to binding to P-glycoprotein. However, higher doses of dexamethasone override the export capacity of P-glycoprotein and enter the brain to produce central activation of GRs. In conjunction with the suppression of endogenous corticosteroids by dexamethasone, this results in skewed ratios of activation of peripheral versus central GRs as well as skewed ratios of activation of GRs versus MRs when compared to non-synthetic corticosteroids. These differences can have significant clinical relevance. Chemistry Dexamethasone is a synthetic pregnane corticosteroid and derivative of cortisol (hydrocortisone) and is also known as 1-dehydro-9α-fluoro-16α-methylhydrocortisone or as 9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. The molecular and crystal structure of dexamethasone has been determined by X-ray crystallography. It is a stereoisomer of betamethasone, the two compounds differing only in the spatial configuration of the methyl group at position 16 (see steroid nomenclature). Synthesis To synthesize dexamethasone, 16β-methylprednisolone acetate is dehydrated to the 9,11-dehydro derivative. This is then reacted with a source of hypobromite, such as basic N-bromosuccinimide, to form the 9α-bromo-11β-hydrin derivative, which is then ring-closed to an epoxide. A ring-opening reaction with hydrogen fluoride in tetrahydrofuran gives dexamethasone. History Dexamethasone was first synthesized by Philip Showalter Hench in 1957. It was introduced for medical use in 1958. On 16 June 2020, the RECOVERY Trial announced preliminary results stating that dexamethasone improves survival rates of hospitalized patients with COVID-19 receiving oxygen or on a ventilator. Benefits were only observed in patients requiring respiratory support; those who did not require breathing support saw a worse survival rate than the control group, although the difference may have been due to chance. A preprint containing the full dataset was published on 22 June 2020, and demand for dexamethasone surged after publication of the preprint. The preliminary report was published in The New England Journal of Medicine on 18 July 2020. The final report was published in February 2021. The World Health Organization (WHO) states that dexamethasone should be reserved for seriously ill and critical patients receiving COVID-19 treatment in a hospital setting, and the WHO Director-General stated that "WHO emphasizes that dexamethasone should only be used for patients with severe or critical disease, under close clinical supervision. There is no evidence this drug works for patients with mild disease or as a preventative measure, and it could cause harm." In July 2020, the WHO stated they are in the process of updating treatment guidelines to include dexamethasone or other steroids. In September 2020, the WHO released