Excess S-Adenosylmethionine inhibits methylation via catabolism to adenine

Abstract The global dietary supplement market is valued at around USD 100 billion. S-adenosylmethionine is available as a supplement to improve joints and “emotional well-being” in the US since 1999, and has been a prescription drug in Europe to treat depression and arthritis since 1975, but recent studies questioned its efficacy. In our body, S-adenosylmethionine is critical for the methylation of nucleic acids, histones and many other targets. It is believed that more S-adenosylmethionine is better since it would stimulate methylations and improve health. In many organisms, methyl metabolism is critical for biological rhythms, the extent of methylation deficiency being proportional to the magnitude of rhythm disruption. Here, using biological rhythms to assess the effects of exogenous S-adenosylmethionine, we reveal that excess S-adenosylmethionine disrupts rhythms and, rather than promoting methylation, is catabolized to adenine and methylthioadenosine, toxic methylation inhibitors. This prompts for a re-evaluation of S-adenosylmethionine’ s safety as a supplement.