2026 ECNP Congress

PS03-3206

Lithium orotate in neuropsychiatry: a narrative review of preclinical evidence and clinical gaps

Inés Oliveira Amat — J.J. Retuerta Rodríguez-Vilariño, R. Albillos Pérez, I. Gundín Menéndez, N. Laherran-Cantera, I. Lizarraga García · Hospital General Universitario Gregorio Marañón, Psychiatry, Madrid, Spain

2026 ECNP Congress

Introduction

Lithium remains a gold-standard maintenance treatment for bipolar disorder, but its use is constrained by a narrow therapeutic window and risks of renal and thyroid dysfunction [1,2]. Lithium orotate, an organic salt marketed as a dietary supplement, has attracted renewed interest on the basis of hypothesised improved tolerability and central nervous system delivery compared with conventional lithium carbonate [3,4]. Concurrently, recent work has implicated endogenous brain lithium deficiency in the early pathophysiology of Alzheimer’s disease, with preclinical attenuation of cognitive and pathological changes using lithium orotate, raising questions about its potential as a neuroprotective agent [5]. This review aimed to examine whether lithium orotate offers any clinically meaningful advantage over conventional lithium salts, and whether emerging neurobiological findings justify its absence or adoption in routine psychiatric practice [3,5].

Methods

We conducted a narrative review of PubMed/MEDLINE, Web of Science and Scopus up to April 2026, using combinations of “lithium orotate” with “pharmacokinetics”, “safety”, “toxicity”, “bipolar” and “Alzheimer’s disease”, alongside comparative terms including “lithium carbonate AND efficacy AND bipolar”, “lithium AND suicide AND meta-analysis” and “lithium deficiency AND Alzheimer’s disease” [1,2,3,5]. We included preclinical and human studies on lithium orotate and systematic reviews of conventional lithium salts, excluding opinion pieces and promotional content without primary data [2,3].

Results

Recent findings suggesting reduced brain lithium levels as an early vulnerability factor in Alzheimer’s disease have prompted renewed interest in how different lithium salt formulations may influence brain delivery and central nervous system exposure [5]. Preclinical work suggests lithium orotate exerts behavioural effects at lower doses than lithium carbonate in rodent models of amphetamine-induced hyperlocomotion, with near-complete prevention of manic-like behaviour at doses several-fold lower than those required for carbonate to produce partial effects [4]. This enhanced potency may reflect differential membrane transport mechanisms involving the orotate anion, although a contribution to differential transport has also been hypothesised, supporting carrier-mediated uptake and potential interactions with pyrimidine metabolism. Interpretation of the preclinical evidence remains limited by non-equivalent dosing and heterogeneous experimental conditions [3,4]. These findings may indicate a formulation-specific effect and provide a plausible mechanistic rationale for further study, but the available evidence remains preclinical and does not establish routine clinical superiority [3,4]. In contrast, robust meta-analyses confirm that conventional lithium salts reduce relapse and suicide in bipolar disorder and characterise their renal and endocrine toxicity in large clinical samples [1,2].

Conclusions

Lithium orotate occupies an uneasy space between experimental neurobiological promise and unregulated supplement use [3,5]. Preclinical and early translational data support its plausibility as a low-dose lithium delivery strategy and suggest potential relevance for Alzheimer’s disease pathophysiology, but the near-absence of adequately powered controlled trials, together with uncertain long-term safety under routine, unmonitored use, does not support its routine adoption as a psychiatric treatment or preventive neuroprotective intervention at present [2,5]. Further controlled studies are required to clarify whether any observed formulation-specific effects translate into clinically meaningful benefit.

References

  1. Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. doi:10.1136/bmj.f3646.
  2. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721-8. doi:10.1016/S0140-6736(11)61516-X.
  3. Pacholko AG, Bekar LK. Lithium orotate: A superior option for lithium therapy? Brain Behav. 2021;11(8):e2262. doi:10.1002/brb3.2262.
  4. Pacholko AG, Bekar LK. Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania. J Psychiatr Res. 2023;164:192-201. doi:10.1016/j.jpsychires.2023.06.012.
  5. Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025;645:712-721. doi:10.1038/s41586-025-09335-x.