The two major neuroactive components in cannabis are the psychoactive Δ 9 -tetrahydro-cannabinol (Δ 9 -THC) and the non-psychoactive cannabidiol (CBD). We use non-psychoactive to indicate a lack of psychotropic effects that produce a ‘high’ similar to Δ 9 -THC; however CBD can have some anti-anxiety and other behavioral effects 1 . C. sativa usually has higher Δ 9 -THC:CBD ratios than C. indica. Sativa strains often have more psychotropic effects, and are more stimulating, while indica strains are typically more sedating 2 . Δ 9 -THC activates the endocannabinoid system, which consists of G-protein-coupled cannabinoid (CB) receptors, synthetic and degradative enzymes, and transporters. In the central nervous system, this system influences synaptic communication and modulates eating, anxiety, learning and memory, and growth and development 3 .
To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regards to their relevance to epilepsy and other selected neuropsychiatric disorders.
J.M-O. receives research support from GW Pharmaceuticals.
Inflammatory pain is caused by noxious stimuli that occur during the inflammatory or immune response. Under normal conditions, inflammation is a crucial protective mechanism, which plays an important role in the wound healing process. It is usually accompanied by redness, heat, swelling, pain/hypersensitivity, and loss of function. Nevertheless, in pathological conditions, inflammation may cause long-lasting pain through activation of sensory neurons .
Another important group of CBD targets is enzymes. The cytochrome P450 superfamily (CYPs) of enzymes is of particular interest as the interaction between CBD and CYPs may influence clearance of various drugs, including very commonly used, non-steroidal anti-inflammatory drugs. It has been shown that CBD binds and inhibits activity of various CYPs, including CYP1B1, CYP2C19, CYP2C9, CYP3A4 and CYPC3A7, in physiologically relevant concentrations, with prominent IC50 values for CYP1A1 and CYP3A5 (IC50 = 77 and 195 nM, respectively). Due to the structural properties of CBD, it may also interact with various enzymes involved in lipid metabolism, most of which are involved in AEA metabolism. CBD inhibits rat FAAH activity with IC50 = 1520 nM , but the IC50 for the human isoform of FAAH is over 25,000 nM , which excludes FAAH as a possible target for CBD activity in humans. On the other hand, CBD inhibits alternative and nonspecific enzymes lipooxygenases (LOXs) involved in AEA degradation and production of inflammatory factors from arachidonic acid: LOX15 with IC50 = 2560 nM and LOX5 with IC50 = 73,730 nM . Other studies have presented CBD as a stimulator of ovine COX1 and human recombinant COX2 with an IC50 approximately 10,000 nM  or as an inhibitor of phospholipase A2 (PLA2) from Naja naja venom with an IC50 = 6400 nM . CBD has also been shown to inhibit mitochondrial complex I, II and IV but with very low potency (IC50 = 8200–19,100 nM) . Moreover, CBD inhibits enzyme involved in the conversion of serotonin to melatonin, aralkylamine N-acetyltransferase (AANAT) with IC50 = 1000 nM , and an enzyme involved in tryptophan catabolism, indoleamine-pyrrole 2,3-dioxygenase (IDO) with IC50 = 8900 nM . Few studies have examined CBD’s interaction with enzymes involved in steroid metabolism such as acyl-CoA cholesterin acyltransferase (ACAT) or testosterone hydroxylase; however, either IC50 values were not specified or the concentration that was utilized extended beyond physiologically relevant values [55,56]. Enzymatic targets are schematically summarized in Figure 4 .
Schematic representation of CBD ionotropic targets. Width of the edges (lines) represents relative EC/IC50 ranging between 60 and 20,000 nM.
3.4. Other Pain Models
This work was supported by National Science Centre, Poland by grant OPUS12 UMO-2016/23/B/NZ7/01143 and by Departmental Statutory funds (Maj Institute of Pharmacology, Polish Academy of Sciences).
Taken together, these initial findings imply that CBD represents a promising phytocannabinoid-based treatment option. However, data regarding its mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding the molecular mechanisms of CBD’s actions with particular focus on its analgesic potential. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide readers with current state-of-art knowledge regarding CBD’s action and future perspectives for research. A summary of the data discussed herein will be shared as Supplementary Materials.
2.5. Nuclear Factors
Although isolated earlier  than Δ9-THC, CBD has remained a more elusive and poorly studied substance, because CBD itself does not produce typical behavioral cannabimimetic effects, and was thought not to be responsible for psychotropic effects of cannabis . The complicated legal status of CBD, throughout the world, further restricted the research and professional knowledge about the therapeutic potential of this compound. In spite of the limitations, numerous anecdotal findings testify to the therapeutic effects of CBD, including anticonvulsant, antipsychotic, anxiolytic, neuroprotective and sleep-promoting effects, which are further supported by research . Initial clinical evidence suggests that CBD possesses a desirable safety profile , while numerous preclinical findings present anti-inflammatory effects of CBD [8,9,10,11,12]. However, the pharmacodynamics of CBD have been difficult to elucidate. Initial reports demonstrated that CBD competes poorly with cannabinoid ligands at the orthosteric site of cannabinoid receptors , leading to the conclusion that any action of CBD occurs independent of cannabinoid receptors. Further studies revealed this conclusion as partially true. Indeed, CBD directly interacts with various receptors, enzymes and ion channels; however, it was also shown to directly and indirectly interact with the endocannabinoid system .
The current state of knowledge has exposed CBD’s mechanism action as distinct from the endocannabinoid system. Studies often present CBD’s effects to be mediated by the serotoninergic 5HT1a receptor (5HT1a), which, similar to cannabinoid receptors, is coupled to the Gi protein. Although CBD’s binding to the orthosteric site of 5HT1a is relatively weak (Ki = 16 mM ), 100 nM CBD produced an upward shift in the log concentration response curve of the 5HT1a agonist 8-OH-DPAT that resulted in a statistically significant increase in the Emax , suggesting positive allosteric modulation of 5HT1a.