# _Cannabis sativa_ L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment
## 3 Chemical Composition
### Phytocannabinoids  
From a phytochemical and pharmacological point of view, phytocannabinoids appear to be the most crucial compounds [41]. They are produced mainly in _Camabis_ sp., although their presence has also been reported among plants belonging to the _Helichrysum_ and _Radula_ genus [42]. So far, over 100 different phytocannabinoids have been described in _Camabis sativa_ L., some of them being the breakdown products of original compounds [43]. Phytocannabinoids have 21 carbon atoms or, in the case of carboxylated forms, 22 [42]. Most often, they are tricyclic terpenoid compounds with a benzopyrene group in their structure. Based on the resorcinol side chain, phytocannabinoids have been classified into two classes: alkyl and \(\beta\)-aralkyl [43]. [PERSON], on the other hand, grouped cannabinoids into 11 chemical classes, which are presented in the diagram below (Figure 2) [44]. The structures of the cannabinoids are shown in Figure 3.  
Two pathways are involved in the production of cannabinoid precursors (Figure 4). The first is the polyketide pathway, which produces olivetolic acid. The second is the pathway located in plastids, leading to geranyl diphosphate (GPP). Initially, the hexanoate, which is a short-chain fatty acid, produces hexanoyl coenzyme A (CoA). The latter, in turn, by combining with three malonyl-CoA molecules, gives olivetolic acid, obtained thanks to the action of polyketide cyclase [42]. Then, under the influence of geranyl transferase, cannabigerolic acid (CBGA) is formed, which is the precursor for most cannabinoids [45]. Further transformations to the proper cannabinoids take place thanks to the appropriate oxidocylases [18]. CBD and THC are synthesized by the independent cyclization of cannabigerolic acid [46]. The oxidase reaction to obtain CBD may be completed at this stage but may also arise during smoking or due to the acidic environment, together with small amounts of \(\Delta^{9}\)-tetrahydrocannabinol (\(\Delta^{9}\)-THC) and \(\Delta^{8}\)-tetrahydrocannabinol (\(\Delta^{8}\)-THC) [43]. However, this reaction does not occur naturally in the plant [46]. Figure 2: Classes of phytocannabinoids, according to [PERSON]. [PERSON] [44]. Quantitative data indicate that \(\Delta^{9}\)-tetrahydroocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabinoic acid (CBNA) are the predominant primary phyto-cannabinoids of fresh _C. sativa_ L. [42]. On heating, THCA and CBDA are converted into the two most essential phytocannabinoids produced by _C. sativa_ L.--namely, \(\Delta^{9}\)-tetrahydrocannabinol and cannabidi [47]. The _Cannabis sativa_ ssp. _sativa_ var. _sativa_ (so-called _C. sativa_) usually contains more CBD than THC, while the _Cannabis sativa_ ssp. _india_ var. _india_ (so-called _C. indica_) usually has more THC than CBD [48]. The _Cannabis sativa_ ssp. _sativa_ var. _spontanea_ (the so-called _C. ruderalis_), in turn, is characterized by small levels of THC [49]. However, there are many hybrid varieties, such as Skunk (75% _sativa_ and 25% _india_) [29]. The hybridization process allows for the creation of new strains with selected characteristics. After creating hybrids with _C. ruderalis_, which has auto-flowering properties (flowers appear according to plant age rather than light conditions), the resulting hybrid has the appropriate cannabinoid content and auto-flowering properties [49]. High THC content strains are also obtained [49]. The European Drugs Report 2006-2014 showed a significant increase in THC's average amount in resin and dried hemp. An analysis by the US Drug Enforcement Administration also confirms this trend. The average THC levels have risen from 4 to 12% over the past two decades. A similar phenomenon has been documented in Australia and the Netherlands. This is likely due to advanced production techniques and the desire to elevate THC levels. However, it should be borne in mind that it may also lead to increased toxicity [29]. Figure 4: Diagram of cannabinoid biosynthesis [42].