### The Endocannabinoid System and Multiple Sclerosis  
For centuries, both recreational and medicinal use of cannabis was blind. The biological explanations for its effects were unknown. With a spike in recreational drug use in America during the 1960s, a similar spike was seen in studying its effects [17]. From studying the endocannabinoid system, researchers have been able to understand the impact cannabis compounds can have on the body and mind [13; 14; 15]. The endocannabinoid system is comprised of at least two types of Class A G-protein-coupled receptors which exhibit primarily Gi/o signaling mechanisms: the cannabinoid 1 receptor (CB\({}_{1}\)) and the cannabinoid 2 receptor (CB\({}_{2}\)) which can be activated by endogenous cannabinoids, synthesized on demand, or exogenously administered compounds [18]. Receptors for these endogenous ligands can be found in the CNS, both in the brain and spinal cord, mainly in the frontal cortex, basal ganglia and cerebellum, and diffusely around the body, most notably in the gastrointestinal tract, adipose tissue, liver and connective tissues [19]. Importantly, cannabinoid receptors can be found in the presynaptic junction, thus engaging in retrograde signaling, a specific feature of this biochemical system [20]. The first endogenous cannabinoid ligand identified, \(N\)-arachidonoylethanolamide, shortened to anandamide after the Sanskrit word Ananda which means \"bliss\", was first discovered in 1992 by mass spectrometry and magnetic resonance spectrometry [21]. Following shortly after, the second endogenous cannabinoid ligand 2-arachidonoylglycerol (2-AG) was discovered [22]. These endo-cannabinoid compounds are produced immediately before excitatory release after being synthesised from fatty compounds in the cell membrane. Once these compounds have been released mostly from the cell body and dendrites, they exert their effect on presynaptic neurons [17]. Interestingly, the most recently defined expanded endocannabinoid system, i.e., the endocannabinoidome, includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes [23], all of which seem to play a role in the therapeutic effects on MS and other neurodegenerative conditions. Cannabinoids are complex and include constituents in the classes of polyketides, terpenoids, sugars, alkaloids, flavonoids, and quinones; they are a class of meroterpenoids. The cannabis plant has two compounds that have been studied extensively, and both are found in greatest abundance in a waxy resin surrounding the cannabis plant leaves and flower [24] The first one is \(\Delta^{9}\)-tetrahydrocannabinol (\(\Delta^{9}\)-THC), the main psychoactive constituent of the cannabis plant and the most abundant one, which was first discovered in 1964 by [PERSON] and [PERSON] [25], and confirmed by synthesis and X-ray crystallography as a benzenesulfonate ester. The second component is cannabidiol (CBD), a non-psychoactive cannabinoid ligand, whose chemical structure was successfully isolated in 1940 and elucidated by [PERSON] and [PERSON] in 1963 [26]; other pharmacologically interesting compounds are cannabinoid (CBN), cannabinoid acids and cannabivarin (CBV). In regards to the chemical structure and biosynthetic pathways of cannabinoids, including \(\Delta^{9}\)-THC and CBD, there is a structural similarity comprising a resorcinol (A-ring) and terpinoid moiety (C-ring). Terpenoids are formulated starting from the (non)-mervalonate pathways which produce dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). Both DMAPP and IPP are then coupled by geranyl pyrophosphate synthase to form geranyl pyrophosphate (GPP) which is a precursor for many terpenoids [27].