The role of endocannabinoids is to maintain an exquisite balance of neurotransmitter levels, on one hand preventing excessive release & potential excitotoxicity while on the other hand ensuring adequate levels for optimal signaling

From “Azalla” to Anandamide: Distilling the Therapeutic Potential of Cannabinoids. Rajiv Radhakrishnan, David A. Ross. Biological Psychiatry, Volume 83, Issue 2, 15 January 2018, Pages e27–e29. https://doi.org/10.1016/j.biopsych.2017.11.017. Refers to Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety, by Gaurav Bedse, Nolan D. Hartley, Emily Neale, Andrew D. Gaulden, Toni A. Patrick, Philip J. Kingsley, Md. Jashim Uddin, Niels Plath, Lawrence J. Marnett, Sachin Patel. Biological Psychiatry, Volume 82, Issue 7, 1 October 2017, Pages 488-499

Rolf Dagen's commentary: The brain's natural marihuana hold a key position in the brain, commanding different unique channels, keeping the system in the so-called Goldilocks zone. https://twitter.com/DegenRolf/status/940099167468208129

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What has emerged from these initial discoveries is one of the most fascinating stories in modern neuroscience: as it turns out, the endocannabinoid system is a unique regulatory neurotransmitter system, defying many properties of conventional neurotransmitters (6). First, unlike other neurotransmitters (e.g., serotonin, dopamine, acetylcholine), endocannabinoids are not stored in vesicles—rather, they are synthesized on demand. A second fascinating detail is that they are produced and released from the postsynaptic terminal (generally in response to the activation of other receptors, such as metabotropic glutamate receptor 1 or metabotropic glutamate receptor 5). Once released, they then diffuse into the synaptic cleft and act on the cannabinoid receptor on the presynaptic terminal to inhibit the further release of neurotransmitters (Figure 1). This process is known as retrograde signaling: a signal sent from the postsynaptic terminal to the presynaptic terminal, in this case acting as an inhibitory “brake” on the action of the neurotransmitter.

Retrograde signaling has been noted for only a few other neurotransmitters (e.g., nitric oxide and dynorphin). A third unique aspect of endocannabinoids is that they exhibit a property known as the entourage effect: their activity can be enhanced by structurally related, but otherwise biologically inactive, endogenous constituents [a property shared by other lipid mediators (7)]. A final property of the endocannabinoid system that is worth highlighting is that activation of the CB1R can have biphasic effects, which is to say that different levels of stimulation can lead to opposite types of outcomes. For example, low-dose stimulation of CB1R can have an anxiolytic effect, whereas high-dose stimulation may be ineffective or even anxiogenic.

The role of endocannabinoids is thus to maintain an exquisite balance of neurotransmitter levels, on one hand preventing excessive release and potential excitotoxicity while on the other hand ensuring adequate levels for optimal signaling. Effectively, they help keep neurotransmitter levels in the synapse in the so-called Goldilocks zone where the balance is “just right.” It is therefore not surprising that the endocannabinoid system is emerging as a significant player in the modulation of many physiological processes, ranging from pain sensation and autonomic system tone to the regulation of intrauterine development, appetite, mood, cognition, and anxiety. Given this wide role across physiological functions, it is not surprising that therapeutic uses have begun emerging for a range of medical conditions.