves, has been shown in preclinical studies to exert anti-inflammatory and antioxidant effects through activation of the CB2 receptor.29 Another known terpene is D-limonene, which is a common terpene found in lemon and other citrus fruits. Both preclinical and clinical studies have shown the effects of D-limonene on gastroesophageal reflux, reducing anxiety and depression, and protection against dermatophytes.24
In addition to phytocannabinoids and terpenes, the effects of eCBs can be enhanced by naturally occurring compounds such as PEA that increase their bioavailability and thereby prolong their action.22,30 PEA is known to exert anti-inflammatory properties, as well as neuroprotective and antinociceptive effects via multiple mechanisms.5,31 Research suggests that some of PEA’s action is mediated by a phenomenon referred to as the “entourage effect.” This mechanism of action is based on the ability of PEA to inhibit the expression or activity of FAAH, thereby increasing levels of AEA and 2-AG, which activate CB receptors and the transient receptor potential vanilloid receptor type 1 (TRPV1) channels.5,31 In addition, PEA can potentiate AEA- or 2-AG-induced TRPV1 activation and desensitization, contributing to its anti-inflammatory or analgesic actions.30 Another possible mechanism to its entourage effects is related to an indirect action of PEA—upregulating CB2 receptor expression mediated by PPAR-α.32
PEA is naturally produced in many plants and foods like egg yolk, peanut oil, or soybean lecithin, as well as in different tissues, cells, and body fluids such as the liver, muscle, central nervous system, and human breast milk.5,22 Like endocannabinoids, PEA is produced in the body on demand from membrane phospholipids, and its concentrations can be altered by pathological states, such as pain and inflammation, indicating its function as a self-repairing mechanism in the body.27 The effects of PEA as an anti-inflammatory and antianalgesic agent have been studied for various conditions from chronic pain syndromes (e.g., fibromyalgia, sciatic pain, diabetic pain, low back pain, carpal tunnel syndrome, poststroke, and multiple sclerosis-related and pelvic pain) and Parkinson’s disease to influenza and cold in nearly 4,000 people.33,34
OEA, another endocannabinoid-like lipid, is synthesized in the small intestine, neurons, astrocytes and adipose tissue, and its biological functions are mainly mediated by interacting with PPAR-α and TRPV1.30 The main functions of OEA are summarized in controlling food intake, reducing inflammation, and providing neuroprotective actions.30 Recent clinical studies in subjects with obesity have shown that OEA reduces serum proinflammatory cytokines, oxidative stress, hunger, and the desire to eat.35,36
Our cells produce and utilize cannabinoids in precise ways to cope with all sorts of environmental stress, thereby keeping homeostatic balance in the body. Given the fundamental nature of the endocannabinoid system, there has been an increasing number of studies identifying approaches to support this system. Along with evidence-based lifestyle approaches, targeted nutritional bioactives and therapies including plant-derived cannabinoid and endocannabinoid-like lipids, can positively modulate the endocannabinoid system, improve tone, and promote overall health.
- Aizpurua-Olaizola O et al. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today. 2017;22(1):105-110.
- Di Marzo V. ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance. Biochim Biophys Acts. 1998;1392(2-3):153–175.
- Di Marzo V et al. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(9):771-784.
- McPartland JM et al. Care and feeding of the endocannabinoid system: a systematic review of potential clinical interventions that upregulate the endocannabinoid system. PLoS One. 2014;9(3):e89566.
- Petrosino S et al. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol. 2017;174(11):1349–1365.
- Morena M et al. Neurobiological interactions between stress and the endocannabinoid system. Neuropsychopharmacology. 2016;41(1):80-102.
- Donvito G et al. The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmacology. 2018;43(1):52-79.
- Hillard CJ. Circulating endocannabinoids: From whence do they come and where are they going? Neuropsychopharmacology. 2018;43(1):155–172.
- Stone NL et al. An analysis of endocannabinoid concentrations and mood following singing and exercise in healthy volunteers. Front Behav Neurosci. 2018;12:269.
