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The Endocannabinoid System and Addiction

Drawing of the chemical structure of the molecule Cannabidiol-C4.

Endocannabinoids (eCBs) are neurotransmitters found naturally in the human body. The endocannabinoid system (ECS) is a “vast network of chemical signals and cellular receptors,” densely packed throughout the brain and body.

The ECS regulates a great many functions, turning them on or off, turning them up or down, including such basics as body temperature, appetite, attention, immune responses, inflammatory responses, learning, memory, and sleeping.

A description of the ECS from Harvard Health Publishing calls eCBs the brain’s “traffic cops,” regulating levels of the other neurotransmitters throughout the brain. CB1 receptors in the brain generate a euphoric response when stimulated. eCB molecules are structurally similar to cannabis molecules, and THC stimulates eCB receptors, generating the euphoric feeling associated with the drug.

There are also cannabinoid receptors in the gut. Known as CB2 receptors, they are important to the immune system, inflammation, and inflammatory bowel syndrome (IBS). Harvard Health Publishing says:

CB2 receptors are particularly exciting targets of drug development because they don’t cause the high associated with cannabis that stimulating the CB1 receptors does.

Stimulation of the ECS increases appetite. That’s why people who smoke marijuana get “the munchies.” This led drug developers to try blocking CB1 receptors to generate weight loss. This in fact worked. The drug rimonabant blocked CB1 receptors, resulting in weight loss. However, the ECS also regulates mood, and when users of the drug became suicidal, it was withdrawn from the market.

Research on the ECS has never stopped, and there are a variety of interesting studies underway on manipulating the ECS to treat substance use disorders (SUDs) and post-traumatic stress disorder (PTSD).

The work on PTSD, says Harvard Health Publishing, has been stimulated in part by the writings of Michael Pollan on the 5,000-year history of marijuana cultivation. Pollan hypothesizes a connection between stimulating the ECS and forgetting. Research bears out that THC impairs short-term memory formation. The theory is that eCB therapy can diminish memories of traumatic events, giving some peace to PTSD sufferers.

Meanwhile, according to researchers in Spain,

The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction.

The ECS is involved in the “development of compulsion,” say researchers, as well as the “loss of behavioral control” that comes with drug addiction. A review of the literature on the role of the ECS in reward processing and addiction found:

In conclusion, pharmacological blockade of endocannabinoid signaling should lead to a reduction in drug craving and subsequently should reduce relapse behavior in addicted individuals.

Once again, the problem with a “pharmacological blockade” of CB1 receptors is it also causes suicidal ideation. Researchers are again looking for a way around this problem by targeting CB2 receptors in the gut. “Cannabidiol, which mainly acts on CB1 and CB2 receptors, is currently being tested in patients with alcohol use disorder and opioid use disorder.”

Just last week, the University of California UC Riverside School of Medicine announced a grant from the Brain and Behavior Research Foundation for research into the ECS and cocaine addiction. There are no approved drugs for the treatment of amphetamine use disorders, including cocaine and meth addictions. Dr. Natalie Zlebnik will be going back to those CB1 receptors, looking for a way to reduce relapse risk. We wish her every success.

Written by Steve O’Keefe. First published January 22, 2025.

Sources:

“The endocannabinoid system: Essential and mysterious,” Harvard Health Publishing, August 11, 2021.

“Targeting the Endocannabinoid System in the Treatment of Posttraumatic Stress Disorder: A Promising Case of Preclinical-Clinical Translation?,” Biological Psychiatry, February 1, 2022.

“Cannabinoids and the endocannabinoid system in reward processing and addiction: from mechanisms to interventions,” Dialogues in Clinical Neuroscience, April 1, 2022.

“Role of the endocannabinoid system in drug addiction,” Biochemical Pharmacology, November 2018.

“Biomedical scientist to investigate endocannabinoids as potential treatment for cocaine addiction relapse,” Inside UCR, January 13, 2025.

Image courtesy of Wikimedia Commons, used under Creative Commons license.

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