This revised application is responsive to FOA PAS-20-160 “Small R-01’s for Clinical Trials Targeting Diseases Within the Mission of NIDDK”. Both Type 1 diabetes (T1D) and Type 2 diabetes (T2D) ultimately result from inadequate numbers of normally functioning, insulin-producing beta cells, yet essentially everyone with T1D or T2D has residual beta cells. This beta cell deficiency underlies the use of pancreas and islet transplant in diabetes and the development of stem cell-derived approaches for beta cell replacement for diabetes. These approaches are effective or feasible, but not scalable to the 463 million people globally with diabetes. Despite the well documented deficiency in beta cell numbers, and despite a plethora of clinically-available diabetes drugs, there are no drugs in current clinical use that induce human beta cells to replicate or regenerate. We and others have identified a novel class of orally available small molecules, the DYRK1A inhibitors, that are highly effective in stimulating human beta cells to proliferate, to increase in number in vitro and in vivo, to enhance human beta cell differentiation, and to reverse diabetes in vivo in a marginal mass human islet transplant setting. In addition, the human beta cell proliferation induced by DYRK1A inhibitors is markedly potentiated by GLP1 receptor agonists in clinical use such as exenatide, liraglutide, semaglutide, lixisenatide and others. Thus, regeneration of human beta cells in diabetes is now feasible, and it is appropriate to begin to analyze the safety of DYRK1A inhibitors. Among the several known DYRK1A inhibitors, most are synthetic and are supported by little or no preclinical data. In contrast, one, harmine, is a natural, plant-derived molecule that has been used in humans for centuries in a concoction called Ayahuasca. Ayahuasca contains a number of biologically and neuro-psychologically active compounds, in addition to harmine, including the likely psychoactive compound, 5-,5’-dimethyltryptamine (DMT). Most authors suggest that the psychoactive component of Ayahuasca is DMT, and not harmine. Harmine - in therapeutic beta cell- regenerative doses in mice - caused no adverse effects in three-month studies. However, it is unknown whether orally administered pure harmine leads to adverse effects in humans, and if so at what doses these might occur. Since harmine is very effective in inducing human beta cell regeneration in vitro and in vivo, since preclinical data suggest that harmine is safe, and since Ayahuasca is not known to have chronic adverse effects in humans, we propose an open label, Phase 1, single dose escalation study of orally administered pure harmine. There is one Specific Aim: Specific Aim. To Perform A Single Rising Dose Human Phase 1 Clinical Trial with Pure Harmine. Our Primary Outcome Measure is the identification of the Maximally Tolerated Dose (MTD) of harmine in humans. Secondary outcome measures include defining the adverse effects of harmine i...