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The mystery of the endocannabinoid system

Publications 6 May 2024 No Comments

There is a good chance that you have come across cannabinoids such as THC and CBD. You may have wondered how they affect the human body. In the following article I will try to investigate this issue. We will discover the components of the endocannabinoid system (ES) and its functions. We will also explore ways to stimulate and support ES as well as the benefits of doing so. But first things first. Let’s start with the basics.

Cannabinoid wiring we are born with

The endocannabinoid system is a complex cell-signaling network that helps regulate physiological processes. It is comprised of endogenous cannabinoids, cannabinoid receptors and the enzymes responsible for the synthesis and degradation of endocannabinoids. Let’s dive further into each component in the following sections.

Major compounds contained in cannabis

Cannabinoids are a class of biological compounds naturally found in a Cannabis sativa plant. They come in three forms – phytocannabinoids (including tetrahydrocannabinol, the main psychoactive ingredient in cannabis), endocannabinoids and synthetic cannabinoids. They affect the human body in many ways, with particular impact on the central nervous system. Cannabinoids differ in properties and biological effects. However, they have one common feature – they all impact on the human body by specific binding to the membranes of cannabinoid receptors.

How can these compounds affect our bodies?

Back in 1990 scientists discovered two types of receptors that specifically bind cannabinoids – CB1 and CB2. Stimulation of CB1 and CB2 results in inhibition of neurotransmitter release influencing the activity of compounds such as: acetylcholine, norepinephrine, dopamine, serotonin, glutamate and GABA. 

CB1 receptors are thought to be one of the most widely expressed receptors in the brain. They are found primarily within the limbic system, hippocampus, cerebral cortex, cerebellum, spinal cord and amygdala. They are also located in peripheral tissues e.g. adipose tissue, the gastrointestinal tract, muscles and the liver. The distribution of CB1 receptors results from respective biological effects of cannabinoids. For example, transient memory impairment after cannabis smoking is associated with binding to the receptors located in the hippocampus. On the other hand, basic motor impairment after the acute use of cannabis is caused by interaction with cannabinoid receptors in the cerebellum. Activation of brainstem and spinal cord receptors causes attenuation of pain perception. 

CB2, a second type of cannabinoid receptors, are mainly expressed in immune tissues. They can be found in organs such as spleen and tonsils, but also within cells e.g. B lymphocytes, macrophages, monocytes and NK cells. Activation of CB2 receptors results in reduction of inflammation and pain relief.

Cannabinoids that are essential for us

After the discovery of endocannabinoid receptors, scientists were searching for their endogenous agonists. Soon after, they discovered endocannabinoids – molecules synthesized in the human body with properties similar to cannabis plants. This group includes anandamide (an amide derivative of arachidonic acid) and 2-arachidonyl-glycerol. Endocannabinoids are derived from omega-6 fatty acids. They are synthesized from membrane phospholipids in the cell membrane of postsynaptic neurons. This reaction is catalyzed by phospholipase C. Endocannabinoids are degraded to arachidonic acid and ethanolamine by fatty acid hydrolase and monoglyceride lipase. They are part of an intercellular communication system similar to classic neurotransmitters. Endocannabinoids, unlike other neurotransmitters, have a lipid structure, which means they are non-water-soluble and cannot be stored in synaptic vesicles. Biosynthesis and release of these compounds is induced by depolarization and calcium ion influx rather than transmission of an electrical impulse along a neuron. They act as retrograde neurotransmitters by inhibiting the release of GABA, glutamic acid and norepinephrine.

What is the function of the endocannabinoid system?

The endocannabinoid system is involved in regulating many of our most critical body functions. It is responsible for maintaining homeostasis (the state of balance) by affecting the metabolism and nervous, endocrine and immune systems. It interacts with the endocrine system in regulating stress response and the hypothalamic-pituitary-peripheral gland axis. It is also involved in controlling metabolism, motor activity, mood, motivation and feelings of hunger or satiety. 

Scientists have found that stimulation of CB1 receptors affects energy balance through increased food intake. It has been found that hunger activates the endocannabinoid system, while food intake does the opposite. It has been shown that leptin (a satiety hormone released after eating) reduces the secretion of endogenous cannabinoids. The endocannabinoid system also regulates gastrointestinal function. Activation of cannabinoid receptors within the gut inhibits peristalsis and has an antiemetic effect. 

In addition, it has been proven that anandamide regulates learning and memory, but also food intake and sleep. Endocannabinoids in general have sedative and analgesic effects. They also show neuroprotective properties since they prevent neuronal cell death induced by glutamate. Furthermore, anandamide plays a different role – it participates in the process of embryo implantation in the uterus. At low concentration it can promote maintenance of pregnancy while at high concentration it can cause a miscarriage. As you can tell, a properly functioning endocannabinoid system is crucial for overall health.

