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How Does Cannabidiol (CBD) Work?

What is CBD and How Does it Work?

Table of contents
  1. Introduction
  2. The Basics – What is Cannabidiol (CBD)?
  3. What Receptors Does CBD Affect?
  4. So How Does CBD Affect the ECS and Other Receptors, and Which Conditions Could CBD Be Helpful For?
  5. Does CBD Block THC?
  6. The Entourage Effect
  7. Anything Else?

Introduction

The fact is, the only definitive answer available at the moment is “nobody knows precisely, as of yet”. Should someone say to you presently, “I know exactly how CBD works, and it’s all you need”, ask to see the science, research and numbers, and be very suspicious. CBD is a very messy compound, as it interacts with a wide range of receptors in the human body in a variety of ways. This has made CBD particularly difficult to understand, especially when it comes to how it interacts with other cannabinoids and medications.

However, if they say, “I might know how it works, here’s some research supporting what I say, and we must also take into account other cannabinoids and terpenes and how they interact with CBD as well,” then sit down, buy that person a coffee and talk to them. They sound like someone worth listening to! For a look at how various cannabinoids and terpenes work, take a look at our handy cannabinoid-terpenoid table here. If you need a definition of a scientific term, see our glossary.

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So here’s where we explain why CBD might work …

Molecular Structure - CBD
CBD molecular structure.

The Basics – What is Cannabidiol (CBD)?

CBD’s chemical formula is C21H30O2. CBD is one of at least 150 cannabinoids found in the cannabis plant. CBD is one of cannabis’s major phytocannabinoids, and accounts for up to 40% of the plant’s extract. CBD does not seem to have intoxicating effects for most people (though some have reported a mild psychoactive effect), and may, in fact, dampen the effects of tetrahydrocannabinol (THC) – more on this below.

In its raw form, CBD is known as cannabidiolic acid (CBDA). CBDA becomes CBD after aging and/or decarboxylation (heating). CBDA also has a precursor – cannabigerolic acid (CBGA), which is the precursor to both tetrahydrocannabinolic acid (THCA) and CBDA. CBGA is turned into CBDA with the help of the plant enzyme CBDA Synthase. Catalysis from CBGA to CBDA follows the same pathway that CBGA to THCA does, with the only difference being that a different enzyme catalyzes them – THCA Synthase catalyzes CBGA to THCA.

CBD and THC Processing in the Human Body
Biosynthesis from THCA to THC and CBDA to CBD in the human body.

What Receptors Does CBD Affect?

As far as we know, CBD is an indirect antagonist of the body’s cannabinoid receptors CB1 and CB2, a 5-HT1A (a serotonin receptor) partial agonist, TRPV1 (vanilloid receptor) agonist, and allosteric modulator – a substance that indirectly influences an agonist or inverse agonist – of the μ- and σ-opioid receptors.

CBD is said to be analogous to the endocannabinoid 2-Arachidonoylglycerol (2-AG), an endogenous agonist of the CB1 receptor. 2-AG’s chemical formula is C23H38O4. However, as 2AG is a full agonist of CB1 and CB2 receptors, whilst CBD is an indirect antagonist, this analogy is not entirely accurate.

So How Does CBD Affect the ECS and Other Receptors, and Which Conditions Could CBD Be Helpful For?

Knowing what receptors CBD effects (and remember, we don’t know precisely how, where and why CBD works as of yet) is key to understanding its medical uses.

5-HT1A Serotonin Receptors

CBD is a partial agonist of the 5-HT1A receptor. CBD being a “partial agonist” means that it binds to a receptor, but only at partial efficacy in comparison to a full agonist. That CBD works on serotonin receptors may explain why it can be so effective as an antidepressant, anxiolytic and even neuroprotective! See our pages on anxiety, depression and PTSD to learn more about how cannabis and CBD can help with mental health and mood disorders.

TRPV1 vanilloid receptor

CBD has the potential to “desensitize” the TRPV1 receptor. This gives CBD its analgesic (pain-killing), antiemetic (nausea-beating) and seizure-beating properties.

μ- and σ-opioid receptor allosteric modulators

Another reason why CBD may have analgesic properties is because it is an allosteric modulator of μ- and σ-opioid receptors, meaning CBD changes how pain signals are processed. “Allosteric modulators” are like a volume control, helping turn up or down how much it “listens” to a particular signal. Allosteric modulators attach themselves on sites other than the main receptor site (which are called “orthosteric modulators”). This may also help explain why CBD may be useful in treating opioid addiction.

