The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain, Ethan B. Russo,

The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No “Strain,” No Gain

Ethan B. Russo

Frontiers in Plant Science, 2019, Volume 9, Article 1969, 1-8.

Doi : 10.3389/fpls.2018.01969

The topic of Cannabis curries controversy in every sphere of influence, whether politics, pharmacology, applied therapeutics or even botanical taxonomy. Debate as to the speciation of Cannabis, or a lack thereof, has swirled for more than 250 years. Because all Cannabis types are eminently capable of cross-breeding to produce fertile progeny, it is unlikely that any clear winner will emerge between the “lumpers” vs. “splitters” in this taxonomical debate. This is compounded by the profusion of Cannabis varieties available through the black market and even the developing legal market. While labeled “strains” in common parlance, this term is acceptable with respect to bacteria and viruses, but not among Plantae. Given that such factors as plant height and leaflet width do not distinguish one Cannabis plant from another and similar difficulties in defining terms in Cannabis, the only reasonable solution is to characterize them by their biochemical/pharmacological characteristics. Thus, it is best to refer to Cannabis types as chemical varieties, or “chemovars.” The current wave of excitement in Cannabis commerce has translated into a flurry of research on alternative sources, particularly yeasts, and complex systems for laboratory production have emerged, but these presuppose that single compounds are a desirable goal. Rather, the case for Cannabis synergy via the “entourage effect” is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory. The astounding plasticity of the Cannabis genome additionally obviates the need for genetic modification techniques.

Keywords : cannabis, cannabinoid, marijuana, hemp, genomics, genetically modified organism, tetrahydrocannabinol, cannabidiol



Earlier data on taxonomy of Cannabis was previously reviewed (Russo, 2007), which will be herein summarized and supplemented. Cannabis is a dioecious annual of the Cannabaceae family which traditionally includes hops, Humulus spp. Alternatively, Cannabis has also been assigned to Moraceae, Urticaceae, or even in the Celtidaceae families on the basis of chloroplast restriction site maps (Weigreffe et al., 1998), and chloroplast mat K gene sequences (Song et al., 2001). More recently, the Cannabaceae have subsumed eight genera : Celetis, Pteroceltis, Aphananthe, Chaetachme, Gironniera, Lozanella, Trema, and Parasponia, comprising 170 odd analysis of four plastid loci (Yang et al., 2013). Current research on fossil pollen samples associated with the ecological associations of Cannabis with steppe companion species (Poaceae, Artemisia, Chenopodiaceae), and Humulus (hops) with forest genera (Alnus, Salix, Populus), have established that although Cannabis seems to have originated in the Tibetan Plateau at least 19.6 million years ago, it has also been indigenous to Europe for at least a million years (McPartland et al., 2018), and refuted the conventional wisdom that this “camp follower” was brought there by man.

The species assignation of Cannabis itself is fraught with great debate. Cannabis sativa, meaning “cultivated Cannabis,” was so named by Fuchs, among others, in 1542 (Fuchs, 1999), an assignation 211 years before the systematization of botanical binomials Linnaeus in his Species Plantarum (Linnaeus, 1753). Lamarck subsequently suggested Cannabis indica, a more diminutive intoxicating Indian plant from India, as a separate species (Lamarck, 1783). The issue has remained unresolved in the subsequent centuries with two opposing philosophies. Ernest Small has championed the single species concept (Small and Cronquist, 1976). Polytypic treatments of Cannabis also gained adherents (Schultes et al., 1974; Anderson, 1980) on morphological criteria suggesting separation of Cannabis sativa L. Cannabis indica Lam. and Cannabis ruderalis Jan., a scheme supported by systematic chemotaxonomy. Principal component analysis (PCA) of 157 Cannabis accessions from around the world assessed allozyme frequencies at 17 gene loci suggested a split (Hillig, 2005b). “Sativa” gene pools from eastern European ruderal samples were linked to narrowleaflet European and Central Asian fiber and seed plants, while an “indica” grouping encompassed Far Eastern seed and fiber plants and drug plants with broad-leaflets from most of the rest of the world, along with wild accessions from the Indian subcontinent. Central Asian roadside samples (Cannabis ruderalis) were thought to represent a third group. Gas chromatography (GC) and starch-gel electrophoresis studies also suggested species separation of sativa and indica (Hillig and Mahlberg, 2004).

Agronomic factors in 69 samples suggested inclusion of eastern hemp and drug plants in Cannabis indica (Hillig, 2005a), a division supported by fragment length polymorphisms (Datwyler and Weiblen, 2006).

More recently, PCA seemed to point to terpenoid content as the most convincing distinguishing chemotaxonomic markers between putative sativa and indica species (Elzinga et al., 2015). Similarly, PCA was felt to separate drug Cannabis from hemp (Sawler et al., 2015). A recent study demonstrated demarcation of Cannabis drug from hemp accessions via genotyping of 13 microsatellite loci across the genome, not merely genes affecting cannabinoid or fiber production (Dufresnes et al., 2017). Professor Giovanni Appendino has reported the presence of the cis-19-THC stereo-isomer only in the hemp accessions (Giovanni Appendino, personal communication). However, these distinctions may well pass by the wayside given the current trend to crossbreed hemp with drug cultivars to avoid legislative restrictions on THC content.

The Cannabis species controversy, Cannabis sativa vs. indica vs. afghanica, has continued unabated to the current day with impassioned arguments advanced by the protagonists (Clarke and Merlin, 2013, 2016; Small, 2015; McPartland and Guy, 2017; Small, 2017). This author, having been on every side of the issue at one time or another, has chosen to eschew the irreconcilable taxonomic debate as an unnecessary distraction (Piomelli and Russo, 2016), and rather emphasize that only biochemical and pharmacological distinctions between Cannabis accessions are relevant. In his recent seminal review, McPartland agreed, “Categorizing Cannabis as either ‘Sativa’ and ‘Indica’ has become an exercise in futility. Ubiquitous interbreeding and hybridization renders their distinction meaningless.” (McPartland, 2018) (p. 210).

An additional non-sensical nomenclature controversy pertains in common parlance to Cannabis “strains,” an appellation that is appropriate to bacteria and viruses, but not plants (Bailey and Bailey, 1976; Usher, 1996; Brickell et al., 2009), especially so with Cannabis where the chemical variety, abbreviated “chemovar” is the most appropriate appellation (Lewis et al., 2018).