Activation of AhR halts inflammation notably through induction of interleukin-22 . Of interest, activation of AhR, dependent or independent of the gut microbiota, has been reported to limit the production of microglial pro-inflammatory mediators such as transforming growth factor alpha  and vascular endothelial growth factor B  in a mouse model of MS. Interestingly, oral administration of Lactobacillus acidophilus was shown to combat in- flammation and nociception through increasing the expression of the CB2 receptor in intestinal epithelial cells, suggesting that probiotics and cannabinoids might work together to halt inflammation and nociception. In support of this, it has recently been shown that THC reduces inflammation and adiposity in mice by increasing the accumulation of mucin-degrading bacteria, Akkermansia municiphila. Of relevance, Akkermansia municiphila supplementation was shown to reduce systemic inflammation in mice, further supporting the notion that microbiota contributes to the anti-inflammatory and analgesic effects of oral cannabinoids.Terpenes are volatile unsaturated hydrocarbons that represent the largest group of plant organic chemicals with around 20,000 fully characterized compounds. Terpenes account for a unique aroma of cannabis, but there is evidence that they may play more of a role in biology than simply affecting taste/aroma of cannabis. Indeed, while > 200 terpenes have been identified in cannabis, 3 monoterpenes, , and sesquiterpenoid, , have been shown to have biological importance. Indeed, sedation and a decrease in motility have been observed in mice upon inhalation exposure to terpenoids in a concentrations equivalent to 0.05% v/w for 1 h. In addition to having their own independent effects, these cannabis-derived terpenoids have beenpostulated to modulate the effects of cannabinoids via what has been termed the “entourage effect”. However, it is important to note that many terpenoids appear to modulate molecular/biological functions only when the concentration of the terpene in full-spectrum cannabis extract is above 0.05% v/w. β-caryophyllene is the most common sesquiterpenoid, a class of terpenes that contain three isoprene units, and one of the most predominant terpenoids in cannabis extracts.

There is evidence that β-caryophyllene may synergize the anti-inflammatory and the analgesic effect of THC through the inhibition of prostaglandin E1 and the activation of the CB2 receptor, respectively. Therefore, the synergistic effect of β-caryophyllene with THC strongly suggests that the potential health benefits of complete cannabis extracts may be more evident in the treatment of inflammation compared to THC alone. Of interest, mobile grow system the anti-inflammatory activity of β-caryophyllene is comparable to the potency of the nonsteroidal anti-inflammatory drug, phenylbutazone, suggesting that this terpene is a potent anti-in- flammatory molecule. β-caryophyllene also inhibits lipopolysaccharide -induced proinflammatory cytokine expression through the activation of the CB2 receptor. On the other hand, β-caryophyllene lacks any anti-inflammatory or anti-nociceptive activities in mice lacking CB2 receptors suggesting that β-caryophyllene exhibits cannabimimetic-dependent effects. In support of this, β-caryophyllene has been identified as a natural selective agonist of the peripherally expressed CB2 receptor. Of importance, oral administration of β-caryophyllene attenuates thermal hyperalgesia, mechanical allodynia and spinal neuroinflammation in a neuropathic pain model and suppresses neuroinflammation in an animal model of MS suggesting that β-caryophyllene is an effective anti-inflammatory molecule for the treatment of MS.D-limonene is the second most widely distributed terpenes found in nature. While D-limonene has a low affinity for cannabinoid receptors, it synergizes the anxiolytic, anti-stress and sedative effects of CBD by increasing serotonin and dopamine in the prefrontal cortex and hippocampus through 5-HT1A receptor. Similar to myrcene, D-limonene suppresses the metabolism of Aflatoxin B1 to its carcinogenic active metabolite and thus it may act as a chemopreventive agent. Furthermore, D-limonene was shown to induce apoptosis in human breast cancer cells, and this effect has been postulated to potentiate the antitumor activity of CBD in advanced stages of breast cancer.Cannabis is commonly administered via inhalation  or orally in the form of syrup , oromucosal aerosol  or capsule. Since inhaled therapies involving cannabis may pose certain health risks, alternative routes of delivery such as oral administration have been studied. Perhaps one of the largest challenges associated with the use of cannabinoids as an orally available medical therapy is their low bioavailability. Although cannabinoids are highly absorbed when administered orally, they have a very low bioavailability due to the first pass metabolism .