Allosteric modulation.
CX614 is an allosteric modulator for an AMPA receptor. It stabilizes the closed conformation of the clamshell around the binding site, slowing agonist release and therefore deactivation of the receptor. Author: Ikenhower / CC BY-SA 4.0 https://commons.wikimedia.org/wiki/File:AMPA_receptor-_Allosteric_Modulation.jpg

CB1 and CB2 receptors both play an important role in the functioning of the immune system

CBD can suppress cytokine production, thereby reducing inflammation. However, CBD has a low affinity for CB1 and CB2 receptors, but can affect the way other cannabinoids interact with these receptors. The immunomodulatory effects of cannabinoids can be both a pro and a con, depending on what they are being used for and medication/treatment interactions. If you are using immunotherapy for cancer, for example, cannabinoids are contraindicated (i.e. they clash).

CBD may help control glutamate N-methyl-D-aspartate (NMDA) receptors in the brain

The NMDA receptor is a type of glutamate receptor, and it is important for synaptic plasticity and memory retention. This gives CBD not only neuroprotective properties, but also potentially helping regulate brain functions like learning, memory formation and mood. Targeting these receptors may also give CBD some of its anticonvulsive effects, as well as having use as an antipsychotic.

There is a lot of complicated scientific theory and supposition behind this, but it’s obviously a very interesting area of research, and targeting the endocannabinoid system (ECS) could be where drugs and medications are going in the future, especially considering cannabis’s safety and therapeutic profile.

CBD inhibits the liver enzyme cytochrome P450 (CYP 450)

This means that CBD can inhibit the processing of many other drugs. Those who are using anti-epileptic drugs (AEDs) and benzodiazepine-based medications will need to taper their use in order to prevent the buildup of dangerous levels of benzodiazepines in the blood. Some types of antibiotics are also processed by the CYP 450 enzyme, so CBD can interfere with their metabolization.

CYP450-51A1; ribbon model of human CYP51A1 with heme (green) and ketoconazole, both as balls, after PDB 3LD6.
Author: Ayacop; from https://commons.wikimedia.org/wiki/File:CYP450-51A1_3LD6.jpeg. CC0.

Does CBD Block THC?

Many people claim that CBD “reduces” the psychoactivity THC gives by “blocking” it. Now, this may be true in rodents like rats and mice, but it seems that THC and CBD work differently when it comes to humans. This means that the “CBD blocks THC” theory is simplistic.

CBD may be competing or working in tandem with THC, rather than “blocking” or “inhibiting” it in all instances. THC is a CB1 receptor agonist, whereas CBD works indirectly on the CB1 and CB2 receptors (and has a low affinity for them), meaning CBD probably does not “block” THC in the strictest sense, but rather modulates the effect THC has on cannabinoid receptors.

However, there are some studies showing that CBD inhibits the conversion of THC to 11-OH-THC, meaning that CBD may have some inhibitory effect on THC after all. How this mechanism works and at what dosage still needs to be found out, and once again this is a study on rats. CBD may also prevent dopamine system disturbance (THC overstimulates the ERK pathway, which leads to dopamine system disturbance)

This also helps explain some things about the effects certain strains or varietals might have. Cannabis varieties high in THC but with little-to-no CBD tend to be very psychoactive, but don’t last very long (which can be made doubly so with the presence of THCV, which in low doses inhibits THC and increases its psychoactive effects in higher doses). High-CBD-low-THC varieties may have little psychoactive effect, but can still produce a “relaxed body” or “even” effect, as CBD enhances anandamide signalling. High-THC-high-CBD strains may have some of their psychoactivity “smoothed out”, but the duration of the effects may last longer.

The Entourage Effect

Remember, CBD works better when other phytocannabinoids and terpenoids are present. CBD on its own may not be  as effective, requiring higher doses or even being ineffective for certain conditions. Combine it with a bit of THC (even in non- or low-psychoactive amounts) and the plant’s terpenes, however, and you have some medication to be proud of!

Anything Else?

Lots, but we’re going to keep it as simple as possible – you can read more details on CBD and other cannabinoids for different conditions here. We might also be able to research all of this better if CBD and cannabis weren’t federally illegal! It is politics rather than science that prevents us from seeing cannabis as medicine.

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