The Endocannabinoid System: Medical Marijuana for Pain and Mood Disorders

Many people wonder why medical marijuana is able to treat such a wide variety of health conditions. They wonder if cannabis is truly some kind of miracle plant, or if it is all just the latest health trend. The answer to this would have to be that medical marijuana is a little bit of both. Any health treatment has its limits, and there is no magic remedy that works for every person. In order to understand how medical cannabis works and why it doesn’t work for everyone, you need to understand a lesser-known body system called the “endocannabinoid system.”

Cannabinoid Receptor 1 (CB1) was discovered in the 1960s [2]. This cannabinoid receptor is located primarily in brain tissue. Cannabinoid Receptor 2 (CB2) was later discovered in the immune system. The discovery of these cannabinoid receptors also led scientists to find the compounds that bind to them (“ligands”). These “endocannabinoids” that the body naturally produces are 2-arachidonoylglycerol (2-AG) and anandamide. The body also produces compounds to inactivate endocannabinoids. These are the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Altogether, this system of receptors, ligands, and enzymes is known as the endocannabinoid system.

What is the Endocannabinoid System?

The endocannabinoid system is complex because it overlaps with a number of other body systems and metabolic processes [2]. In addition to cannabinoid receptors, there are also other biochemical signaling systems that allow the endocannabinoid system to indirectly act on other parts of the body. Here are just a few of the biological processes that the endocannabinoid system is involved with:

• Homeostasis
• Reward and habit formation
• Cognition
• Nervous system
• Serotonin balance
• Pain sensing
• Immune response
• Inflammation response

While CB1 is most concentrated in the brain and nervous system, CB2 receptors are most abundant in the organs and immune system [2]. While cannabinoid receptors are the most well-known targets of cannabinoids, there are also a number of “vanilloid” receptors (TVRPs), “metabotropic” receptors (GRPs), and other receptors that the endocannabinoid system can also act on.

CB1 Distribution in the Body

• Brain
• Cardiovascular System
• Lungs
• Muscles
• Gastrointestinal Tract
• Reproductive System
• Immune System
• Liver
• Bone Marrow
• Pancreas

CB2 Distribution in the Body

• Immune System
• Bones
• Spleen
• Skin
• Liver
• Bone Marrow
• Pancreas

Phytocannabinoids vs Endocannabinoids

Phytocannabinoids like cannabidiol (CBD) and tetrahydrocannabinol (THC) affect our bodies because they share a similar structure to endocannabinoids. The main difference is that phytocannabinoids are produced by plants and endocannabinoids are produced by most mammals. The goal of medical cannabis is to supplement the body with extra cannabinoids to help balance the endocannabinoid system, or harness that system to counteract diseases and disorders. Some physicians and scientists believe that an endocannabinoid deficiency can contribute to conditions such as fibromyalgia, irritable bowel syndrome (IBS), migraine, and neurodegenerative disorders [1].

Treating Pain Through the Endocannabinoid System

Through studying the use of acetaminophen, researchers have learned that CB1 stimulation mediates analgesic (pain relieving) effects [2]. However, CB1 is activated by THC which can have adverse effects that make it impractical or intolerable to some pain patients. That is why medical marijuana protocols typically start by using CBD products that act on CB2.

CB1 Activation

• Activated by THC
• Psychoactivity
• Pain relief via the central nervous system
• Can cause adverse effects like memory impairment, headache, numbness, cough, burning sensation, dizziness, feeling high, somnolence, and dry eyes and mouth

CB2 Activation

• Activated by the terpene beta-caryophyllene and weaker activation by CBD
• Non-psychoactive
• Pain relief via multiple pathways (peripheral nervous system, immune system)
• Mild and less common adverse effects such as stomach discomfort and diarrhea

Treating Mood Disorders Through the Endocannabinoid System

“Genetic polymorphisms” are changes to DNA that produce variations. An example of this is blood type. These variations also occur in cannabinoid receptors. Researchers have found that major depression, bipolar disorder, and resistance to therapy may be linked to polymorphisms in cannabinoid receptors, especially in CB1 [2]. Along with balancing this genetic predisposition, cannabinoids also impact our serotonin signaling system. That is why medical marijuana is a useful treatment option for mood disorders as well as pain and neurodegenerative conditions.

5-HT Serotonin Signaling System

• Cannabinoids activate serotonin 2A receptors (5-HT2AR)
• This influences memory but also can impart anti-anxiety effects
• Cannabinoids can have benefits to mood but can also potentially make mood disorders worse

Many people are interested in cannabis for its calming effects that can ease anxiety and promote sleep. However, some individuals experience quite the opposite: paranoia, irritation, dysphoria, depression, depersonalization, and demotivation. Cannabis affects individuals very differently because everyone has a uniquely tuned endocannabinoid system. In addition to an individual’s unique endocannabinoid levels, the dosage, formulation, and type of cannabis product used can all influence how a person will react to cannabis products. This makes it especially important to see a medical marijuana doctor if you are interested in using cannabis to treat a health condition.

The Endocannabinoid System and Medical Marijuana

Overall, the endocannabinoid system plays a surprisingly significant role in regulating things like stress response and urges for addictions in addition to regulating mood. However, patients with such disorders may not have an objective view of their condition which gives clinical practitioners hesitation to recommend a substance that could also have adverse effects. That is why it is especially important for a physician to guide a patient through a medical cannabis protocol when treating mood disorders.

References

1. Rezende, B., Alencar, A. K. N., de Bem, G. F., Fontes-Dantas, F. L., & Montes, G. C. (2023). Endocannabinoid System: Chemical Characteristics and Biological Activity. Pharmaceuticals, 16(2), 148.

https://www.mdpi.com/1424-8247/16/2/148

2. Siracusa, L., Ruberto, G., & Cristino, L. (2023). Recent Research on Cannabis sativa L.: Phytochemistry, New Matrices, Cultivation Techniques, and Recent Updates on Its Brain-Related Effects (2018–2023). Molecules, 28(8), 3387.

https://www.mdpi.com/1420-3049/28/8/3387