How Does CBD work?

So you have tried CBD and it seems to help with your overactive mind, your bum knee, and more. Now you are wondering, “How does CBD actually work?” In a previous article on CBD fact vs. fiction we touched on the fact that many people will falsely claim CBD is acting on CB2 receptors and the truth is that we really do not fully understand how CBD is doing its job, but we know it does do something. As a similar example, Tylenol (acetaminophen) works for many people, but we do not know how it helps to relieve pain.

So, what the heck are CB2 receptors and why is the statement wrong asserting that CBD acts on CB2 receptors? CB2 receptors are part of your own endocannabinoid system. Endo is short for endogenous, which mean originating inside your own body, and cannabinoid refers to compounds originating from the cannabis plant, which were the first compounds shown to act on your body's endocannabinoid system.

The endocannabinoid system is made of two main receptors (cannabinoid 1 and 2 (CB1 and CB2)) and two main compounds (2-Arachidonoylglycerol (2-AG) and Anandamide (AEA)). These are naturally produced by the body and help control many aspects of your biology, from temperature and heart rate to memory and pain.

These act like keys and locks. The receptor is the lock and the compounds are the key. Many people still claim that CBD produces its main effect from interacting with CB2 receptors (CBD as the key and CB2 as the lock), however the evidence doesn’t really support this.

CBD can act on the endocannabinoid system, just in a different way than some people will state. CBD is thought to inhibit the breakdown and reuptake of AEA1. This effectively increases the amount of endocannabinoids working in your body and can help improve endocannabinoid tone.

CBD might also regulate THC’s activity at CB1 receptors that are more associated with the “high”2. Instead of play or pause like many molecules act, CBD might just slightly turn down the volume of CB1 receptors and reduce the intoxicating effects from THC.

Another major target for CBD is the 5HT-1A receptors3. 5HT (or 5-hydroxytryptamine) is the scientific name for serotonin. So, that is to say that CBD will interact with your body’s serotonin system. This interaction might be related with relief from stress and an overactive mind as well as upset stomach.

PPAR gamma is a target for CBD as well4. PPAR-gamma has major roles in metabolic homeostasis specifically with adipose tissue (fat) and glucose. PPAR-gamma can also be involved in inflammation. So, CBD may help regulate your metabolism and inflammation through PPAR-gamma. PPAR-gamma is thought to inhibit the COX-2 enzyme5, which NSAIDS like naproxen work through to reduce pain and inflammation.

CBD can also interact with different TRP channels6. Mainly acting on TRPV1, but also TRPA1 and TRPM8. TRPV1 is known as the capsaicin receptor and is related to temperature and pain, TRPA1 is associated with irritation, itch, and pain, and TRPM8 is thought to be involved in temperature and pain. So, CBD may help with pain and inflammation related to this activity.

For skin health, CBD is thought to inhibit sebocytes and decrease inflammation associated with acne7. Sebocytes are oil producing cells on the face that can make your skin too oily and lead to an increase in acne. This action is thought to be produced by CBD’s interaction with TRPV4 channels to inhibit the sebocytes and adenosine A2a receptor to decrease inflammation.

GPR55 is another potential target for CBD8. GRP55 is among GPR18 and other “orphan” receptors (GPR3, GPR6, and GPR12) that may be closely related or in the same endocannabinoid class. Orphan receptors are called as such because we have no known endogenous or natural ligand (an activating molecule like AEA to CB1) for these receptors. GPR55 might be called CB3 in the future. GPR55 is thought to be involved in glucose and insulin homeostasis, pain and inflammation, and potentially bone health.

To make things even more complicated receptors can exist in dimers or monomers9. A monomer is a single receptor and a dimer is two receptors attached to each other. Further, you can have a homodimer (two of the same receptor) and a heterodimer (two different receptors). For example, you can have a CB1-CB1 dimer or a CB1-5HT dimer. The dimers make understanding the full pharmacological action of CBD even more convoluted and not much is well known on the subject.

Overall, the way CBD actually works is abundantly confusing. There is no classical cannabinoid receptor (CB1 and CB2) activation like many other cannabinoids, most notably THC. CBD does act on the endocannabinoid system, just in a somewhat unique fashion. CBD also acts through a variety of receptors including GPR55, various TRP channels, PPAR-gamma, and more (even opioid receptors involved in pain10). As Science progresses, we will undoubtedly start to create a more full and accurate picture of how CBD work, but for now, if you find relief with CBD, then it does not really matter that we do not know how it works (see Tylonol).

1 Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.

2 Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.

3 Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.

4 Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors.

5 Inhibition of COX‐2 expression by endocannabinoid 2‐arachidonoylglycerol is mediated via PPAR‐γ.

6 Cannabinoid Ligands Targeting TRP Channels.

7 Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.

8 The orphan receptor GPR55 is a novel cannabinoid receptor.

9 An Update on Non-CB1, Non-CB2 Cannabinoid Related G-Protein-Coupled Receptors.

10 Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors.