How does depression affect the endocannabinoid system?

Doctors are way too generous with antidepressants that target serotonin when so few of them understand cannabis, and the endocannabinoid system (ECS) in particular. Serotonin and the ECS are closely related. In fact, serotonin-deficient depression can have a myriad of mind and immune system effects by disabling the endocannabinoid system (ECS).

Associated with cannabinoids – and bacteria

The ECS consists of messenger molecules and receptors as well as endogenous substances from the cannabis plant.

The “happy” molecules in your brain connect via pathways that are greatly underestimated. For example, the microbiome is made up of one trillion creatures that house the insides of your body. It’s a major benefit for both serotonin and the ECS.

A feedback loop is maintained by cannabinoid receptors, gut bacteria and serotonin receptors (5-HT receptors). This feedback loop is influenced both positively and negatively by external factors that can have a profound effect on mental health. (Green arrows represent an agonist-like function, red arrows represent an inhibitor function, and the blue arrows with a dashed line represent a modulator-like function.)

Serotonin Deficiency System

A deficient serotonin system can cause episodes of mental illness, including major depression. However, we do know that serotonin receptors bind directly to the endocannabinoid system – a system that is primarily prepared to ingest components of cannabis.

On the one hand, the endocannabinoid known as 2-AG, a biological workhorse, is partly driven by the serotonin receptor 5-HT2a. Second, AA-5-HT (Arachidonoyl Serotonin) is a powerful endocannabinoid made up of serotonin. AA-5-HT largely helps regulate the sleep and mood cycle by activating CB1 receptors. As an almost love child between arachidonic acid and serotonin, AA-5-HT also prevents the breakdown of anandamide.

To ask which came first, the deficient serotonin receptor or the poor endocannabinoid tone is almost a chicken or egg case. However, the answer could lead to long-term relief. For example, ECS health will be difficult to maintain if other mechanisms lower serotonin, including poor microbiome health and depression.

Serotonin helps promote the endocannabinoid 2-AG through the 5HT2a receptor. Low serotonin levels lead to 2-AG exhaustion. However, lack of CB2 receptors could be the real cause of a depression episode through an interconnected loop of action.

Endocannabinoid System Health and Depression

One solution to depression might be an endocannabinoid-positive lifestyle and diet rather than serotonin boosters. Mental health will return when your entire body shifts back into homeostasis, but we are not here to make promises. Serotonin and ECS deficiencies can be genetic or caused by uncontrolled factors that require an exogenous therapeutic. Many doctors focus on SRIs, drugs that absorb serotonin, but this ignores that deeper connection to the ECS and the world we interact with.

Endocannabinoid deficiency can lead to widespread health effects that go well beyond depression, including pain and autoimmune complications. Depression caused by depleted serotonin levels can lead to many physiological problems that are secretly linked to the endocannabinoid system.

Let us know how to treat depression in the comments. And check out this story to learn how THC works as the human half of an endocannabinoid, a compound linked to ADHD.

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1. Arnold, WR, Carnevale, LN, Xie, Z. et al. Anti-inflammatory endocannabinoid epoxides based on dopamine and serotonin mutually regulate cannabinoid receptors and the TRPV1 channel. Nat Commun 12, 926 (2021).
2. Aso, E., Renoir, T., Mengod, G., Ledent, C., Hamon, M., Maldonado, R., Lanfumey, L. & Valverde, O. (2009). A lack of CB1 receptor activity affects negative serotonergic feedback. Journal of Neurochemistry, 109 (3), 935-944.