Discussion

This study presents that various dose ranges of elemental lithium are marketed in the US as dietary supplements, as a sole ingredient, or in combination with other active ingredients such as vitamins/minerals. The median dose of elemental lithium across supplements was 1.5 mg, which is approximately 37 times lower than 300 mg of lithium carbonate, as carbonate salt at that dose includes 56 mg of elemental lithium (Table 3).^{(Reference Meyer and Stahl18,Reference Kim, Chen and Cheng19)} Various lithium salts are used in dietary supplements, but the majority are lithium orotate. At these doses, lithium-containing products are generally considered dietary supplements, although some include 20 to 25 mg of elemental lithium, comparable to the elemental lithium content of the lowest available dose of lithium carbonate (150 mg). While human studies of lithium-containing supplements are lacking, some preclinical data exist. An earlier study suggested that lithium orotate may be nephrotoxic at concentrations comparable to lithium carbonate in a rodent model.^{(Reference Smith and Schou20)} Although the kinetics of lithium salts might be different, as another suggested that the orotate form has higher brain lithium concentrations than carbonate salt in a preclinical model, which might imply that lower doses of lithium orotate compared to carbonate salt could achieve therapeutic brain levels.^{(Reference Kling, Manowitz and Pollack21)} Aligning with this, a recent study on a preclinical mouse model of mania suggested that lithium orotate is more potent, efficacious, and tolerable compared to lithium carbonate.^{(Reference Pacholko and Bekar22)} Regardless, this evidence remains preclinical, and further studies are required to determine how these findings translate to clinical settings. Furthermore, the health impact of lithium supplements at varying doses and in different salt forms remains unclear. Given these potential pharmacokinetic and tolerability differences between salt forms, it is notable that 26.3% of products did not disclose the lithium salt formulation despite reporting an elemental lithium amount, raising transparency concerns and limiting interpretability. Even though these supplements contained substantially lower lithium than standard psychiatric doses, it remains unclear how such trace to microdoses could affect people with comorbidities such as kidney disorders, those on other medications, or older adults, who are typically monitored during clinical lithium use.^{(Reference Tondo, Alda and Bauer23)}

Table 3.

Lithium salt forms and their approximate elemental lithium amounts per 100 mg salt

Table 3. Long description

A table comparing different lithium salt forms and their approximate elemental lithium amounts per 100 mg salt. The table has six rows and two columns. The first column lists the salt forms, and the second column lists the approximate elemental lithium amounts per 100 mg salt. Row 1: Lithium carbonate, 18.8 mg. Row 2: Lithium orotate, 3.8 mg. Row 3: Lithium citrate, 7.4 mg. Row 4: Lithium aspartate, 5 mg. Row 5: Lithium chloride, 16.4 mg.

Lithium is well established for its mood benefits in clinical practice, while its effects on cognition have been a long-debated topic. A recent study suggested that lithium may be the only metal reduced in the human brain in mild cognitive impairment and demonstrated that lithium depletion in a rodent model leads to amyloid-β accumulation and tau phosphorylation, effects that were prevented by lithium orotate replacement.^{(Reference Aron, Ngian and Qiu24)} It is essential in the context that there is increasing evidence that low-dose lithium treatments might lead to benefits in various conditions, including cognitive decline or augmentation of mood disorders.^{(Reference Strawbridge, Kerr-Gaffney and Bessa25)} Although these represent active areas of research, they do not yet establish the safety, efficacy, or appropriate dosing of lithium-containing dietary supplements in humans and warrant further evaluation.

Lithium-only products reported markedly higher elemental lithium than combination products. This likely reflects product design, as lithium-only supplements are marketed specifically for lithium intake, whereas combination products were predominantly broad multi-mineral or multivitamin formulations in which lithium appeared as one of many trace ingredients. Products that made mood claims had significantly higher reported elemental lithium than those that did not, which might be related to the benefits of lithium on mood, and manufacturers might infer a perception of dose–response correlation in marketing. Nevertheless, there are no human studies evaluating the mood effects of different microdoses of elemental lithium to date. Elemental lithium amount correlation was not evident for cognitive claims. It is important to note that most of the products did not make mood or cognitive claims, nor did they identify kidney-related or concomitant antidepressant use as a caution. This can align with trace to micro doses of lithium and the common understanding that dietary supplements might not have harmful effects, while studies are lacking related to lithium as dietary supplementation and possible harmful effects in the short or long term. Although we have multiple studies in the last decades on the safety of lithium carbonate in humans, including across different age groups and long-term effects,^{(Reference Amerio, Ossola and Scagnelli26,Reference Ferensztajn-Rochowiak and Rybakowski27)} the literature is scarce on the safety of other lithium salts. Given the over-the-counter nature of these supplements, intentional or unintentional toxicities can also occur, as toxicity with lithium orotate supplements is reported in the literature.^{(Reference Pauzé and Brooks28)} Not only lithium supplementation itself but also its interactions with medications are important, as supplement-drug interactions are a general concern and well described in the literature.^{(Reference Gardiner, Phillips and Shaughnessy29)}