Activation of this system can provide benefits

All components of the endocannabinoid system may be target points for drugs used for treating a wide range of medical conditions. Research is being conducted on the use of endocannabinoids in pain management, neurological diseases, immunosuppression or appetite regulation. 

Scientists have proven that obesity can result from chronic hyperactivity of the endocannabinoid system. There is ongoing study on the use of CB1 receptor antagonists (a drug called rimonabant) to treat this condition. It has been shown that rimonabant contributed to reduction in cravings and 5-10% weight loss in obese patients. At the end of the study, scientists observed waist circumference reduction and lowered cholesterol levels of participants. In addition, they noted an improvement in insulin resistance and glucose tolerance. 

Recent studies have shown the role of endocannabinoids in treating neurological diseases due to their neuroprotective properties. They have been proven to protect dopaminergic neurons from degradation and inhibit glutamine release. It is an approach for treatment of Parkinson’s disease. In addition, research is being conducted on the use of synthetic cannabinoids to treat stroke and post-traumatic nervous system damage. 

Cannabinoids are also used in treatment of pain caused by inflammation, cancer or neuropathy. In clinical studies patients with chronic cancer pain were administered biological compounds with ability to bind CB1 and CB2 receptors which resulted in pain relief. Cannabinoids are also used in palliative care due to their ability to alleviate nausea, vomiting, increase appetite and relieve pain. Additionally, they prevent excessive weight loss and cachexia, which are often associated with cancer. It has been shown that CB1 and CB2 agonists suppress tumorigenesis by altering physiological and biochemical state of cancer cells. They induce apoptosis, inhibit cell cycle and suppress angiogenesis, metastasis as well as tumor growth. 

Recent studies also suggested the cardioprotective effects of cannabinoids. Research is underway to investigate the use of cannabinoids in the prevention of atherosclerosis. Their effects on the cardiovascular system are not fully examined. Only a single administration of THC can cause tachycardia and increase in blood pressure. However, after multiple use of cannabinoids, we may observe reduction in heart rate and blood pressure. This effect is linked with inhibition of sympathetic nerves and activation of the parasympathetic nervous system.

Consider possible issues as well

As you can see in the examples above, endocannabinoids regulate several bodily functions. Because of their widespread use they are becoming more and more popular in the scientific world. However, you should keep in mind that these compounds are not indifferent to the human body and may be health-threatening. They interact in a non-specific way with the entire nervous system which may cause side effects. The most common ones are: dizziness, drowsiness, concentration problems or sleep and vision disturbances. There may also occur symptoms of psychiatric disorders such as hallucinations, psychosis and depression. This is crucial especially in the case of long term therapy, which increases the risk of side effects and addiction. 

So how can we take advantage of the health benefits of cannabinoids while limiting its side effects? Scientists are still trying to find a solution. One of the approaches is to apply compounds that will boost the effects of endogenous cannabinoids. Second approach involves using substances that prevent the degradation of natural anandamide. The goal is to obtain selective drugs that would be delivered topically and have fewer side effects. Hopefully, it will be accessible in the future.

How can we stimulate endocannabinoid release?

To some extent, we can stimulate the endocannabinoid system naturally. Research results proved that aerobic exercises such as cycling and running can increase anandamide levels in the brain. The boost of anandamide is thought to be the reason for “runner’s high” – a state of bliss after completing a workout. In addition to physical activity, a proper diet can stimulate the endocannabinoid system. Eating products rich in omega-6 fatty acids (such as vegetable oils and walnuts) will provide us with a precursor for the synthesis of endocannabinoids so that we can produce more of these substances. There are also certain nutrients with the ability to bind directly to CB1 and CB2 receptors. For example beta-caryophyllene acts as a full agonist of the CB2 receptor. It is a natural compound found in plants that gives them flavor and aroma. Beta-caryophyllene is present in spices such as cinnamon, rosemary, black pepper, hops, cloves and oregano. Another way to support our endocannabinoid system is by relieving stress and anxiety. This can be achieved by using relaxation techniques or practicing meditation and yoga. 

When our body is unable to produce enough endocannabinoids we can consider supplementation of plant cannabinoids such as THC, CBD or CBG found in hemp. Nowadays, you can find various products containing these compounds, such as oils, cosmetics or food. Before you decide to supplement, remember that a lot depends on our lifestyle choices. We should start with the basics – improve our diet and sleep hygiene, move our body on a daily basis and learn to manage stress. Only if these methods fail, should you consider visiting a specialist and together decide on supplementation.

Some final remarks

It has been proven that targeting the endocannabinoid system by means of pharmacology offers great therapeutic opportunities. Further research should be conducted to investigate the functioning of the endocannabinoid system and different ways to increase its activity. Overall, endocannabinoids seem to be promising therapeutic targets.

Categories: Publications

olga-szeidl

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