The Brain’s Critically Important Natural Cannabinoid System

What does our brain’s THC-like chemistry do?

Posted May 26, 2020

In 1973, scientists first discovered brain receptors activated by morphine and called them “opiate receptors." People naturally wondered why evolution created receptors capable of creating heroin addicts. It took only another two years before the question was answered when small protein molecules were found in the brain that also activate the opiate receptors. The word “endogenous," meaning originating within the brain, was combined with the word “morphine” to create what has become the commonplace word “endorphin."

Precisely the same blueprint was repeated with cannabis research. Receptors activated by THC were discovered in 1988. Cannabinoid receptors are long proteins that fold in upon themselves many times found in the outer membranes of nerve cells. When the portion of these receptors sticking outside the cell is activated by a molecule capable of slipping into it like a key into a lock, activity inside the cell is altered. 

Endogenous molecules activating these cannabinoid receptors began being discovered in 1992. Following the tradition of contracting “endogenous” and “morphine," the word “endocannabinoid” was coined. I believe the general public will eventually talk as blithely of endocannabinoids as they do today about getting an endorphin high. 

The first endocannabinoid isolated and having its structure analyzed was named anandamide—Sanskrit for bliss. The second was more prosaically named 2-AG. Both activate two slightly different cannabinoid receptors, CB1 found mostly in the brain and CB2 throughout the body, especially in the immune system and the gut. 

Packed in our chromosomes is the DNA code for producing all the components of the “endocannabinoid system” (ECS)—endocannabinoid neurotransmitters, enzymes to synthesize and metabolize them, and neuroreceptors. The question can now be addressed, “Why?” What is the function of the ECS? How does it serve normal brain function?

The answer lies in two opposing actions—maintaining chemical balance within the brain and providing mental and physiologic flexibility.   

Chemical Balance in the Brain

Biologic organisms need a relatively stable internal environment, a concept called homeostasis. For example, our bodies can function within only a very narrow range of internal temperature. We sweat when our core temperature begins to rise and the sweat’s evaporation cools us. We shiver when we get too cold and the muscle action warms us. Two opposing forces act to maintain optimal temperature—homeostasis.

Our ECS acts in a similar way to put both a ceiling and a floor on the activity level of other neurotransmitters, including serotonin, dopamine, GABA, and glutamate, to name a few. The ECS accomplishes this function by virtue of the unique positioning of CB1 receptors.

Most neurotransmitters travel downstream. They are released when a neuron fires and travel across a minute gap to activate their receptors on the next downstream neurons to stimulate or inhibit its activity. The ECS comes into play only after a typical neurotransmitter such as serotonin or dopamine activates its receptors. At that point, anandamide and 2-AG are synthesized out of fatty molecules in the downstream neuron’s outer membrane. These newly synthesized endocannabinoids then travel retrograde, back across the gap to activate CB1 receptors on the upstream neuron. When CB1 receptors are activated, the upstream neuron releases less of its characteristic neurotransmitter with each firing. 

The result is a perfect rheostat. The more active a typical neuron becomes, the more neurotransmitter is released and the more negative feedback from the ECS is produced, thereby quelling further neurotransmitter release from the upstream neuron. The less active, the less inhibitory negative feedback, making the ECS the master neurotransmitter system. The ECS’ function is to regulate the rest of brain chemistry. 

When THC activates CB1 receptors, the normally transient negative feedback by the ECS becomes more profound and longer-lasting. The result is reduced activity of multiple neurotransmitter systems in multiple areas of the brain. We call this “getting high” and is enjoyed by many people for four hours when cannabis is inhaled and up to 8 hours when ingested orally.


As explained in the previous post, THC’s activation of CB1 receptors in the hippocampus is well known to reduce short term memory. This suggests that the ECS is capable of modifying memory and learning. 

We can easily see that different lengths of short term memory are likely to optimize performance on different tasks. For example, when I want to write down a phone number but cannot find a pencil, it is useful for my short term memory to last a good period of time. However, when I am running a fast break during a basketball game, still thinking about what happened a few seconds ago at the other end of the court is not useful. Short term memory is best kept very short in this situation. Flexibility in a wide variety of mental functions is beneficial and a sign of health.

An interesting experiment demonstrated how good health requires the flexibility that is based on a functioning ECS. Scientists manipulated the genetic code in mice to eliminate CB1 receptors. The mice had no working endocannabinoid system. They appeared grossly normal, though they had less motor activity in general and specifically less exploratory activity. However, their lifespan was significantly shortened. Their increased mortality rate was not from any specific cause. They died from the same illnesses as normal mice, just earlier. 

Researchers interpreted this increased rate of mortality in CB1 knockout mice as due to physiologic rigidity. They lacked the flexibility provided by a functioning ECS to respond to different stresses with different, modulated physiologic responses.


An intact, well-functioning, and balanced endocannabinoid system is necessary for a healthy, optimally working brain. Intermittent use of cannabis alters brain chemistry only temporarily, apparently without lingering consequences. The fly in the ointment, however, lies in the meaning of “intermittent." This critical point will be explored in a later post when the concept of healing from addiction will become important. The more we understand the interaction between bud and brain, the safer and more effectively cannabis can be used.