- Raichlen DA et al. Exercise-induced endocannabinoid signaling is modulated by intensity. Eur J Appl Physiol. 2013;113(4):869-875.
- Heyman E et al. Intense exercise increases circulating endocannabinoid and BDNF levels in humans–possible implications for reward and depression. Psychoneuroendocrinology. 2012;37(6):844–851.
- Chiurchiù V et al. Endocannabinoid signalling in innate and adaptive immunity. Immunology. 2015;144(3):352-364
- Pandey R et al. Endocannabinoids and immune regulation. Pharmacol Res. 2009;60(2):85-92.
- 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.
- Richardson JD et al. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. J Neurosci. 1998;18(1):451–457.
- Hill MN et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. 2013;38(12):2952-2961.
- Gruden G et al. Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol. 2016;173(7):1116-1127.
- Pyszniak M et al. Endocannabinoid system as a regulator of tumor cell malignancy – biological pathways and clinical significance. Onco Targets Ther. 2016;9:4323–4336.
- Martínez-Martínez E et al. Cannabinoids receptor type 2, CB2, expression correlates with human colon cancer progression and predicts patient survival. Oncoscience. 2015;2(2):131-141.
- Moreira FA et al. Central side-effects of therapies based on CB1 cannabinoid receptor agonists and antagonists: focus on anxiety and depression. Best Pract Res Clin Endocrinol Metab. 2009;23(1):133-144.
- Moreira FA et al. The psychiatric side-effects of rimonabant. Braz J Psychiatry. 2009;31(2):145-153.
- Gabrielsson L et al. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br J Clin Pharmacol. 2016;82(4):932–942.
- Turner SE et al. Molecular pharmacology of phytocannabinoids. Prog Chem Org Nat Prod. 2017;103:61-101.
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344–1364.
- DiMarzo V et al. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015;12(4):692–698.
- Leweke FM et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.
- Shannon S et al. Cannabidiol in anxiety and sleep: a large case series. Perm J. 2019;23:18-041.
- Elms L et al. Cannabidiol in the treatment of post-traumatic stress disorder: A case series. J Altern Complement Med. 2019;25(4):392-397.
- Askari VR et al. The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation. Life Sci. 2019;219:40-73.
- Iannotti FA et al. Endocannabinoids and endocannabinoid-related mediators: targets, metabolism and role in neurological disorders. Prog Lipid Res. 2016;62:107–128.
- Petrosino S et al. The anti-inflammatory mediator palmitoylethanolamide enhances the levels of 2-arachidonoyl-glycerol and potentiates its actions at TRPV1 cation channels. Br J Pharmacol. 2016;173(7):1154-1162.
- Guida F et al. Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci Rep. 2017;7(1):375.
- Keppel Hesselink JM et al. Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. J Pain Res. 2015;8:729–734.
- Keppel Hesselink JM et al. Palmitoylethanolamide: a natural body-own anti-inflammatory agent, effective and safe against influenza and common cold. International Journal of Inflammation. 2013;2013 (Article ID 151028).
- Payahoo L et al. Oleoylethanolamide increases the expression of PPAR-Α and reduces appetite and body weight in obese people: a clinical trial. Appetite. 2018;128:44–49.
- Payahoo L et al. Oleoylethanolamide supplementation reduces inflammation and oxidative stress in obese people: a clinical trial. Adv Pharm Bull. 2018;8(3):479–487.
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.
Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.
Elnaz Karimian Azari, PhD is Therapeutic Platform Lead for Cardiometabolic and Obesity platforms at Metagenics. She earned her PhD in Nutritional Physiology from ETH Zurich in Switzerland, studying the role of metabolic signals on eating and control of body weight. Elnaz completed her postdoctoral fellowship at the SBP Medical Discovery Institute, Center for Metabolic Origins of Disease (CMOD). Dr. Karimian Azari has acquired extensive theoretical and practical skills in nutritional physiology and metabolism with focus on the pathogenesis of metabolic disease induced by overconsumption of nutrients. She enjoys traveling, meeting new people, and exploring different cultures with her husband and daughter.