CBD and the Endocannabinoid System

The Role of CBD in Maintaining the Endocannabinoid System and HPA Axis Balance

By: Clifford Morris, Ph.D. Cand., Chief Chemist and Research Scientist


In this article, we will shed light on the nebulous topic of cannabidiol (CBD), including the effects of CBD on the Hypothalamic-Pituitary-Adrenal (HPA) axis, stress, and inflammation. The legalization of medical cannabis has brought a new wave of cannabinoid science and healthcare to the world, and CBD has exponentially grown in popularity as a dietary supplement.1–5 One of the reasons for this boom is that CBD can assist the body in maintaining homeostasis – the fine art of balancing hormones, immune functions, metabolism, sleep, and stress responses.6 Society is plagued by chronic stress and inflammation caused by poor health and diets, overworking, low quality sleep and negative environmental impacts. It is a global pandemic that must be addressed, as it exacerbates the pathology of cancers, neurodegenerative diseases, heart attacks, diabetes, obesity and many more. The majority of these contemporary issues could be a consequence of the prohibition of hemp and cannabis under the Marihuana Tax Act of 1937.7 For thousands of years, humans have epigenetically coevolved a dependence on hemp, but in 1937, Americans experienced a sudden and total starvation of cannabinoids due to the prohibition of hemp.8 Is this endocannabinoid crisis one of the major causes of modern chronic illness? It certainly could be.


The Endocannabinoid System (ECS)

CBD is one of many cannabinoids extracted from the industrial hemp plant, Cannabis sativa. Another famous cannabinoid is tetrahydrocannabinol (THC). However, CBD has unique properties that make it attractive for therapeutic purposes over THC. Recently, in January of 2019, the Farm Bill removed CBD from the Federal list of regulated substances. From a pharmacologic perspective, CBD has no obvious intoxicating (psychotropic) effects as well as no chance of excitotoxicity, both of which contribute heavily to therapeutic decision making.9,10 This leads us to discussing CBD’s mechanism of action.


The endocannabinoid system (ECS) is a biological network distributed throughout the entire body. It is composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors and proteins that are expressed throughout the central nervous system, including the brain and peripheral nervous system.4,6,12 The ECS is comprised of two important receptors; cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). CB1 and CB2 are transmembrane G-protein coupled receptors (GPCRs) located throughout the central and peripheral nervous system. They are the most abundant GPCRs in the nervous system and work with cannabinoids to maintain the homeostasis of the cell. The ECS also contains arachidonate-based endocannabinoids, known as anandamide (AEA) and 2-arachidonoylgycerol (2-AG), along with enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which break down AEA and 2-AG, respectively.


Effects of CBD on the HPA Axis and Stress

The HPA axis and ECS act in concert, balancing and regulating a variety of physiological and cognitive processes including homeostasis, metabolism, inflammation, pain-sensation, mood, memory, and many more.6 Interestingly, THC can bind to CB receptors directly, with a preference for the CB1 receptors which are more densely located in the central nervous system and thus the source of THC’s psychoactive effects. However, CBD interacts indirectly with other cells that then interact with these receptors and others, manipulating cellular function.1 CBD is a competitive inhibitor that binds to FAAH and MAGL, with a higher affinity then 2-AG and AEA, resulting in an elevated concentration of AEA and 2-AG in the body. Increasing endocannabinoid levels in the body allows the ECS to do its job well, maintaining balance through times of change or stress.4,6 The fight-or-flight response, also called acute hyperarousal, is a physiological reaction that occurs in response to perceived (real or not) threat or stressor.13 In brief, an external stress signal is perceived by the cerebral cortex, initiating the hypothalamus to produce corticotrophin-releasing hormone (CRH), which in turns makes the pituitary gland produce adrenocorticotropic hormone (ACTH), cascading to the adrenal glands and finally resulting in the production of cortisol, epinephrine, and norepinephrine. This allows the body to respond in a heightened state, but chronic activation of this system can lead to permanent damage. There are also areas in the hippocampus and amygdala which are densely covered in CB1 receptors. The amygdala’s main role in the body is intelligence and processing emotions, most notably stress, anxiety, fear, and PTSD.1,2,4 Physiologically, most stress and anxiety is a result of the bed nucleus of the stria terminalis (BNST) coordinating a stress-based response in conjunction with the amygdala. Here, CBD produces its anxiolytic effects via activation of the 5HT-1a receptor associated with serotonin, as well as the BNST of the amygdala. It is important to note that CBD only mildly increases AEA concentrations. This is shown to give enough stimulation to decrease FAAH levels, as well as the neurotransmitter glutamate, thereby relieving stress and allowing the brain to respond to stress effectively.

