Delta-9 THC is the most common active ingredient in cannabis. And CBD is the second most common on the market today. But are THC and CBD the first and second most active ingredients in cannabis?
Two cannabis ingredients more active than D9-THC
CBN (cannabinol) and delta-8 THC, byproducts of THC-acid or CBD, lightly agonize CB1 receptors with less activity than delta-9 THC.
Pharmacologists use a binding efficacy measure to deduce a molecule’s activity on a receptor. At CB1 receptors, D9-THC is nearly two times more active than a minor variant of itself known as THCv. Albeit an agonist in small doses, THCv (tetrahydrocannabivarin) is more commonly known as a neutral CB1 receptor antagonist. Neutral antagonism and inverse agonism is still activity, though.
Infamously, a minor ingredient in cannabis chemovars known as THCp is thirty-three times more active than D9. (2) However, hexyl-THC is also present in cannabis with an unknown affinity and efficacy. (3)
THCp is the most potent ingredient in cannabis, with hexyl-THC in second place. Yet, more research needs to confirm hexyl-THC’s affinity at CB1 receptors. Furthermore, THC-oct, also known as THCj, has not yet been seen in cannabis but is more active than THCp given its longer side chain.
The most active ingredient in hemp
CBD partially binds to and agonizes the therapeutic human cannabinoid receptor, CB2. But let’s not forget about one terpene and ingredient in most hemp and cannabis chemovars, b-caryophyllene — a full CB2 receptor agonist. B-caryophyllene does not directly affect CB1 receptors, whereas CBD works as a Negative Allosteric Modulator (NAM) at CB1 receptors. That means CBD changes how THC’s stone feels, reducing part of the CB1 receptor’s spectrum.
Hexyl-CBD is, however, also present in cannabis. (3) With a longer-side chain, hexyl-CBD is more active than its common cousin, according to studies in mice. And a renowned study documented the discovery of CBDp and THCp in chemovars from the Italian government a year earlier — but only tested the latter. (2)
At the end of the day, efficacy and affinity at CB1 or CB2 receptors still cannot deduce the ‘activity’ of a cannabinoid. Cannabidiol is broad, affecting a large umbrella of biological mechanisms. The promiscuous cannabinoid, therefore, is often descriptive of CBD.
Then again, it is one of the most thoroughly studied cannabinoids. And more research on CBG (cannabigerol) has come to light in recent years, with CBC (cannabichromene) and other ingredients still in the background.
CBD protects the endocannabinoid known as anandamide, which partially activates the CB1 receptor agonist. Likewise, ibuprofen and chocolate protect anandamide. In contrast, CBG protects 2-AG, an endocannabinoid that functions as a full CB1 and CB2 receptor agonist. Not surprisingly, drugs that protect 2-AG face delays due to their more broad cannabimimetic effect.
Furthermore, CBG and CBGa are both more potent COX-2 inhibitors than CBD, but not necessarily CBDa. The plant produces acidic phytocannabinoids, whereas COX-2 enzymes degrade the endocannabinoids.
What is the second most active ingredient in cannabis?
That question depends on many factors, and researchers can only make estimations at this time.
Efficacy at CB Receptors — Hexyl-THC (given THC-oct/THCj does not occur naturally.)
Activity at CB1 Receptors respective to abundance in current chemovars — CBN (cannabinol)
Activity at CB2 Receptors respective to abundance in current chemovars — Beta-caryophyllene
General cannabimimetic — THCa (with full spectrum extract) (4)
Most sites affected — CBD
Opining that CBD is the second most active ingredient in cannabis exposes two problems in cannabis science and endocannabinology. Firstly, the quantified answer to photodynamic activity is not straightforward. Secondly, the answer is not known.
Let us know in the comments what you think defines a cannabinoid’s activity level. And check out this story to learn more about hexyl-THC.
Coll, Anthony. (2013). “Are melanocortin receptors constitutively active in vivo?”. European journal of pharmacology. 719. 10.1016/j.ejphar.2013.04.051.
Citti C, Linciano P, Russo F, et al. A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol. Sci Rep. 2019;9(1):20335. Published 2019 Dec 30. doi:10.1038/s41598-019-56785-1
Linciano P, Citti C, Russo F, et al. Identification of a new cannabidiol n-hexyl homolog in a medicinal cannabis variety with an antinociceptive activity in mice: cannabidihexol. Sci Rep. 2020;10(1):22019. Published 2020 Dec 16. doi:10.1038/s41598-020-79042-2
De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011;163(7):1479-1494. doi:10.1111/j.1476-5381.2010.01166.x