Of interest, this issue might be less pronounced in the full extract, as it has been suggested that other components present in the full-spectrum cannabis extract modulate the bioavailability of THC and CBD.The high absorption rate of THC upon inhalation either by smoking or vaporization results in a time to peak plasma levels of 6–10 min and a bioavailability of 10–35%. In contrast, when THC is administered orally, the time to peak plasma levels is between 2 and 6 h and the bioavailability is very low. Similar to THC, CBD has poor oral bioavailability but CBD has a higher absorption rate than THC with a time to peak plasma level of 2 h. Notably, the absorption of both THC and CBD can be improved using oil vehicle such as sesame oil or a glycocholate solution, suggesting that the administration of THC and CBD using oil based formulation might be the best existing oral dosage form for THC and CBD . The poor oral bioavailability of cannabinoids is largely attributed to the first pass metabolism in hepatic tissue. CYP2C9 and CYP2C19 are the main enzymes responsible for the metabolism of THC into 11-OH-THC. While 11-OH-THC is psychoactive like THC, it is oxidized in the liver into an inactive metabolite THC-COOH which is eventually conjugated to glucuronic acid by UDP-glucuronosyltransferase . The presence of the glucuronide group increases the polarity and thus water solubility of this metabolite, which facilitates its excretion in the urine. Thus, the THC-COOH glucuronide conjugate in the urine is considered to be a good biomarker for THC-containing cannabis use. Interestingly, while 25% of THC metabolites are excreted in the urine, > 65% of these metabolites are eliminated in the feces. Similar to THC, orally administered CBD is extensively metabolized into an inactive metabolite, 7-OH-CBD, by the CYP2C19, CYP3A4, CYP1A1, CYP1A2 and CYP2D6 enzymes in the liver. CBD and 7-OH-CBD are then eliminated in the feces, with a minor amount being excreted in the urine. Interestingly, CBD has been shown to bind to the catalytic site of CYP2C9 and CYP2C19 and competitively suppress the activity of these enzymes. Thus, CBD has been reported to inhibit CYP2C9 mediated hydroxylation of THC to 11-OHTHC providing a molecular mechanism that may explain why CBD can improve the oral bioavailability of THC. Intriguingly, β-myrecene and other terpenoids in cannabis have been shown to enhance the effect of CBD on hepatic CYP enzymes. Importantly, the effect of CBD on CYP enzymes could have implications for the metabolism of other drugs and thus may be either additive or contraindicated for specific existing pharmacotherapies.

Indeed, CBD was shown to decrease the metabolism and the excretion of anti-convulsant drugs, hexobarbital and clobazam in human subjects, which results in an increase in the plasma level of the aforementioned drugs and subsequently their side effects. Thus, care should be taken when CBD is co-administered with hexobarbital and clobazam.Epidiolex is an oil formulation of purified, plant-derived CBD that has been recently approved by FDA for the treatment of certain rare and catastrophic forms of childhood-onset epilepsy such as Lennox–Gastaut Syndrome and Dravet Syndrome. Another clinically approved product derived from cannabis extract is Sativex. Sativex is an oromucosal spray containing a full-spectrum cannabis extract with a standardized ratio of THC and CBD in addition to other cannabinoids and terpenes in an aromatized water-ethanol solution. Sativex has been approved in many countries such as Canada, UK, Spain and Germany for the treatment of symptoms associated with MS. In addition to Epidiolex and Sativex, Cannador is an oral capsule containing a full plant extract, mobile vertical rack with a standardized ratio of THC and CBD that has been used in several clinical trials for the treatment of symptoms associated with MS.While numerous studies have investigated the effects of cannabis extracts in multiple disease conditions, some of the most impactful effects appear to occur in the treatment of inflammation and neuropathic pain. For instance, the role of full-spectrum cannabis extract in the treatment of spasticity and neuropathic pain has been investigated in a mouse model of amyotrophic lateral sclerosis . In a mouse model of ALS, mice treated daily with 20 mg/kg Sativex for 20 weeks displayed significantly reduced progression of neurological deficits and had improved survival, particularly in females. The protective effect of Sativex has also been confirmed in a mouse model of MS. This study utilized the Biozzi ABH mice with chronic relapsing experimental allergic encephalomyelitis as a model of MS. These mice were treated with a full-spectrum cannabis extract, Sativex, baclofen  or vehicle and the stiffness of limbs of the mice were evaluated by measuring the force required to flex the hind limb. In a manner similar to baclofen, Sativex significantly reduced neuropathy and spasticity by approximately 40% compared to control. Overall, the study proposes that Sativex is as effective as baclofen in the treatment of symptoms associated with MS. The neuroprotective effect of Sativex has also been studied in the Theiler’s murine encephalomyelitis virus-induced demyelinating disease model of MS.

