Nabiximols is not an inducer of CYP3A4 or other major CYP enzymes. Risk for gastrointestinal adverse events in the form of anorexia, reduced appetite, obstipation, diarrhoea, nausea and vomiting motivates vigilance against insufficient intake of food, especially of carbohydrate.

Nabiximols consists of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in 50% v/v ethanol.

Nabiximols is for oromucosal use. Nabiximols is indicated as treatment for symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. Common side effects that can be potentially porphyrinogenic through reduction in carbohydrate intake and that also can be confused with an acute porphyria attack are anorexia, reduced appetite, obstipation, diarrhoea, nausea and vomiting. A less common side effect is abdominal pain.

Through distribution to adipose tissue and trapping in cerebral CB ECS receptors, the oromucosal administration mode reduces the fractions of the total daily maximal dose (32.4 mg THC and 30 mg CBD) reaching the liver for first pass metabolism. The summary of product characteristics reports that 10.8 mg THC (4 sprays) gave a median Cmax of about 4 ng/ml. The maximal dose is 18.9 mg THC (7 sprays) which means that Cmax most probably will be less than 10 ng/ml. This concentration is more than 30 times lower than the 1 µM (314 ng/ml) concentration needed to significantly activate PXR.

THC and CBD are both metabolised by CYP2C9, CYP3A (SPC), CYP1A2, CYP2D6 and CYP2C19 (Product monograph). The initial half-life elimination is 4 hours. The terminal half-life elimination is 24-36 hours or more. Both THC and CBD are mechanism-based inhibitors of CYP1A1 in vitro. CBD is also a mechanism-based inhibitor of CYP1A2 and CYP1B1 (Yamaori 2010). A study in human liver microsomes (preincubated with CBD at 64 µM concentration) showed that the formation of 6-β-hydroxy-THC (catalysed by CYP3A) and the formation of cyclosporine metabolites (catalysed by CYP3A4) were both decreased in a time-dependent manner by 60 to 89% respectively (Jaeger 1996). This indicates that CBD is a mechanism-based inhibitor of CYP3A (Jaeger 1996), and CBD is also listed as a mechanism-based inhibitor of CYP3A4 in vitro by other authors (Grimm 2009). Jaeger (1996) is however, not taken into account since the CBD concentration in vitro was 2000 times higher than those reached in therapeutic use. Another in vitro study showed that CBD inhibits CYP3A competitively and that THC also inhibit CYP3A (Yamaori 2011). CBD is listed as a potent inhibitor of CYP3A4 and a weak inhibitor of CYP2C9 (Nadkarni 2012). In an in vivo study CBD (600 mg/d) decreased the clearance of hexobarbital and increased the AUC by 36% and 51%, respectively (Benowitz 1980). Hexobarbital is metabolised by CYP2C9 and CYP2C19 (Zhou 2009) and the data therefore indicates that CBD is an inhibitor of CYP2C9 or CYP2C19, or both of them in vivo. An in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS showed no relevant induction of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses up to 1 µM (SPC).