7-hydroxycannabidiol as well as the 6α- and 6β-hydroxy isomers and derivatives hydroxylated on the alkyl side chain, followed by glucuronidation. CYP3A4 facilitates decarbonylation of CBD to liberate carbon monoxide, a bioactive gasotransmitter and pharmaceutical candidate. CBD may have a wide margin in dosing. Pharmaceutical preparations Nabiximols (brand name Sativex), an oromucosal spray made of a complex botanical mixture containing cannabidiol (CBD), delta-9-tetrahydrocannabinol (THC), and additional cannabinoid and non-cannabinoid constituents from cannabis sativa plants, was approved by Health Canada in 2005, to treat central neuropathic pain in multiple sclerosis, and in 2007, for cancer-related pain. In New Zealand, Sativex is "approved for use as an add-on treatment for symptom improvement in people with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication." Epidiolex is an orally administered cannabidiol solution. It was approved in 2018, by the US Food and Drug Administration (FDA) for treatment of two rare forms of childhood epilepsy, Lennox–Gastaut syndrome and Dravet syndrome, and seizures associated with tuberous sclerosis complex. In the US, it is approved in these indications for patients one year of age and older. Chemistry At room temperature, cannabidiol is a colorless crystalline solid. In strongly basic media and the presence of air, it is oxidized to a quinone. Under acidic conditions it cyclizes to THC, which also occurs during pyrolysis, but not during combustion (smoking). The synthesis of cannabidiol has been accomplished by several research groups. Biosynthesis Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the next to last step, where CBDA synthase performs catalysis instead of THCA synthase. Isomerism Pyrolysis In the typical operating temperature range of e-cigarettes (), 25–52% of CBD is transformed into other chemical substances: Δ9-THC, Δ8-THC, cannabinol and cannabichromene as predominant pyrolysates. From a chemical point of view, CBD in e-cigarettes can be considered as a precursor of THC. History Efforts to isolate the active ingredients in cannabis were made in the 19th century. Cannabidiol was studied in 1940 from Minnesota wild hemp and Egyptian Cannabis indica resin. The chemical formula of CBD was proposed from a method for isolating it from wild hemp. Its structure and stereochemistry were determined in 1963. Plant breeding Selective breeding of cannabis plants has expanded and diversified as commercial and therapeutic markets develop. Some growers in the US succeeded in lowering the proportion of CBD-to-THC to accommodate customers who preferred varietals