Treatment of these mice with 10 mg/kg i.p. of Sativex significantly improved the neurological deficits associated with MS . Specifically, Sativex significantly improved motor activity, reduced axonal damage and restored myelin morphology in MS mice. Mechanistically, Sativex was shown to act as an anti-in- flammatory agent as it suppressed microglial reactivity, the expression of proinflammatory cytokine IL-1β and adhesion molecules, and it upregulated the anti-inflammatory cytokines, arginase-1 and IL-10. Furthermore, Sativex was able to decrease the accumulation of chondroitin sulfate proteoglycans and astrogliosis in the spinal cord of MS mice and in astrocyte culture in vitro. In order to explore whether or not the protective effects observed with Sativex were due to extracted CBD, THC or both, MS mice were treated with extracted CBD or THC alone. In a manner similar to Sativex, extracted CBD was sufficient to significantly lessen the motor deterioration and axonal damage whereas extracted THC induced much weaker effects. Together, these findings suggest that the neuroprotective and anti-inflammatory effects of Sativex are mainly due to CBD. Contrary to the previous study , another study found evidence that the neuroprotective effect of Sativex was due to THC. In that study, female C57BL/6 mice with a bacteria-induced experimental autoimmune encephalitis and MS were treated with Sativex, extracted THC, or extracted CBD. Notably, while administration of Sativex, extracted THC, and extracted CBD all produced beneficial effects in neurological function, only Sativex and extracted THC maintained improvement of the neurological function along with reduced cell in- filtrates in the spinal cord and thus slowed disease progression. Importantly, the beneficial effect of extracted THC was abolished by the treatment of mice with the CB1 receptor antagonist, rimonabant, suggesting a CB1-dependent mechanism.Although the discrepancy between the two studies discussed above is unknown, it is possible that the differences may be attributed to different environmental conditions for each study and/or sex differences For instance, the first study was performed on male mice using virus-induced demyelinating disease model of MS, while the later study was conducted on female mice with bacteria-induced experimental autoimmune encephalitis disease-related MS. Thus, it is possible that the effects of Sativex, THC and/or CBD are dependent on sex, species, or pathogenesis of MS. Nevertheless, given that the beneficial effect of fullspectrum cannabis extract was consistent in both studies, this would highlight a crucial role of full-spectrum cannabis extract, in this case Sativex, in the treatment of neuropathic pain and inflammation associated with MS. As mentioned, in addition to MS, cannabis extracts have also shown promise in the treatment of neuropathic pain associated with other conditions. Indeed, an important role of full-spectrum cannabis extract in the treatment of neuropathic pain compared to purified THC or purified CBD has been studied in a rat model of chronic constriction injury of the sciatic nerve. In this study, rats were treated with full-spectrum cannabis extract, purified CBD or purified THC. Of note, the full-spectrum cannabis extract used in this study contained 64.5% CBD, 4% THC, < 4% of other cannbinoids  and additional minor components.