The increasing public interest in cannabis together with the impressive variability of chemotypical characteristics inspired the division of cannabis into five recognized groups (or chemotypes) within the genus, depending on different concentrations of major cannabinoids (Δ9-THC 1; CBD 2; and CBG 3). The five (OR should I say 6 including VARIN Type) recognized chemotypes of cannabis include: (I) the drug-type plants (narcotic) with a high content of the psychotropic Δ9-tetrahydrocannabinol (Δ9-THC 1); (II) medicinal cannabis with a 1:1 content of Δ9-THC 1: CBD 2; (III) industrial fiber hemp that has CBD 2 as a predominant constituent and a minimum content of Δ9-THC 1 (0.2% w/w); (IV) fiber-type plants that contain cannabigerol (CBG 3) as the main cannabinoid; (V) fiber-type plants largely devoid of cannabinoids. Also in the mix is the Varin-type Chemotype which is specifically rich in the cannabinoid THCv. The latter cannabinoids are certainly spectacular secondary metabolites that have long been in the spotlight of biomedical attention. However, it is also important to discriminate and define the qualitative and quantitative aspects of other chemotypes beyond cannabinoids. Such a systematic approach allows further insights into bioactive constituents, such as cannflavins, which might synergistically contribute to the anti-inflammatory activity of cannabis.
 Moreover, cannabinoid-free strains are necessary for controlled studies to mimic the sensory properties of hemp, guarantee blinding and explain the typical synergy of many botanical extracts besides the isolated cannabinoids. Of all the chemotypes, type V (cannabinoid-free) has been overlooked in terms of phytochemical composition because cannabinoids are absent. Many hypotheses have arisen regarding this inability to produce cannabinoids. For example, the absence of this biosynthesis could be due to the disabling of terpeno-phenolic condensation or a total absence and dysfunctionality of glandular trichomes. The presence of a cannabinoid knock-out factor that leaves unaffected the biosynthesis of other compound classes is decisive in inactivating the pathway toward the phenolic cannabinoid precursor.
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Anyway, cannabis is a prolific producer of metabolites and besides cannabinoids, the plant biosynthesizes other molecules, such as terpenoids responsible for the typical scent, oxylipins, amines and amides, phytosterols and a plethora of non-cannabinoid phenolic compounds [7]. Among non-cannabinoid phenols, denbinobin 4 deserves particular mention for its biological activity and for its recurrence, which is extremely rare in the plant kingdom. Denbinobin 4, a typical ingredient of several orchidaceous plants, has been identified in the IV chemotype of fiber-hemp [8]. Its anti-tumor potential has cogently been conveyed by the title of a commentary in the British Journal of Pharmacology: Escaping immune surveillance in cancer: is denbinobin the panacea? [9]. Other unique compounds of cannabis are canniprene 6 and cannflavins 7a and 8, which open a new field for chemical and biological exploration [1,10]. In particular, canniprene 6 potently inhibits the production of inflammatory eicosanoids via the 5-lipoxygenase (5-LOX) pathway. It outperforms the structural analogue resveratrol in suppressing pro-inflammatory readouts in diverse cell-free test systems and shows a remarkable potential for application in skin care.
The prenylated lipophilic flavonoids, cannflavins 7a and 8, are potent inhibitors of inducible inflammatory enzymes such as microsomal prostaglandin E2 synthase (mPGES)-1 and act as “intelligent” suppressors of the inflammatory response.Given the huge number of bioactive compounds beyond cannabinoids, we were interested in the non-cannabinoid phenolic profile present in the V chemotype, the anti-inflammatory activity of individual components, and the impact of breeding on the chemical and functional fingerprint. For this reason, we here investigated, for the first time, the composition of the Ermo fiber hemp (a variety of hemp with almost no cannabinoids) provided by Canvasalus and reported on the isolation, phytochemical characterization, and biological evaluation of phenolic compounds, of which three derivatives are new. Our phytopharmacological studies employed a targeted metabololipidomics approach and focused on molecular targets within anti-inflammatory, pro-resolving and immunomodulatory lipid mediator biosynthesis pathways.