Once dismissed by lawmakers as a purely recreational drug, cannabis is showing real medical potential, especially when it comes to helping patients ease the feelings of pain. New research in the journal Phytochemistry suggests that this ability comes from some lesser-known chemicals in cannabis and has great potential to form the basis for nonaddictive pain relievers of the future.

In the paper published in the journal’s August issue, researchers at the University of Guelph showed how the Cannabis sativa L plant produces two molecules, cannflavin A and cannflavin B, that were shown in 1985 to be approximately 30 times more effective than aspirin by weight at reducing inflammation in cell models.

“There’s clearly a need to develop alternatives for relief of acute and chronic pain that go beyond opioids,” Tariq Akhtar, Ph.D., the study’s corresponding author and an assistant professor of molecular and cellular biology, said. “These molecules are non-psychoactive and they target the inflammation at the source, making them ideal painkillers.”

Even for those who are well acquainted with the landscape of cannabis science, cannflavin A and cannflavin B, which belong to the flavonoid family, may be unfamiliar names.

In the study, the team examined the genome and biochemistry of Cannabis to identify the genes responsible for producing the two cannflavins as well as the chain of chemical reactions that produce them. This is the first time that this biological process has been documented for these supporting actors in the cannabis repertoire.

Akhtar and his team hope this will help scientists develop opioid alternatives for patients living with either acute or chronic pain, not by interacting with the brain’s opioid receptors but by reducing inflammation at the site of pain.

CBD and THC get a lot of attention, but cannflavin A and cannflavin B may be the next big things for medical cannabis research. Unsplash / Kimzy Nanney

“What’s interesting about the molecules in cannabis is that they actually stop inflammation at the source,” Akhtar told The Toronto Star on Tuesday. “And most natural products don’t have the toxicity that’s associated with over-the-counter pain relief drugs, which, even though they’re very effective, do come with health risks. So, looking at natural products as an alternative is a very attractive model.”

For now, most scientific and popular attention goes to Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), two of the more abundant active molecules in cannabis by volume. Known for its psychoactive properties, THC can help treat chronic pain, but it has also been linked to psychosis with frequent and heavy use. CBD, meanwhile, is the active ingredient in Epidiolex, the first FDA-approved cannabis-based medicine for childhood seizure disorders, but its long-term side effects are poorly understood.

If they can be synthesized in large enough quantities, cannflavin A and B could become just as well known. Akhtar and several of his co-authors have applied for a US patent for the eventual results of this research, so given the thorny regulatory landscape of CBD, they may eventually cash in on a new class of cannabis-derived products that aren’t hampered by the stigma and baggage associated with the drug.

Abstract: In addition to the psychoactive constituents that are typically associated with Cannabis sativa L., there exist numerous other specialized metabolites in this plant that are believed to contribute to its medicinal versatility. This study focused on two such compounds, known as cannflavin A and cannflavin B. These prenylated flavonoids specifically accumulate in C. sativa and are known to exhibit potent anti-inflammatory activity in various animal cell models. However, almost nothing is known about their biosynthesis. Using a combination of phylogenomic and biochemical approaches, an aromatic prenyltransferase from C. sativa (CsPT3) was identified that catalyzes the regiospecific addition of either geranyl diphosphate (GPP) or dimethylallyl diphosphate (DMAPP) to the methylated flavone, chrysoeriol, to produce cannflavins A and B, respectively. Further evidence is presented for an O-methyltransferase (CsOMT21) encoded within the C. sativa genome that specifically converts the widespread plant flavone known as luteolin to chrysoeriol, both of which accumulate in C. sativa. These results therefore imply the following reaction sequence for cannflavins A and B biosynthesis: luteolin ► chrysoeriol ► cannflavin A and cannflavin B. Taken together, the identification of these two unique enzymes represent a branch point from the general flavonoid pathway in C. sativa and offer a tractable route towards metabolic engineering strategies that are designed to produce these two medicinally relevant Cannabis compounds.