Lithium orotate: distinct compound or simply Li ⁺ after administration?

Summary The recent study by Aron et al about lithium deficiency and the onset of Alzheimer’s disease provides a valuable explanatory framework for understanding how very small doses of lithium, delivered via environmental exposure, can exert neuroprotective effects. It also contains results which will need to be reconciled with foundational chemistry and existing evidence and which could be potentially misleading. The suggestion that lithium orotate (LiO) exhibits benefits relative to the more traditionally used lithium carbonate (LiC) requires further scrutiny in light of the following arguments: (a) no study has demonstrated the presence of stable LiO in physiological fluids; (b) acid–base chemistry predicts that LiO will be largely protonated in the stomach, causing it to dissociate and be absorbed as Li + ; (c) experimental studies indicate that LiO and LiC have comparable pharmacokinetics after oral administration; and (d) previous research has shown that LiC also has neuroprotective effects, including at very low doses. Disproportionate focus on a specific lithium salt could have safety implications and may distract from answering fundamental questions about the effects of very low doses of lithium. More experiments are needed to provide evidence of a stable LiO complex in physiological fluids before this becomes the main form of lithium in future clinical trials.