### The Endocannabinoid System and Multiple Sclerosis
Many of the genes regulated by PPARs are involved in energy homeostasis, lipid uptake and metabolism, insulin sensitivity, and other metabolic functions. \(\Delta^{9}\)-THC antitumor effects, as well as those of vascular relaxation have been linked to its agonism at PPAR-gamma. Further, low concentrations of \(\Delta^{9}\)-THC significantly enhance the amplitudes of glycine-activated currents and it is this activity of \(\Delta^{9}\)-THC at the glycine receptors (GlyRs) that seems to contribute to the cannabis-induced analgesia in mouse models [34]. \(\Delta^{9}\)-THC undergoes hepatic metabolism to 11-hydroxy-\(\Delta^{9}\)-THC, which is more potent than \(\Delta^{9}\)-THC and also crosses the blood barrier. \(\Delta^{9}\)-THC has a short plasma half-life, because it rapidly diffuses into lipid tissue, but the biological half-life is prolonged. Thus, the tissue elimination half-life of \(\Delta^{9}\)-THC is about 7 days, and complete elimination of a single dose may take up to 30 days. The chemistry, pharmacology and molecular targets of CBD have recently been reviewed extensively [36]. Thus, briefly here, unlike \(\Delta^{9}\)-THC, the more neglected for decades phytocannabinoid CBD has little binding affinity for either CB\({}_{1}\) or CB\({}_{2}\), which likely accounts for its lack of psychotropic activity. Interestingly, and similarly to \(\Delta^{9}\)-THC, CBD is also considered a multi-target compound. At low micromolar to sub-micromolar concentrations, CBD inhibits the equilibrative nucleoside transporter (ENT), the orphan G-protein-coupled receptor GPR55, and the transient receptor potential of melastatin type 8 (TRPM8) channel [37]. On the other hand, CBD enhances the activity of the 5-HT\({}_{\rm 1a}\) receptor, the a3 and a1 GlyRs, the transient receptor potential of ankyrin type 1 (TRPA1) channel,  
Figure 1: Chemical structure of the two most studied cannabinoid molecules; (**a**) \(\Delta^{9}\)-tetrahydrocannabinol, and (**b**) cannabidiol. and has a bidirectional effect on intracellular calcium. Quantitative results of CBD's membrane protein interactions by target, cell type, and IC\({}_{50}\) or EC\({}_{50}\) indicate that CBD IC\({}_{508}\)/EC\({}_{508}\) are considerably similar between all its targets (with the exception of GlyRs), with IC\({}_{508}\)s ranging between 0.06-4 \(\upmu\)M for the different receptor targets [38], while for the sodium channels specifically the IC\({}_{50}\) range is 1.9-3.8 \(\upmu\)M [39]. At higher micromolar concentrations, CBD acts primarily through receptor-independent channels and by binding with various non-cannabinoid receptors. It activates the TRPV1 and TRPV2 channels (EC\({}_{50}\) = 3.2 \(\pm\) 3.5 \(\upmu\)M) [40]. Further, recent studies indicate that CBD influences the expression of some genes by directly activating PPARs, specifically the PPAR-gamma subtype. It also promotes PPAR-\(\upalpha\) activity by inhibiting fatty acid amide hydrolase (FAAH). The ability of CBD to activate PPAR-\(\upgamma\) has promising therapeutic implications, particularly with respect to cancer and metabolic disorders [41]. For a very recent and detailed presentation of phytocannabinoid concentrations and corresponding receptor potencies of cannabis extracts, as well as pure phytocannabinoids and reference compounds, please see the very interesting study by [PERSON] and colleagues [42]. At a very recent systematic review on the pharmacokinetics of CBD in humans [43], it was found that, while in animal studies oral bioavailability is low, in human studies, the half-life of CBD was reported between 1.4-10.9 h after oromucosal spray, 2-5 days after chronic oral administration, 24 h after intravenous administration, and 31 h after smoking. As with other disorders, the question that arises is whether cannabinoid compounds can be used to treat MS. If so, are they effective and what is their mechanism of action in improving symptomatology?