“The endocannabinoid system has been found to be pervasive throughout mammalian species. It has also been described in invertebrate species as primitive as the Hydra.” 8
The Endocannabinoid System
The endocannabinoid system consists of cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R)4. Endocannabinoid system research also investigates endogenous ligands (endocannabinoids) — along with the enzymes responsible for metabolizing cannabis4,8.
Conceptions, definitions, and theories about the endocannabinoid system have continued to expand over the last two decades4. Experts predict the definition of “endocannabinoids” is bound to change as research continues to develop, as well.
For a complex flowchart of the endocannabinoid system, please refer to page 2 of this study by Di Marzo and Piscitelli (2015) in the Neurotherapeutics journal.
The endocannabinoid system is involved in regulating a variety of biological processes, including22:
- Brain reward systems
- Drug addiction
- Metabolic processes (such as homeostasis and glucose metabolism37)
- Social, behavioral, and emotional responses37.
Evolutionary, it’s believed the endocannabinoid system developed concurrently with the nervous system as multicellular animals evolved8. However, it wasn’t discovered until the mid-1990s.
CB1 & CB2 Receptors
Although the name “endocannabinoid receptors” inadvertently implies all cannabinoids target these receptors, it’s still unclear how CBD and some of its non-psychoactive derivatives interact with the endocannabinoid system2,7. As a Healthline article by Crystal Raypole & Alan Carter, Pharm.D. explains:
“Experts aren’t completely sure how CBD interacts with the ECS. But they do know that it doesn’t bind to CB1 or CB2 receptors the way THC does.
Instead, many believe it works by preventing endocannabinoids from being broken down. This allows them to have more of an effect on your body. Others believe that CBD binds to a receptor that hasn’t been discovered yet.”
Alternatively, a 2015 Neurotherapeutics Journal study suggests that cannabinoid receptors be renamed “THC/THCV” receptors since THC and THCV are the only cannabinoids that bind with high-affinity to CB1 and CB24.
Moreover, the authors propose the definition of “cannabinoid receptors” should be expanded to include proteins that are modulated by cannabinoids, such as the transient receptor potential (TRP) channels.
Naturally, the authors then advocate for expanding the definition of “endocannabinoid enzymes” to include additional enzymes that mediate the endocannabinoid system. They also note that other researchers sometimes use an extended definition of the endocannabinoid system called the “enlarged endocannabinoid system.”
Transient Receptor Potential (TRP) Channels
Transient Receptor Potential (TRP) channels are a group of cell membrane (the membrane is the outermost layer of a cell) proteins involved in the transduction of chemical and electric stimuli9. TRPs mediate neural signals involved in sensing temperature, pressure, pH, smell, taste, vision, and pain perception by modulating ion entry.
“Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory diseases,” says a study by Muller et al9. “In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels.”
Furthermore, all cannabinoids can influence these channels — that includes endogenous, phytogenic, and synthetic cannabinoids.
There are a total of six TRP subfamilies recognized in mammals. The three TRP subfamilies that cannabinoids can modulate include:
- TRP vanilloid (TRPV)
- TRP ankyrin (TRPA)
- TRP melastatin (TRPM)
Of these three subfamilies, six TRP channels in particulate are modulated by cannabinoids:
(For context, there are 28 different TRP channels across all six TRP subfamilies.)
These six TRP channels mediated by cannabinoids are sometimes referred to as “ionotropic cannabinoid receptors”9,13.
TRPV1 and at least five other TRP channels have been discovered in the dorsal root ganglia, which carry sensory signals from the peripheral nervous system (the nerves and ganglion that branch out from the brain and spinal cord) to the central nervous system (the brain and spinal cord)9,10.
“Until recently, the dorsal root ganglion has been considered a passive organ that metabolically assists functions and pathways between the PNS and CNS. New studies suggest, however, that the DRG is an active participant in peripheral processes, including PAF injury, inflammation, and neuropathic pain development.”10
Desensitization, particularly through TRPV1, is a key feature currently being explored9. TRPV1 becomes rapidly desensitized when activated, which produces analgesic (pain relieving) effects.
Hence, understanding the interaction between cannabinoids and transient receptor potential channels (TRPs) could provide valuable insight into the cause of cannabis’ pain-alleviating effects.
So far, it appears CB1 receptors colocalize (occur within the same cell) with TRP channels in brain and sensory neurons. On the other hand, CB2 receptors colocalize in sensory neurons and osteoclasts (osteoclasts are cells responsible for the dissolution and absorption of bone12).
Anandamide (an endocannabinoid) activates TRPV1 and blocks TRPM8. N-arachidonyl dopamine (another endocannabinoid) blocks TRPM8, too.
THC “acts most potently at TRPV2” and “moderately modulates” TRPV3, TRPV4, TRPA1, and TRPM89. However, it does not appear to modulate TRPV1 — the TRP channel researchers are exploring for its analgesic effects.
On the other hand, CBD (which has anti-inflammatory properties14,15), shows “little affinity” for CB1 and CB2 receptors, yet CBD has the most potent effects on TRPV1 and TRPM89. CBD also activates TRPV2, TRPA1, and TRPV314.
Additionally, the synthetic cannabinoid “WIN55,212-2” exerts analgesic effects by desensitizing TRPV1 and TRPA1, further supporting the notion that TRPV1 plays a central role in the perception of neuropathic pain and other “harmful stimuli”16.
“CBD not only activates TRP through a direct agonist-receptor interaction, but also by lowering the level of oxidative stress.”14
The Endocannabinoid system primarily consists of CB1 and CB2 receptors, as well as endocannabinoids (cannabinoids naturally produced by your body, regardless of cannabis consumption)4,8. However, many have proposed the endocannabinoid system should be expanded to include other receptors, metabolites, and proteins, as THC is the only psychoactive cannabinoid that targets CB1 and CB2 receptors.
ECS receptors are located throughout your body and regulate a variety of biological processes, including your brain’s reward systems, metabolic processes, and memory22,37. The ECS also regulates addiction, social, behavioral, and emotional responses.
Both phytocannabinoids and endocannabinoids have extensive influence over TRP channels, which serve a variety of functions throughout the body, as well9. As a result, some experts refer to TRP channels as “ionotropic cannabinoid receptors”9,13.
Although it’s widely believed that the ECS evolved alongside the nervous system in mammals, it wasn’t discovered until the mid-1990s.
Thus, despite the well-recognized interplay between cannabinoids, the endocannabinoid system, terpenes, and flavonoids, many areas of cannabis pharmacokinetics remain critically under-researched.
Nevertheless, our understanding of the ECS is rapidly evolving as research progresses in the field of cannabis research.
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