Dutch scientists solve the mystery of the origins of THC, CBD and CBC

For decades, scientists have known how cannabis produces its main cannabinoids, but are unaware of the why these molecules exist in their current form.

A new study conducted by researchers at the’Wageningen University and Research Center (WUR) is now shedding light on the evolutionary origins of the THC, from CBD and CBC, revealing that these compounds are the result of a long process of trial, error and enzymatic specialization.

Published in Plant Biotechnology Journal, This research combines evolutionary biology, molecular genetics and biotechnology to experimentally retrace the history of the human body. how cannabis has developed its unique chemical profile.

From a flexible enzyme to specialized cannabinoid synthases

In the Cannabis sativa modern, the production of THC, CBD and CBC depends on highly specialized enzymes called cannabinoid oxidocyclases. Each enzyme converts the same precursor molecule, the’cannabigerolic acid (CBGA), into a different cannabinoid acid, which can then be converted to its neutral form by heat.

However, according to the WUR team, this precision is a relatively recent evolutionary development. By reconstructing ancient enzymes that existed millions of years ago, the researchers demonstrated that the first cannabinoid-producing enzymes were versatile: they could generate several cannabinoids at once.

«It was only after genetic duplications that enzymes began to specialize,» explains Robin van Velzen, one of the study's authors. In evolutionary terms, cannabis has evolved from a «Swiss Army knife» enzyme to a finely-tuned set of molecular tools.

Bringing extinct enzymes back to life in the lab

To reach these conclusions, the researchers used a method called reconstruction of ancestral sequences. By comparing the DNA of modern Cannabis plants and their close relatives such as hops, they calculated what the ancestral enzymes probably looked like. These extinct enzymes were then recreated and expressed in yeast cells for testing purposes.

The results were striking. The oldest reconstructed enzyme capable of metabolizing CBGA simultaneously produced THCA, from CBDA and CBCA. Subsequent evolutionary stages reduced this activity, leading eventually to the THCA synthase and CBDA synthase highly selective.

Above all, the study provides the first experimental evidence that cannabinoid biosynthesis arose within the Cannabis lineage itself, rather than having been inherited as such from a distant plant ancestor.

Why the CBC could be of particular importance

Among the discoveries, the CBC is particularly noteworthy. Researchers have identified an ancestral variant of the enzyme that preferentially produces CBCA, the acid precursor of CBC. This is remarkable because no known cannabis variety naturally produces high levels of CBC, despite growing interest in its properties anti-inflammatories and analgesics potential.

«There are currently no cannabis plants with a high CBC content,» explains van Velzen. «Introducing this enzyme into a plant could lead to the creation of innovative medicinal cultivars.»

This observation reinforces the idea that CBC may have been one of the first cannabinoids produced by the ancestors of cannabis, before evolutionary pressures favored THC and CBD.

Implications for biotechnology and medical cannabis

In addition to evolutionary insights, the study has direct implications for the biotechnological production of cannabinoids. The reconstituted ancestral enzymes proved easier to express in micro-organisms than modern enzymes, a key advantage for the manufacture of cannabinoids by fermentation.

While pharmaceutical interest in cannabinoids is growing, microbial production is often presented as an evolutionary alternative to cultivation. However, the low efficiency of enzymes remains an obstacle. According to the authors, ancestral enzymes could provide a more solid starting point for industrial applications.

«What was once evolutionarily «unfinished» is now proving very useful,» notes van Velzen, highlighting how ancient biology can inspire modern innovation.

A clearer picture of the evolution of cannabis

On the whole, this research reframes cannabinoids not as fixed traits, but as the result of evolutionary experimentation. The THC, CBD and CBC are the survivors of a much larger chemical landscape, shaped by gene duplication, mutation and natural selection.

For Cannabis science, this study fills a long-standing gap in our understanding of the formation of the plant's characteristic compounds, while opening up new avenues for breeding, biotechnology, and medical research.