In cases of chronic stress and inflammation, both the HPA axis and ECS are imbalanced and dysfunctional. It is critical to address the endocannabinoid shortage and rebalance the HPA axis. The ECS can be rectified by lowering CRH and FAAH with exogenous cannabinoids, such as CBD, thereby raising AEA and lowering glutamate.3,5 Increased levels of AEA are directly correlated with improved wellness, mood, and stress response. The HPA axis can be rectified by focusing on lowering cortisol and CRH levels through stress, diet and sleep management. Piecing it all together, CBD is an excellent way to boost endocannabinoid signaling, improve the regulation of the HPA axis, and promote a healthy endocrine system. CBD naturally increases ECS tone which helps to improve the regulation of homeostasis across the HPA axis. Physicians Lab offers comprehensive diurnal hormone testing to determine cortisol and cortisol metabolite levels, and address the sources of HPA axis dysfunction. This will improve both the physiological and psychological responses to stress, making a person more likely to resist the cascade leading to HPA dysfunction and endocrine-related health problems.


Neuroprotective and Anti-inflammatory Properties of CBD

CBD also has anti-inflammatory and neuroprotective effects.4,5,9,14 This, however, is achieved without involving the endogenous cannabinoid receptors. A major component of inflammation is the response to reactive oxygen species (ROS), which can accumulate and cause DNA damage and cytotoxicity. Antioxidants are molecules that have the ability to detoxify ROS. CBD has been shown in various studies to have a much higher antioxidant ability than vitamin C and E, and comparable to that of BHT – a synthetic antioxidant used as a food and drug preservative.14 In addition to acting as an antioxidant itself, CBD causes a noted increase in the presence of other antioxidants as well. CBD upregulates an important antioxidant, glutathione, as well as the enzyme superoxide dismutase (SoD), which is the body’s strongest antioxidant and responsible for around a third of the total antioxidation in our bodies. Earlier we mentioned glutamate, which is the brain’s primary excitatory neurotransmitter. When glutamate levels are too high, excitotoxicity and oxidative stress both occur. CBD is shown to prevent this by agonizing serotonin 5-HT1a receptors, which have the opposite effect of glutamate receptors, thereby reducing excitotoxicity and oxidative stress.10 Many neurodegenerative diseases are characteristic of excitotoxicity, including Alzheimer’s Disease and Parkinson’s disease, anxiety, schizophrenia, and even autism. Finally, CBD is fast becoming a treatment of choice for effective pain relief, spasticity and seizures, with plenty of high-quality evidence supporting it.4,5,15 CBD’s action as a protectant against inflammation and oxidative stress could explain the success that many have found using CBD to add to their therapeutic strategy for these conditions and others.


Supporting Balance with CBD

In conclusion, CBD is a non-toxic, non-psychotropic, powerful dietary supplement that can help maintain ECS and HPA axis homeostasis. It supports lower levels of stress, anxiety and inflammation, along with antioxidant and neuroprotective properties. Dosing varies according to route of administration, with 25-50 mg per day being a normal dose via ingestion, and up to 1500 mg per day, according to the Florida Department of Health (Rule 64-4.015). We highly recommend opting for high-grade full-spectrum CBD products with independent third-party lab testing to ensure efficacy. All in all, CBD is a great natural dietary supplement, and when used right, can be an excellent therapy for a wide variety of acute and chronic health and wellness issues.





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(13)        Jansen, A. S. P.; Van Nguyen, X.; Karpitskiy, V.; Mettenleiter, T. C.; Loewy, A. D. Central Command Neurons of the Sympathetic Nervous System: Basis of the Fight-or-Flight Response. Science (80-. ). 1995.

(14)        Hampson, A. J.; Grimaldi, M.; Axelrod, J.; Wink, D. Cannabidiol and (-) 9-Tetrahydrocannabinol Are Neuroprotective Antioxidants. Proc. Natl. Acad. Sci. 1998.

(15)        Campos, A. C.; Fogaça, M. V.; Scarante, F. F.; Joca, S. R. L.; Sales, A. J.; Gomes, F. V.; Sonego, A. B.; Rodrigues, N. S.; Galve-Roperh, I.; Guimarães, F. S. Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders. Frontiers in Pharmacology. 2017.


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