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How THC & CBD Work -The biochemistry (1 of 2)

So how does THC & CBD work?

In short: they work on CBD1 (found in the brain) & CBD2 (immune system) receptors
In long: check out below
Quick fact: Tolerance in chronic users was found to occur, though it only took 4 weeks of no cannabis use to recover

Why is the chemistry important?

The receptors cannabis work on has been found to be imbalanced in many neurological disorders. (Including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), traumatic brain injury, stroke, epilepsy & glioblastoma)
THC & CBD are compounds in the family called cannabinoids.
In addition to THC & CBD, there are 100+ cannabinoids found in the cannabis plant. (THC & CBD are just the most notorious of the bunch)

The Endocannabinoid System

Everyday our bodies make substances that stimulate the same receptors that THC & CBD bind to within the endocannabinoid system (i.e. CB1 & CB2). These substances are called Anandamide & 2-AG. When THC & CBD enter our bodies, it is like taking a big spoon full of anadamide & 2-AG.

Here is the biochemistry behind it all:

Human Ligands: Anandamide & 2-AG (2-Arachidonoylglycerol)

CB1 receptors (g protein-coupled receptor)

  • Location: Mostly brain (basal ganglia, hippocampus, cingulate cortex & cerebellum)

Actions:

  • Our neurons: Works Presynaptically in excitatory & inhibitory neurons, Inhibits voltage-gated Ca channels & vesicular release of GABA or glutamate
  • Appetite suppression (story & example of a medication targeting this receptor)
  • In astrocytes, CB1 → regulates synaptic plasticity in hippocampus & in leptin signalling in the hypothalamus
  • Activation stimulates proliferation of adult progenitor stem cells & their differentiation into neurons or astrocytes ~editor note: CB2 also does this~
  • Tolerance: Chronic use does down regulate CB1 → recovery begins at 2 days & takes 4 weeks for CB1 to be back to normal (chronic users defined as: avg 10 Joint x 12 yrs)

CB2 receptors (g protein-coupled receptor)

  • Immune modulation (For example: CB2 receptor activation reduces pro-inflammatory cytokine release from activated microglia in AD)
  • Increased # of receptors in microglia of patients with MS, ALS, Alzheimer disease (AD)

The First drug approved that targets CB1

Rimonabant: – used to decrease appetite (anti-obesity drug)

  • Approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects (it was never approved in the United States)
  • How it works: An inverse agonist for the cannabinoid receptor CB1
  • Interesting positives of the drug: when used in combo with smoked cannabis –> shown that the cardiovascular (heart) and subjective effects of cannabis are blocked by Rimonabant
End of part 1

Please check out part 2 of “How does THC & CBD work – the biochemistry” (click here)

Reference: Cristino L, Bisogno T, Di Marzo V. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020;16(1):9-29. doi:10.1038/s41582-019-0284-zLink to reference (click here)
Author: David Katz | DavidKatz@cox.net

Figure 1: The expanded endocannabinoid system

Figure 2: Neurophysiological roles of the expanded endocannabinoid system

Figure 3: Endocannabinoidome receptors in acute or degenerative neurological disorders

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