The endocannabinoid system, cannabinoids and brain health

Mass-market CBD sales are poised to reach $430 million by the year 2020, according to New Frontier Data. Is society ready?

One issue to overcome is the fundamental misunderstanding of the body’s own endocannabinoid system (ECS), and how non-psychoactive, non-euphoric cannabinoids can complement ECS’s productivity. Hemp plant cannabinoids are associated with a long list of health benefits;¹ however, consumers have historically made the mistake of confusing non-psychoactive CBD products with the euphoria associated with THC found in marijuana. Cannabinoids in the hemp plant are not addictive, habit-forming or psychoactive, according to the World Health Organization.

Cannabinoids from the hemp plant interact with the body’s ECS, an innate signaling system that performs different tasks in each part of the body. The goal of the ECS is always the same: maintain bodily homeostasis despite fluctuations in the external environment.² Since the discovery of the ECS in the late 1980s, research has shown it integral to normal physiology, including brain health, and it has been implicated in the pathology of neurodegenerative diseases and a number of neurological and neuropsychiatric conditions.^2,5,8,10,11 This opens new perspectives on hemp’s involvement in brain function.

The ECS consists of the cannabinoid receptors CB1 and CB2, endogenous cannabinoids (endocannabinoids) produced by the body, and the enzymes that synthesize and degrade the endocannabinoids.

The two major endocannabinoid molecules, anandamide (AEA) and 2-arichidonylglycerol (2-AG), activate the cannabinoid receptors that sit on the surface of cells throughout the body. Unlike classical neurotransmitters and neuropeptides, endocannabinoids are produced “on demand,” meaning they get made and used exactly when and where they’re needed rather than pre-made and saved for later use.²

AEA is a lipophilic (fat-friendly) compound whose name originates from the Sanskrit word ananda, which translates to “bliss” or “joy,” an indication of its ability to support emotional balance. AEA can bind to both CB1 and CB2 receptors but has a much greater affinity for CB1 receptors, which are abundant in the brain. AEA production is triggered by elevated intracellular Ca²⁺ concentration, indicating that this bliss compound is produced during moments of intense exercise. AEA crosses the blood-brain barrier and binds to cannabinoid receptors in the brain, yielding the infamous “runner’s high” felt during and after a workout.² The main enzyme responsible for degradation of AEA is FAAH (fatty acid amide hydrolase). Drugs targeting the FAAH enzyme have been extensively studied for the treatment of endocannabinoid-related disorders, such an anxiety, depression, inflammation and neuropathic pain.³

CB1 receptors are the most abundant receptors in the brain, especially the hippocampus and cerebellum,^4,5 but also are found in the olfactory bulbs, prefrontal cortex (mood), basal ganglia (motor), amygdala (emotions) and the brainstem (information transfer).^4,6 CB1 receptors are located on distinct types of axon terminals throughout the brain, including GABAergic and glutamatergic synapses, and cannabinoids can effectively modulate neurotransmission at inhibitory (GABA) and excitatory (glutamate) synapses.^4,7 In general, endocannabinoids serve as mediators in neuronal communication, which differs from synaptic and non-synaptic transmission in its range and function.⁴

CB2 receptors are most abundant peripherally in the circulating immune cells, the spleen, microglia in the central nervous system (CNS), and on macrophage-derived cells including osteocytes, osteoclasts and hepatic Kupffer cells.⁸ However, more than 70% of the total cell population in the brain is made up of immune cells and represents the first line of defense against inflammation and other insult, which means they have CB2 receptors associated with them.^8,9

Following situations of acute inflammation or injury, CB2 expression is highly inducible on immune cells in the CNS, and activating the CB2 receptor may be part of the active process of limiting or downregulating the acute inflammatory process.⁸ As a result, CB2 receptors have shown potential as a therapeutic target in diseases, including neuropathic pain and neurodegenerative conditions such as Alzheimer’s disease, where activation of the microglia and neuroinflammation are present.^8,10

It's very easy to throw the ECS out of balance. Stress levels, diet and exercise all influence the body’s ECS, and a modern lifestyle may be taking its toll on this natural system. Since homeostasis is always the ECS’s goal, legalization of hemp in many states has made it possible for people to more easily achieve a balanced state. There are more than 100 different plant cannabinoids, and each has a slightly different interaction with the CB1 and CB2 receptors throughout the body. A growing number of people are using cannabinoids (i.e. CBD) as a way to support mental and emotional brain-related conditions.^2,5,8,10,11

The number of CBD products available for purchase on the market seems to increase daily. At this point, it’s like the Wild West as far as quality, testing, regulations and standards, making it very confusing for consumers. It’s important to educate the marketplace on priorities to consider when purchasing or manufacturing a CBD product. Here are five things to consider when purchasing, manufacturing or marketing a CBD product:

Supplementing the body’s own supply of cannabinoids with hemp-based compounds supports the ECS’s duty to maintain homeostasis and, more specifically, supports brain health. The exact role of the ECS within the brain is complex, and future research will hopefully shed light on its involvement in normal brain operations and disease mechanisms that are poorly understood, like schizophrenia, anxiety, and brain diseases characterized by cognitive impairment and neurological defects, such as Alzheimer’s, Huntington’s and Parkinson’s diseases.

To read related content, check out the “Hemp/CBD: Market evolution” digital magazine.

Kelly Harrington is the Registered Dietitian Nutritionist (RDN) for Healthy Goods, and has a master’s degree in human nutrition. She is a holistically minded expert with more than 20 years of experience in a variety of nutrition fields. She follows an intuitive eating and functional nutrition approach to addressing individual health and nutrition needs.

References

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2 De Laurentiis A, Araujo HA, Rettori V. “Role of the endocannabinoid system in the neuroendocrine responses to inflammation.” Curr Pharm Des. 2014;20(29):4697-4706.

3 Ahn K et al. “Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders.” Expert Opin Drug Discov. 2009;4(7):763-784.

4 Freund TF, Katona I, Piomelli D. “Role of endogenous cannabinoids in synaptic signaling.” Physiol Rev. 2003;83(3):1017-1066.

5 Hampson RE, Deadwyler SA. “Cannabinoids, hippocampal function and memory.” Life Sci. 1999;65:715–723.

6 Mackie K. “Distribution of cannabinoid receptors in the central and peripheral nervous system.” Handb Exp Pharmacol. 2005;(168):299-325.

7 Howlett AC et al. “Classification of cannabinoid receptors.” Pharmacol. Rev. 2002;54:161-202.

8 Bihua B et al. “An overview of the cannabinoid type 2 (CB2) receptor system and its therapeutic potential.” Curr Opin Anaesthesiol. 2018;31(4)407-414.

9 Romero-Sandoval EA, Horvath RJ, Deleo JA. “Neuroimmune interactions and pain: Focus on glial-modulating targets.” Curr Opin Investig Drugs. 2008;9:726.

10 Onaivi ES et al. “Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects.” PLoS One. 2008;3(2):e1640

11 Basavarajappa BS et al. “Endocannabinoid system in neurodegenerative disorders.” J Neurochem. 2017;142(5):624-648.