Mitragynine, an analgesic alkaloid from the kratom plant, has a more favorable side effect profile than clinical opioids like morphine. The biosynthetic pathway for mitragynine was previously unknown. Researchers identified several reductases and an enol methyltransferase forming a new clade within the SABATH methyltransferase family from kratom and related Rubiaceae transcriptomes. They also discovered a methyltransferase from Hamelia patens that catalyzes the final step. Using a tryptamine 4-hydroxylase from Psilocybe cubensis, they achieved four-step biosynthesis of mitragynine and its stereoisomer speciogynine in yeast and E. coli supplied with tryptamine and secologanin. This marks the first microbial biosynthesis of kratom opioids. The enzyme promiscuity suggests potential for generating derivatives and analogs.
A meta-analysis of nine randomized controlled trials involving 1,449 patients found that esketamine improves symptoms in treatment-resistant depression but significantly increases dose-dependent adverse events. Compared with controls, esketamine raised the risk of nine adverse events including nausea, dissociation, dizziness, vertigo, elevated blood pressure, and somnolence. Risks were strongly dose-dependent: the high-dose group (≥56 mg or 0.40 mg/kg) had a greater risk than the low-dose group (≤28 mg or 0.20 mg/kg), with relative risk for nausea of 3.72 versus 1.69 and for dissociation of 10.65 versus 3.27. Although esketamine improved clinical response rate (relative risk = 1.94), it increased treatment discontinuation due to adverse events by 2.22-fold. Clinical use should adopt personalized dosing strategies balancing efficacy and tolerability.