Cannabis, from plant to pill

Abstract

The therapeutic application of cannabis is attracting substantial public and clinical interest. The cannabis plant has been described as a veritable 'treasure trove', producing more than 100 different cannabinoids, although the focus to date has been on the psychoactive molecule delta-9-tetraydrocannabinol (THC) and cannabidiol (CBD). Other numerous secondary metabolites of cannabis, the terpenes, some of which share the common intermediary geranyl diphosphate (GPP) with the cannabinoids, are hypothesized to contribute synergistically to their therapeutic benefits, an attribute that has been described as the 'entourage effect'. The effective delivery of such a complex multicomponent pharmaceutical relies upon the stable genetic background and standardized growth of the plant material, particularly if the raw botanical product in the form of the dried pistillate inflorescence (flos) is the source. Following supercritical CO2 extraction of the inflorescence (and possibly bracts), the secondary metabolites can be blended to provide a specific ratio of major cannabinoids (THC : CBD) or individual cannabinoids can be isolated, purified and supplied as the pharmaceutical. Intensive breeding strategies will provide novel cultivars of cannabis possessing elevated levels of specific cannabinoids or other secondary metabolites.

Keywords: cannabinoids; cannabis; flos; flower; terpenoids.

© 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1

Geographical distribution of the four major domesticated groups 1, 2, 3, 4 of Cannabis sativa, with the centre of origin and ancestral genotype illustrated to be in Central Asia. Significant hybridization, predominantly during the last century, has given rise to two additional groups, hemp and marijuana hybrids (reproduced from 5; ©Government of Canada)

Figure 2

Schematic depiction of cannabinoid and exemplar mono‐, sesqui‐, and diterpenoid biosynthesis. The isoprenoid and prenyl precursors for cannabigerolic acid (CBGA), are provided by the hexanoate and 2‐C‐methyl‐D‐erythritol 4‐phosphate (MEP) pathways, respectively. Geranyl diphosphate (GPP), is a key intermediate metabolite and building block for both cannabinoid and terpenoid biosynthesis. The seven‐step mevalonate (MVA) pathway converts pyruvate and glyceraldehyde‐3‐phosphate (G‐3‐P) into isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Key catalytic enzymes controlling flux through this pathway include the first two steps, 1‐deoxy‐D‐xylulose 5‐phosphate synthase (DXS) and 1‐deoxy‐D‐xylulose 5‐phosphate reductase (DXR). In the six‐step MEP pathway, three units of acetyl coenzyme A (CoA) are converted to IPP, which is isomerized with DMAPP by IPP isomerase. The enzyme catalysing the synthesis of MEV, 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGR), is considered to control flux through this pathway. The number of consecutive condensations of the five‐carbon monomer isopentenyl diphosphate (IPP) to its isomer, dimethylallyl diphosphate (DMAPP) is indicated by 1x, 2x, 3x. Longer‐chain isoprenoids, GPP, farnesyl diphosphate (FPP) and geranyl geranyl diphosphate (GGPP), are the products of IPP and DMAPP condensation catalysed by GPP synthase, FPP synthase and GGPP synthase, respectively. GPP, FPP and geranyl‐geranyl diphosphate (GGPP) are the precursors for mono‐, sequi‐, and di‐terpines, respectively. The final steps catalysing the synthesis of major active cannabinoids, cannabichromenic acid (CBCA), cannabidiolic acid (CBDA) and Δ9‐tetrahydrocannabinolic acid (THCA), are oxidocyclases, CBCA synthase (CBCAS), CBDA synthase (CBDAS) and THCA synthase (THCAS). Components of Figure 2 are derived from 29. AAE, acyl‐activating enzyme; CBD: cannabidiol; CYP76F39, α/β‐santalene monooxygenase; GPP synthase small subunit; OLS, olivetol synthase; P450: haemoprotein cytochrome P450; PT, prenyltransferase; STS, santalene synthase; TS, gamma‐terpinene synthase; TXS, taxadiene synthase