and gastrointestinal conditions. Moreover, in cases involving topical therapeutics, the role of MSM as an active agent, per se, versus its having a role in promoting skin permeation (in manner, akin to its solvent relative DMSO) must be characterized/controlled. The biochemical effects of supplemental methylsulfonylmethane are poorly understood. Some researchers have suggested that MSM has anti-inflammatory effects. The spectrum of biological effects of dimethyl sulfoxide (DMSO) and MSM differ, but those of DMSO may be mediated, at least in part, by MSM. U.S. FDA action In July 2007 a manufacturer of MSM submitted a notification to the U.S. FDA claiming generally recognized as safe (GRAS) status. GRAS status is for safety, and has no evaluation of efficacy. The FDA responded in February 2008 with a letter of non-objection, functionally designating OptiMSM, the branded form of MSM, as GRAS. The designation allows MSM to be added to meal supplement and meal replacement foods, fruit smoothie-type drinks, fruit-flavored thirst quencher-type beverages, and food bars such as granola bars and energy-type bars. Evidence from clinical trials Small-scale studies of possible treatments with MSM have been conducted on both animals and humans. These studies of MSM have suggested some benefits, particularly for treatment of oxidative stress and osteoarthritis, but evidence for other uses is lacking. Natural Medicines Comprehensive Database contains a continually updated list of health-related MSM studies. Cancer A South Korean study focussing on the role of MSM affecting growth factors associated with breast cancer identifies MSM to have multiple targets, both in vitro and in vivo, including STAT3, STAT5b, IGF-1R and VEGF, confirming the ability of MSM to suppress tumor initiation, growth and metastasis in a dose dependent manner. The expression of triple negative hormone receptors is also down regulated by MSM. In a xenograft model the mice showed inhibited tumor cell migration and suppressed tumor growth in a dose dependent manner when receiving MSM as part of their drinking water at nul, three or five percent MSM weight over volume. The authors strongly recommend MSM as a trial drug for treating breast cancers because of its multi-targeting mechanism. HDL Cholesterol A small 2021 Randomized Controlled Trial on cardiometabolic markers found a possible relationship between a daily dose of 3 g of MSM and High-density lipoprotein (HDL) levels on overweight and obese people. The MSM group demonstrated higher HDL levels after 16 weeks (51.8 ± 2.8 mg/dL) when compared to the baseline