The cannabis plant has two primary cannabinoids, THC and CBD (or cannabidiol). These substances are becoming more and more well known, but what surprises many people is that humans have receptors in our bodies and brains that are specifically receptive to cannabinoids. These are called CB receptors (cannabinoid receptors).
Even more surprising is that we can produce our own cannabinoids in our bodies without consuming any cannabis at all. Cannabis becomes useful when we want to increase a certain mechanism by feeding a cannabinoid receptor with more cannabinoids.
How do we know we make our own cannabinoids? For a long time, endorphins were believed to be the home-brewed opiates responsible for the feeling known as a “runner’s high” since elevated levels were observed in the bloodstream after intensive jogs. What they didn’t consider back then is that endorphins are made up of rather large molecules that don’t cross the blood-brain barrier. They were in the bloodstream, yes, effectively at work in reducing pain in the body, but they were not the ones responsible for that peaceful state of mind.
So what gives a person a runner’s high? Almost too coincidentally, turns out it is the same stuff that can actually get you high. A 2003 study published in the Journal of Neuroreport examined male college students running on a treadmill or cycling on a stationary bike for 50 minutes. They found the first evidence that exercise activates the endocannabinoid system.
Cannabinoid receptors are a part of this system, and they’re located throughout the body, including the brain. Their main function is to regulate physiological processes like appetite, mood, pain and memory.
Research History of CB Receptors
Who was the true discoverer?
Cannabis has an ancient history dating all the way back to 8,000 BCE, but it wasn’t until recently in the 20th century that we actually discovered these cannabinoid receptors. Most sources will tell you that THC was first isolated in 1964 by Raphael Mechoulam, Yechiel Gaoni, and Habib Edery from the Weizmann Institute of Science. With further investigation, however, an article published in the British Journal of Pharmacology as well as an article on Cannabis Digest’s site (“Setting the Record Straight”) reveal to us that the timeline is a little different.
THC was apparently already being experimented on for its potential as a truth serum in World War II and the Cold War era. So, as it turns out, while Mechoulam and his colleagues were first to synthesize THC, THC had already been extracted as early as 1942 by Wollner, Matchett, Levine and Loewe. This was all just the beginning for cannabis research.
What changed the consensus on how THC works?
Here is a little preliminary chemistry. The way many things work in our bodies on a microscopic scale is according to chemical shape. Many drugs are made by creating chemical shapes (like a key) that will fit into specific receptors in your body (the lock).
Initially, there was hot debate over whether receptors for cannabinoids existed. It seemed intuitive, though, partly because the effects of psychotropic cannabinoids seemed to be largely influenced by their chemical structure.
Yet other researchers thought that THC worked by being hydrophobic enough to interact with cell membrane lipids; in other words, they thought it interacted simply with our body’s cells. Ultimately, this was shown to be false, and that gave scientists cause to inquire about just how THC functioned in the body. They began the search for receptors.
The First Cannabinoid Receptors Found and Identified
What finally settled the question of CB receptors was the work of Allyn Howlett in his St. Louis University lab in the mid 80s. He discovered that psychotropic cannabinoids had in common an ability to inhibit adenylate cyclase by acting through Gi/o proteins.
Then, in collaboration with Bill Devane in 1988, Howlett conducted experiments with radio labeled CP55940, and the first of these receptors was identified: CB1. Not long after, cloning of such receptors began in 1990 and well into 1993, when CB2, the other cannabinoid receptor, was successfully cloned. Research since then has focussed their location and exactly what turns them on or off.
Where Are They?
Most cannabinoid receptors are located in the brain. According to information from Medical News: Life Sciences and Medicine, CB2 receptors are found mostly on white blood cells and in the spleen while CB1 receptors can be found on nerve cells abundantly in parts of the brain such as the cerebellum, basal ganglia, hippocampus and dorsal primary afferent spinal cord regions. These receptors spread throughout the body are referred to collectively as the endocannabinoid system, which we mentioned earlier.
It is because of the specific locations of the cannabinoid receptors that we observe specific effects from cannabinoids. For example, one study illustrates how THC can create an immunosuppressant response by reacting with CB2 receptors. Additionally, since the cerebellum is primarily responsible for smooth motor function and movement, when THC binds to receptors in that area, motility can be affected.
How THC Affects Receptors
THC can both activate and deactivate receptors, as another article published in the British Journal of Pharmacology points out. The efficacy of THC on a cannabinoid receptor can sometimes depend on the density and activation efficacy, or receptiveness, of the cannabinoid receptor itself. But this receptiveness varies greatly within the brain’s receptors.
According to the article, THC has relatively low cannabinoid receptor efficacy, but, to quote, “THC can inhibit depolarization-induced suppression of excitation, and hence presumably it may inhibit endocannabinoid-mediated retrograde signaling in at least some central neuronal pathways.”
What this means overall is that THC can cause excitation, act as an antagonist rather than an agonist in some receptors, or cancel out agonists. Whether or not THC is an agonist or antagonist also depends on whether those cannabinoid receptors are being down- or up-regulated. Up-regulation can occur as a result of some disorders. When this happens, THC typically acts as a partial agonist.
Another interesting thing to consider is that CB1 receptors generally have an inhibitory effect on any ongoing transmitter release from the neurons on which they are located. However, when these receptors are activated in vivo, this sometimes leads to increased transmitter release from other neurons. More specifically, there is evidence that in vivo administration of THC produces CB1-mediated increases in the release of acetylcholine in rat hippocampuses; of acetylcholine, glutamate and dopamine in rat prefrontal cortexes; and of dopamine in mouse and rat nucleus accumbens.
How CBD Affects Receptors
CBD usually acts by affecting different receptors. According to an article published in Epilepsia in early 2016, CBD is unlike THC in that it does not activate CB1 and CB2 receptors. This partially explains its lack of psychotropic effect. However, it interacts in other signaling systems. For example, in a study on mice, CBD protected against cocaine-induced seizures through the mTOR pathway and by reducing glutamate. The article lists the following receptors affected by CBD.
- the equilibrative nucleoside transporter (ENT),
- the orphan G-protein-coupled receptor GPR55, and
- the transient receptor potential of the melastatin type 8 (TRPM8) channel.
CBD enhances the activity of….
- the 5-HT1a receptor,
- the ?3 and ?1 glycine receptors, and
- the transient receptor potential of the ankyrin type 1 (TRPA1) channel
Other effects include…
- a bidirectional effect on intracellular calcium,
- activation of the nuclear peroxisome proliferator-activated receptor-? and the transient receptor potential of vanilloid type 1 (TRPV1) and 2 (TRPV2) channels, and
- Inhibition of cellular uptake and fatty acid amide hydrolase-catalyzed degradation of anandamide.
Of course, if you’re not an organic chemist or biologist, it is hard to know what all of that means, so let’s use the 5-HT1a receptor as an example.
The 5-HT1a receptor is a subtype of the 5-HT receptor that binds the endogenous neurotransmitter serotonin. Serotonin is something we are all a bit more familiar with these days with the epidemic levels of depression and sleep problems. Serotonin plays contributing roles in mood and sleep. So, if CBD enhances receptivity to serotonin, this might explain some of its usefulness.
The human body contains a complex system that produces its own forms of cannabinoids at small doses. The effects of CBD and THC on this natural system are of great interest to researchers and enthusiasts alike.
To learn more about CBD (cannabidiol), Healthy Hemp Oil has a whole page devoted to answering common questions and clearing up misinformation.
What else would you like to know about cannabinoid receptors? Leave a note in the comments below.