There were no label claims related to suicide identified in this study, which is most likely attributable to common labelling practices and regulatory prohibitions against claiming to prevent, treat, or reduce a clinical outcome, as well as legal liability in the US. On the other hand, most products used precautions to warn consumers about lithium use in pregnancy or breastfeeding, which might reflect the well-known risks of cardiac and other congenital malformations.^{(Reference Fornaro, Maritan and Ferranti30)} However, the effects of lithium supplements at trace to micro doses on pregnancy outcomes have not been studied. Products that included pregnancy and breastfeeding precautions were labelled with significantly higher lithium doses than products with no such precautions, which might indicate similar labelling practices for linear dose-adverse outcome perception. Regardless of whether trace-dose lithium poses a risk in pregnancy, these products are marketed with inconsistent precautions and limited labelling detail, leaving consumers without reliable guidance on safe use. Neither kidney-related nor concomitant antidepressant use precautions were significantly associated with lithium amounts after correction for multiple comparisons. This may reflect limited subgroup sizes or the absence of a true relationship.

About 10% of products reported lithium carbonate or lithium citrate, the two salt forms approved by the FDA for prescription lithium therapy. Although the elemental lithium in these supplements was substantially below prescription levels, the presence of these conventional prescription salts in over-the-counter products is worth noting. Prescription products report the salt amount (e.g., 300 mg lithium carbonate), whereas most supplements report the elemental lithium amount and only name the salt form, which may confuse consumers and clinicians. As noted, some products did not disclose the salt form, while others listed lithium as an ingredient without specifying any amount, leaving consumers unable to determine the dose or the form they are obtaining. While unreported lithium amounts could be assumed to be trace levels, this cannot be confirmed. More broadly, dietary supplements are not subject to pre-market approval by the FDA, whose authority is largely limited to post-market enforcement.^{(Reference Wallace and Koturbash15)} As a result, the accuracy of labelled ingredients is not independently verified before these products reach consumers.

Some limitations apply to this study. DSLD was used to gather label information, which does not represent the entire market or every product sold in the US. DSLD is a database that collects voluntary product label submissions and may miss products that are not submitted to the database. The DSLD reproduces label information exactly as submitted by manufacturers and does not verify compliance with FDA labelling regulations, so it may contain errors or inaccuracies.^{(Reference Dwyer, Bailen and Saldanha31)} Although only products designated as on market were included, this designation reflects database records rather than verified current market availability. This study also excluded supplements that listed lithium on the label but did not report their dosing, which is an inherent limitation. These products could not be entered into the dosing analyses because no lithium amount was reported. Almost all were multi-ingredient mineral formulations, often trace-mineral or ‘colloidal’ blends, in which lithium was one of many ions rather than the main ingredient. This is likely why their individual amounts were not given. Also, the amounts and chemical verification of compounds in dietary supplements were not validated with experiments, and the full validity of labels requires laboratory confirmation. More than half of the supplements in the final sample included a combination of ingredients with lithium, and some label claims or precautions might not be specific to lithium but to other active ingredients or their combinations. Given that this study focused on label claims through DSLD, there were no consumer exposure data or adverse events reported by consumers. It should be noted that the analyses conducted in this study were exploratory, and the findings should be considered hypothesis-generating. Finally, data extraction and classification were performed by a single reviewer, without independent verification.

It is currently unclear what the frequency of supplemental lithium use is in the population. A recent cross-sectional international survey identified some consumer perspectives and experiences of users who are using lithium supplements, indicating that most of the users are utilising lithium supplements for anxiety, cognition, and mood, while side effects were also reported, such as headaches or nausea.^{(Reference Strawbridge, Myrtle, Carmellini, Hampsey, Cousins and Young32)} Given consumer practices, the increasing use of dietary supplements, and the re-emerging interest in lithium, it is essential to identify labels, the range of use, consumer perceptions and experiences, and outcomes. To our knowledge, this is the first study that evaluated commercially available dietary supplements that include lithium in the US. Clinicians should be aware of the general characteristics of lithium supplements and their labelling and inquire whether patients are taking lithium supplements to inform clinical care.