What are the most active ingredients in hemp and cannabis?

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 common compounds in cannabis?

Two cannabis ingredients are more active than D9-THC

CBN (cannabinol) and delta-8-THC, by-products of THC acid or CBD, slightly agonize CB1 receptors with less activity than delta-9-THC.

Pharmacologists use a binding potency measure to infer a molecule’s activity on a receptor. At CB1 receptors, D9-THC is nearly two times more active than a smaller variant of itself known as THCv. Although THCv (Tetrahydrocannabivarin) is an agonist in small doses, it is more commonly known as a neutral CB1 receptor antagonist. However, neutral antagonism and inverse agonism are still active.

Different types of activity at receptor sites. Courtesy of Coll, A. 2013. (1)

Famously, a small 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 unknown affinity and potency. (3)

THCp is the most potent ingredient in cannabis, with hexyl-THC in second place. However, more research is needed to confirm hexyl-THC’s affinity for CB1 receptors. Additionally, THC-oct, also known as THCj, has not yet been observed in cannabis but is more active than THCp due to its longer side chain.

The most active ingredient in hemp

CBD partially binds to and antagonizes the therapeutic human cannabinoid receptor CB2. But let’s not forget a terpene and an ingredient found in most hemp and cannabis chemovars, b-caryophyllene – a full CB2 receptor agonist. B-caryophyllene does not directly affect CB1 receptors, while CBD acts as a negative allosteric modulator (NAM) at CB1 receptors. This means that CBD alters how high THC feels by reducing part of the spectrum of the CB1 receptor.

However, hexyl CBD is also found in cannabis. (3) With a longer side chain, hexyl CBD is more active than its common cousin according to mouse studies. And a renowned study a year earlier documented the discovery of CBDp and THCp in Italian government chemovars — but only tested the latter. (2)

Cannabimimetic Activity

Ultimately, potency and affinity at CB1 or CB2 receptors still cannot be indicative of a cannabinoid’s “activity”. Cannabidiol is broad and affects a wide range of biological mechanisms. The promiscuous cannabinoid is therefore often descriptive of CBD.

On the other hand, it is one of the most thoroughly studied cannabinoids. And in recent years, more research on CBG (cannabigerol) has come to light, with CBC (cannabichromene) and other ingredients still taking a backseat.

CBD protects the endocannabinoid known as anandamide, the partially activates the CB1 receptor agonist. Likewise, ibuprofen and chocolate protect anandamide. In contrast, CBG protects 2-AG, an endocannabinoid that acts as a full CB1 and CB2 receptor agonist. Not surprisingly, drugs that protect 2-AG face delays due to their broader cannabimimetic effects.

Additionally, CBG and CBGa are both more potent COX-2 inhibitors than CBD, but not necessarily CBDa. The plant produces acidic phytocannabinoids while COX-2 enzymes break down the endocannabinoids.

What is the second most active ingredient in cannabis?

That question depends on many factors, and researchers can only make guesses at this time.

• Efficacy at CB receptors — Hexyl-THC (since THC-oct/THCj does not occur naturally.)
• activity at CB1 receptors in terms of frequency in current chemovars – CBN (cannabinol)
• Activity at CB2 receptors in relation to abundance in current chemovars – beta-caryophyllene
• General cannabimimetic — THCa (with full spectrum extract) (4)
• Most websites are affected — CBD

The notion that CBD is the second most abundant compound in cannabis exposes two problems in cannabis science and endocannabinology. First, the quantified response to photodynamic activity is not easy. Second, the answer is not known.

Let us know what you think defines a cannabinoid’s activity level in the comments. And check out this story to learn more about it hexyl-THC.

Sources

1. Col, Anton. (2013). “Are melanocortin receptors constitutively active in vivo?”. European Journal of Pharmacology. 719. 10.1016/j.ejphar.2013.04.051.
2. Citti C, Linciano P, Russo F et al. A novel phytocannabinoid isolated from Cannabis sativa L. with in vivo cannabimimetic activity higher than that of Δ9-tetrahydrocannabinol: Δ9-tetrahydrocannabiphorol. Sci Rep. 2019;9(1):20335. Published December 30, 2019. doi:10.1038/s41598-019-56785-1
3. Linciano P, Citti C, Russo F, et al. Identification of a new cannabidiol-n-hexyl homologue in a medicinal cannabis strain with antinociceptive activity in mice: cannabidihexol. Sci Rep. 2020;10(1):22019. Published December 16, 2020. doi:10.1038/s41598-020-79042-2
4. De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of cannabinoids and cannabinoid-enriched cannabis extracts on TRP channels and endocannabinoid metabolizing enzymes. Br J Pharmacol. 2011;163(7):1479-1494. doi:10.1111/j.1476-5381.2010.01166.x