### The Endocannabinoid System and Multiple Sclerosis
Further, coupling of olivetolic acid with GPP by geranyl transferase (i.e., through the assembly and modification of a C12 polyketide unit and a monoterpene unit from the deoxyxylulose phosphate pathway) forms cannabigerolic acid (CBGA), which is the biosynthetic starting point for most cannabinoids and a direct precursor of CBD and \(\Delta^{9}\)-THC [28]. CBD is the result of CBGA oxidative cyclisation which results in the formation of a link between C-1 and C-6 of the prenyl unit [29]. Importantly, very recent findings show that a significant amount of CBD transforms to \(\Delta^{9}\)-THC in a hot gas chromatography injection system when acidic precipitation agents, such as TFA, TCA, HClO4, H2 SO4, ZnSO4 or CHCl3, are used for plasma protein precipitation, a finding that can be very important not only for the definition of effective doses and plasma concentrations by pharmacologists and medical doctors examining the pharmacokinetics of CBD-containing drugs for therapeutic purposes, but also for forensic scientists who may find innocent people guilty of using marijuana or its preparations by mistake [30]. \(\Delta^{9}\)-THC, a highly lipophilic (i.e., low water soluble) low vapor pressure resinous oil with a light yellow colour, is a 21-carbon terpenoid with an internal double bond (C9-C10) and two stereocenters (6a, 10a), with the levorotatory trans stereoisomer, (\(-\))-_trans_-\(\Delta^{9}\)-THC (6 aR, 10 aR) [31]. \(\Delta^{9}\)-THC, \(\Delta^{9}\)-THC acid (\(\Delta^{9}\)-THCA) and cannabidiolic acid (CBDA) are the results of CBGA cyclisation through a cationic intermediate with positive charge at C-3 [32]. Specifically for the synthesis of CBDA and \(\Delta^{9}\)-THCA, a stereoselective ring-closure induced either by CBDA or THCA synthase needs to take place, while CBN and CBD subvariants are also formulated from CBGA. [27; 33]. Please see Figure 1 below for the structure of both \(\Delta^{9}\)-THC and CBD. \(\Delta^{9}\)-THC activates both CB\({}_{1}\) and CB\({}_{2}\). It has the highest potency at both CB\({}_{1}\) and CB\({}_{2}\) compared to all other phytocannabinoids. However, it acts as a moderate partial agonist towards both receptors because it cannot induce their full activation to produce a maximal response. Thus, as a partial agonist, it presents a mixed agonist-antagonist profile depending on the cell type, expression of receptors and presence of endocannabinoids or other full agonists [34]. When compared to the endogenous cannabinoids, the CB\({}_{1}\) affinity and potency of \(\Delta^{9}\)-THC is comparable to that of both AEA and 2 AG. \(\Delta^{9}\)-THC also resembles AEA in its functional properties (i.e., they are both partial agonists) and differs from 2 AG, which induces a full response from both receptors as a full agonist [35]. Except for its effects at CB\({}_{1}\) and CB\({}_{2}\), \(\Delta^{9}\)-THC acts as a potent agonist for the putative cannabinoid receptor GPR18, while it also exhibits activation of GPR55 in different assays, without affecting ERK1/2 phosphorylation or \(\beta\)-arrestin recruitment, a discrepancy that needs to be studied further. Moreover, \(\Delta^{9}\)-THC does not affect the vanilloid type 1 receptor (TRPV1; i.e., the capsaicin receptor), while it shows agonistic effects at the TRPV2, TRPV3, and TRPV4 channels [34]. \(\Delta^{9}\)-THC also appears to be a serotonin 5 HT\({}_{\rm 3A}\) receptor antagonist and an allosteric modulator of the opioid receptors. Specific non-G-protein-coupled receptors have also been suggested as agonistic targets of \(\Delta^{9}\)-THC, such the peroxisome proliferatorator activated receptors (PPARs), specifically of the PPAR-gamma subtype, a non-cannabinoid receptor situated on the cell's nucleus. PPARs are a group of three nuclear receptors, namely PPAR-\(\alpha\), PPAR-\(\gamma\), and PPAR-\(\delta\). PPARs are triggered by hormones, endogenous fatty acids, and various nutritional compounds. When activated, PPARs bind to certain segments of DNA to promote or prevent transcription of specific genes.