Lithium is commonly prescribed for bipolar disorder due to its proven efficacy on patients. Despite this effectiveness, the molecular mechanisms underlying its action remain poorly understood, as it appears to influence numerous unrelated pathways. We propose that these diverse effects may stem from a specific physicochemical event: the binding of lithium cations to phospholipid headgroups. In model membrane systems enabling direct observation of the lithium effects on lipid bilayers, we reveal that lithium binding stiffens the membrane, subsequently altering membrane protein activities. This mechanical impact of lithium links existing rationales, drawing a way to decipher the complex lithium effect in bipolar disorder (BD). To illustrate this global effect of lithium, we use the example of intracellular trafficking, a ubiquitous mechanism involving membrane reorganization in all organelles.