Domesticating Cannabis

Cannabis was one of the first plants cultivated by humans and it has been adapted to a variety of human needs: technical (fiber hemp), nutritional (hemp food), medicinal, and recreational (“marijuana”). But although cannabis has been “tamed”, it is far from being fully domesticated – there are too many gaps in our knowledge.

Cannabis produces a galaxy of over 150 unique isoprenylated alkylresorcinols, known as phytocannabinoids and a host of equally unique polyphenolics (1), but biomedical interest has so far focused only on two compounds: ∆⁹tetrahydrocannabinol (∆⁹-THC) and cannabidiol (CBD). ∆⁹-THC, a narcotic and socially divisive compound, has fostered the discovery of the endocannabinoid system, its two receptors (CB₁ and CB₂), and its endogenous modulators (endocannabinoids) – just like nicotine and muscarine did for the cholinergic system, ephedrine for the adrenergic system, and morphine for the opioid system. Conversely, CBD (e.g., Epidiolex GW Pharmaceuticals, UK) is still challenging molecular pharmacologists to unravel the molecular bases of its clinical activity in medical conditions where conventional treatment is of avail, such as genetic forms of epilepsy.

∆⁹-THC and CBD are the easiest compounds to purify from cannabis, but some say they are only the tip of the iceberg. There is growing evidence that the cannabinoid structural motif is a privileged platform for bioactivity and that its chemical space is still substantially unexplored. For cannabinoids, narcotic properties are not a sequitur; just because a compound is a cannabinoid and comes from cannabis does not mean that it will be psychoactive. A small change, like shortening the n-pentyl residue to a n-propyl as in ∆9-THCV – the naturally occurring lower homologue of ∆9-THC – switches the activity from CB1 agonism to antagonism (1), while the carboxylated native form of ∆9-THC (pre-THC or THCA-A) is a powerful PPARy agonist with remarkable neuroprotective activity and negligible activity on CB₁ (2).

While the biomedical potency of ∆9-THC and CBD is remarkable, there is surprisingly scarce awareness that these compounds do not belong to the native branch of the phytocannabinoid lineage. They are produced, just like all the other analogues in the plant, as carboxylated precursors, and, to a limited extent, as terpenyl esters of the carboxylated precursors. The native carboxylated forms (pre-cannabinoids or acidic cannabinoids) are thermally unstable, and are converted to neutral phytocannabinoids by loss of carbon dioxide. In turn, phytocannabinoids can be oxidized to cannabinoquinoids, another class of interesting compounds, whose instability has spurred the generation of stable semi-synthetic analogues, exemplified by VCE-004.8. This aminoquinoid is interesting for autoimmune diseases like multiple sclerosis, and has received orphan drug status by FDA and EMA for the treatment of scleroderma (in development by Emerald Health Pharmaceuticals, USA).

The chemical diversity of cannabis is, thus, not only expressed by native compounds, since acidic phytocannabinoids are generated with an expiry date and are primed to undergo a series of degradative modifications that generate neutral phytocannabinoids and cannabinoquinoids. These are, in turn, excellent templates for the development of novel semi-synthetic analogues with superior activities. All these changes are associated with distinct biological profiles – a “cannabinome” that still waits to be disentangled and domesticated to the benefit of medicine. Cannabis has long been considered a social issue or a book to be read in Smithsonian terms – a catalogue of structures. Seeing it as a source of solutions for unmet medical needs is a big step forward, and should spark optimism (rather than skepticism) in the medicinal chemistry community.