How does depression affect the endocannabinoid system

Doctors are far too liberal with anti-depressants that target serotonin when so few of them understand cannabis and especially the endocannabinoid system (ECS). Serotonin and the ECS are tied tightly together. In fact, serotonin deficient depression can cause a host of effects on the mind and immune system by disengaging the endocannabinoid system (ECS).

Connected with cannabinoids — and bacteria

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

The “happy” molecules in your brain interconnect through vastly underappreciated pathways. For example, the microbiome consists of a trillion creatures calling the inside of your body home. It’s a primary asset to both serotonin and the ECS.

A feedback exists between the endocannabinoid system, the CB1 recepto, serotonin, and gut bacteria
A feedback loop is maintained by cannabinoid receptors, gut bacteria, and serotonin receptors (5-HT receptors.) This feedback loop is both positively and negatively influenced by external factors which can greatly impact mental health. (Green arrows represent an agonist-like function, red arrows represent an inhibitor function, and the blue arrows with dotted-line represent a modulator-like function.)

Serotonin deficient system

A deficient serotonin system can cause episodes of mental distress, including major depression. Yet, we know serotonin receptors tie directly into the endocannabinoid system — a system predominantly primed to receive cannabis constituents.

Firstly, the endocannabinoid known as 2-AG, a biological workhorse, is partially driven by the serotonin receptor 5-HT2a. Secondly, AA-5-HT (Arachidonoyl serotonin) is a potent endocannabinoid built from serotonin. AA-5-HT largely helps regulate sleep and mood cycles by activating CB1 receptors. An almost love-child between arachidonic acid and serotonin, AA-5-HT also prevents the degradation of anandamide.

To ask what came first, the deficient serotonin receptor or the poor endocannabinoid tone is almost a case of the chicken or the eggYet, the answer might lead to long-term relief. For example, ECS health will be difficult to maintain if other mechanisms also drive down serotonin, including bad microbiome health and depression.

depression and endocannabinoid system
Serotonin helps promote the endocannabinoid, 2-AG, through the 5HT2a receptor. Low serotonin levels will cause a depletion of 2-AG. However, deficient CB2 receptors might be the true root cause behind an episode of depression through an interconnected loop of effects.

Endocannabinoid system health and depression

A solution to depression might be an endocannabinoid positive lifestyle and diet, rather than serotonin boosters. Mental health will return as your entire body shifts back into homeostasis, but we aren’t here to make promises. Deficiencies in serotonin and the ECS can be genetic or driven by uncontrolled factors that do require an exogenous therapeutic. Many doctors focus on SRIs, drugs that pick up serotonin, but this ignores that deeper connection to the ECS and the world we interact with.

Endocannabinoid deficiencies can lead to widespread health effects that reach far beyond depression, including pain and autoimmune complications. Depression caused by a depleted serotonin level can lead to many physiological issues secretly tied to the endocannabinoid system.

Let us know in the comments how you treat depression. And, check out this story to learn how THC functions as an endocannabinoid’s human half, a connection that ties into ADHD.


  1. Arnold, W.R., Carnevale, L.N., Xie, Z. et al. Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally 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). Lack of CB1 receptor activity impairs serotonergic negative feedback. Journal of neurochemistry109(3), 935–944.