Lex Pelger's Endocannabinoid System & Cannabinoids #2: The CB1 Receptor

Lex Pelger's Endocannabinoid System & Cannabinoids #2:  The CB1 Receptor 

As its discoverer Dr. Raphael Mechoulam said, “The endocannabinoid system acts essentially in just about every physiological system that people have looked into… Actually, the cannabinoid receptors are found in higher concentrations than any other receptor in the brain, and they are found in very specific areas. They are not found all over, but rather in those places that one would expect them to be—such as areas that have to do with the coordination of movement, emotions, memory, reduction of pain, reward systems, and reproduction. So, I believe that this is a very central and essential system that works together and communicates with many other systems.”

And as the story goes, when the discoverer of the CB1 receptor, Dr. Allyn Howlett, first glimpsed the distribution pattern left by the radioactive cannabinoid probes, she saw a section of pig’s brain so lit up that she assumed the probe must be unselective and binding all over the place. But further work only confirmed that this first cannabinoid receptor is heavily found in many of the higher parts of the brain - but in none of the lower regions associated with breathing that could lead to overdoses. The wide distribution of CB1 in any organism with a spinal column and the unique pattern of receptors seen in humans finally helped researchers to understand the huge variety of reactions of people stoned on grass.

As you can see from this chart, perhaps the best single work diagramming the relationship between all the psychoactives, cannabis rests directly in the middle. It should surprise few that in different people and at different times, cannabis can act as an antipsychotic, a stimulant, a depressant and/or a psychedelic. In fact, if this chart was three dimensional, the old hemp plant would be floating above the page.

We’ll concentrate on the physiological aspects here because the mental effects are better learned from the stoner literature than the peer-reviewed research.

The density of CB1 receptors in the hippocampus is a double edged sword. It means that smoking a joint before a movie will make one less able to remember the plot - but when addressing PTSD, the greatest gift is forgetting. Research shows that CB1 is necessary to extinguish traumatic memories, "Mice lacking CB1 receptors show strongly impaired extinction but unaffected acquisition and consolidation of aversive memories. These effects are associated with elevated levels of endocannabinoids in the basolateral amygdala [25], and suggest that endocannabinoids are crucial for the extinction of aversive memories."

The CB1 receptors present in the basal ganglia explains the worsening of motor control exhibited with the use of marijuana - this is especially true with novice users. That’s why newbie stoners really should not be driving cars. That being said, tolerance to motor effects is one of the first to develop, so when an old head says that it doesn’t affect his or her driving- it’s probably true.

In the spinal cord, CB1 receptors help to modulate the pain signals coming in from the rest of the body. Known technically as nociceptive fibers, these ascending pain pathways relay the signal of painful stimuli from the body and up the spinal cord to the brain. Not only does activation of the CB1 receptor dampen the transmission of pain signals, it also lessens the activation in higher levels of the brain like the thalamus and the cortex where the pain is processed.

It’s in the hypothalamus that CB1 receptors regulate feeding, and in the substantia nigra they relate to addiction. Then, in the amygdala, CB1 receptors are responsible for fear and stress response. CB1 receptors have particularly pronounced presence in the cerebral cortex, the highest part of our brains where there’s control of decision making, emotions and cognition.

When THC was originally tested on thousands of (mostly) college students in research studies, the data- taken as a whole- was confusing and difficult to decipher. Depending on the conditions and the participants, the researchers were consistently confronted with a confounding opposite in every trial group. The widespread presence of CB1 receptors in the brain, with such multiplicity of actions and interactions, has been a biochemical puzzle of such complexity that we just now begin to grasp the previously incomprehensible mass of apparently contradictory evidence found in the 70’s and 80’s. 

Now, let’s take a look at the mechanisms by which CB1 has a regulatory influence on so many varied functions. 

In a further revolution of scientific understanding, researchers found that the CB1 receptors of the endocannabinoid system mediate retrograde transmission. To understand the immensity of this in neuronal history, remember the canonical story of the brain: a neuron shoots an electrical signal to the end of its dendrites, calling for the release of neurotransmitters that seep across the synaptic cleft to the next neuron and pass the message downstream. 

In retrograde signaling, a phenomenon so new that it wasn’t defined until Regehr et al proposed criteria in 2009, the neurotransmitter reverses the flow of information. Via the CB1 receptor, anandamide and 2-AG - the first discovered endocannabinoids - return back across the synaptic cleft and tell the upstream neuron passing the message to relax. It’s a communication system for calming the brain that has only recently been identified. It’s part of what has led some scientists to refer to the endocannabinoid system as a system of homeostasis - of balance.

This control system allows cannabinoids to modulate the release of important neurotransmitters like dopamine, glutamate, acetylcholine, adrenaline, GABA and more. The CB1 receptors apparently form dimer complexes with dopamine and opioid receptors - a finding so new and strange that the functional implications are still in the early moments of contemplation and investigation in the research community. 

In mice engineered to have no CB1 receptors, there is a negative impact on social performance, they’re more aggressive, they eat, explore and copulate less, their hearts pump more, and they die younger. 

Besides being present in the brain and nervous system, CB1 receptors are widely distributed in the body. In Howlett & Pertwee’s thorough receptor review, research indicates the presence of CB1 receptors in the adrenal gland, bone marrow, heart, lung, prostate, testis, thymus, tonsils, and spleen. There are also a large number of CB1 receptors in our olfactory bulbs, but the sense of smell is so frighteningly complex that the implications have yet to be meaningfully explored. We do know that the olfactory bulb is directly connected to two brain areas that are strongly implicated in emotion and memory- the amygdala and hippocampus- and both regions are flush with CB1 receptors as well. 

In addition, the relationship between the hormone-pituitary axis and cannabinoids are so overwhelming that we’ll devote a coming article to that topic alone.

In the liver, activating CB1 receptors increases the formation of lipids. In fat cells, that activation causes resistance to insulin signals and can help diabetics control the surge and crash of their blood sugar levels. In the muscle, it increases glucose uptake. This suggests that CB1 plays an important role in the body’s management of fuel and energy metabolism.  

The gastrointestinal tract is also host to CB1 receptors, and studies indicate that inflammation of the gut up-regulates CB1 expression, reduces intestinal inflammation, and regulates intestinal motility. These features impact not only GI conditions directly, but also strongly impact the genesis of autoimmune conditions, which are associated with the leaky gut that accompanies intestinal inflammation.  With regard to CB1 in the gastrointestinal tract, blocking the receptor leads to less eating, suggesting a role of intestinal inflammation and the resulting up-regulation of the CB1 receptor in overeating. (The pharmaceutical drug rimonabant was marketed as a weight loss drug for just such a reason - until it turned out that blocking the CB1 receptor in otherwise healthy humans causes them to commit suicide at significantly higher rates).

According to Dr. Marzo himself, one of the great scientific chroniclers of the widespread endocannabinoid system, its purpose here in the body is to help one “relax, eat, sleep, forget and protect.”

Lex