The Endocannabinoid System: A Deeper Look

The Endocannabinoid System: A Deeper Look

Cannabinoid receptors and their natural ligands were first discovered in the human body during research on how cannabis induces its euphoric effects.  Since then, further research has brought into focus a widespread system involved in restoring homeostasis (normality) after pathologic insult (disease). Called the endocannabinoid system, it operates alongside the nervous, immune, and cardiovascular systems (among others) to keep us healthy.  

All of these systems function by secreting molecules from one group of cells, through bodily fluids, to receptors on another group of cells downstream. These receptors, in turn, switch on a specific response, such as nerve transmission or an immune attack on an invading organism, for example.

For working order to be maintained in our bodies, however, the stimulation of these receptors must be balanced by mechanisms that put on the brakes. The inadequate inhibition of stimulatory responses is present in such diseases as seizures, muscle spasms, auto-immune diseases, and even over-exuberant immune reactions to influenza or COVID-19. 

The endocannabinoid system is a modulatory system, which in the nervous system runs in the opposite direction of neurotransmitter-mediated nerve pulses to prevent overstimulation. When we are stressed, the number of cannabinoid receptors in our bodies actually increases, augmenting their effect. If the secretory cells can manufacture enough of an endocannabinoid, such as  anandamide, to bind to these receptors, then they can dampen over-active responses in the system.  Supplementing the internal endocannabinoids, then, might conceivably help to restore the system to homeostasis.

Interestingly, this modulation of nerve conduction can result in psychotropic effects––such as the 'runner’s high' or the euphoria associated with the use of THC––which might ordinarily be considered stimulatory responses.  Although the mechanism of these phenomena is not fully understood, it could be that moving into a more balanced state from the stress of modern life is naturally associated with feelings of pleasure. 

That the endocannabinoid system is modulatory and not directly responsible for stimulating effects is the reason that exocannabinoids such as CBD and even THC are so safe.  Even at very high doses, the side effects are not life-threatening (acute overdose does not occur) and few tissues seem to be damaged from chronic administration.

Though CBD produces none of the psychotropic effects associated with THC, it appears to be able to modify the effects of THC.  For instance, THC reliably produces reductions in anxiety at low doses and increases in higher doses, but coadministration of CBD with THC eliminates the anxiety experienced at higher doses.  On its own, CBD shows some evidence of anxiety reduction.  Cognition deficits associated with THC use appear to be ameliorated by coadministration of CBD.  THC has analgesic (pain-relieving) qualities which may be enhanced by coadministration of CBD.


Busquet-Garcia A et al CB1 signaling in the brain Neuropsychopharmacology Reviews 2018 43:4-20.

Boggs DL et al  CBD and THC Neuropsychopharmacology Reviews 2018 43:142-154.