Cannabis sativa: Interdisciplinary Strategies and Avenues for Medical and Commercial Progression Outside of CBD and THC

Abstract

Cannabis sativa (Cannabis) is one of the world's most well-known, yet maligned plant species. However, significant recent research is starting to unveil the potential of Cannabis to produce secondary compounds that may offer a suite of medical benefits, elevating this unique plant species from its illicit narcotic status into a genuine biopharmaceutical. This review summarises the lengthy history of Cannabis and details the molecular pathways that underpin the production of key secondary metabolites that may confer medical efficacy. We also provide an up-to-date summary of the molecular targets and potential of the relatively unknown minor compounds offered by the Cannabis plant. Furthermore, we detail the recent advances in plant science, as well as synthetic biology, and the pharmacology surrounding Cannabis. Given the relative infancy of Cannabis research, we go on to highlight the parallels to previous research conducted in another medically relevant and versatile plant, Papaver somniferum (opium poppy), as an indicator of the possible future direction of Cannabis plant biology. Overall, this review highlights the future directions of cannabis research outside of the medical biology aspects of its well-characterised constituents and explores additional avenues for the potential improvement of the medical potential of the Cannabis plant.

Keywords: Cannabis sativa (Cannabis); Papaver somniferum (opium poppy); cannabidiol (CBD); cannabinoid receptors (CB1 and CB2); cannabinoids; secondary metabolites; tetrahydrocannabinol (THC).

Figure 1

A close up of the female floral architecture of mature Cannabis sativa plants. The cannabinoid-containing glandular trichomes are visible in the magnified image, and are characterised by a globular head which is connected to the plant via a stalk. Colouration of the heads ranges from translucent, to a creamy white, to brown.

Figure 2

An overview of the mevalonate and methylerythritol 4-phosphate pathways in Cannabis sativa. The MEP (A) and MVA (B) pathways both produce terpenoid precursors, as well as the substrate for cannabinoid production, GPP. (A) The MEP pathway begins in the plastid with the condensation of pyruvate and glyceraldehyde 3-phosphate by DXS to produce DXP, prior to a series of enzymatic reactions to produce HDMPP. HDR then converts HDMPP to IPP and DMAPP, serving as the precursor to GPP, GGPP, and subsequently monoterpene and diterpene production. (B) The cytosolic MVA pathway is initiated by the conversion of acetyl-CoA to HMG-CoA and then to MVA, catalysed by the regulated, and rate-limiting enzyme, HMGR. MVA undergoes phosphorylation and then is decarboxylated to produce IPP, which is then converted to FPP as the basis for sesquiterpene and triterpene synthesis, or for GPP production for use in the cannabinoid biosynthesis pathway.

Figure 3

An overview of the cannabinoid biosynthesis pathway in Cannabis sativa. Malonyl-CoA, formed from acetyl-CoA, is used downstream with hexanoyl-CoA to produce olivetolic acid (OA). Next, OA is used as substrate along with other biomolecules by the GOT enzyme to produce the major cannabinoid precursor, CBGA. When GOT uses substrates additional to OA, such as divarinic acid or nerylpyrophosphate, a range of other minor cannabinoids are produced.