Mounting evidence that lithium may be a crucial trace element There is mounting evidence that people who live in areas where the land or water supply is relatively lithium rich have lower rates of mental illness (e.g. suicide, aggression or homicide) compared to areas where the land or water supply is relatively lithium poor. Over the past 28 years, there have been at least eight studies (all but one study were done in the past decade) that have demonstrated this link in different localities around the world, the study by Shiotsuki et al. (2016) being the latest. In addition, a recent, large, population-based Danish study concluded that long-term exposure to higher lithium levels in drinking water may be associated with a lower incidence of dementia (Kessing et al., 2017). The growing evidence from epidemiological studies mirror the cellular studies (as summarised in the following review) that suggest lithium is perhaps a crucial trace element necessary for optimum brain functioning (Dell’osso et al., 2016). All these studies imply that adequate lithium intake may be neuroprotective. Conversely, inadequate lithium intake (especially in vulnerable individuals) may predispose and/or perpetuate a range of psychiatric and neurodegenerative conditions. If further studies confirm this hypothesis, then a safe and effective lithium mineral supplement will be needed to correct this specific mineral deficiency. Advocates of lithium orotate (LO) argue that such a supplement already exists and that it is both safe and effective. LO has been used worldwide, mainly by non-medical health practitioners for over 30 years. LO can be purchased through a number of sources and does not require a doctor’s prescription. Furthermore, as a mineral supplement, LO does not require approval from the Food and Drug Administration (in the United States of America). Thus, the mineral supplement LO may potentially mimic the neuroprotective effects of lithium gained from living in areas where there are relatively high concentrations of lithium in the food chain and water supply. However, to date, there has been insufficient evidence to definitively confirm this assertion. Despite the absence of Level 1 evidence, the large number of positive anecdotal reports (in articles, verbally and reported on various websites), and more importantly the absence of any documented concerns regarding tolerability and safety, suggests that LO could be a useful supplement in the future.

Is LO equivalent to lithium in the drinking water? No studies have yet been done to determine if LO is equivalent to lithium in the drinking water. The benefit of lithium has been established after years of clinical experience, following the profound work of John Cade. The epidemiological evidence also suggests some benefits from trace natural sources of lithium in the environment. The assumption would therefore be that it is the lithium ion itself, which supplies some form of therapeutic benefit. Furthermore, it is reasonable to hypothesise that alternative sources of lithium such as LO may also be a clinically useful source of the lithium ion. LO is not necessarily equivalent to these sources. It may well differ in its delivery of lithium, and therefore its toxic or therapeutic effects. If the efficacy of lithium has been implied in the epidemiological data (natural lithium salts in food and water) and firmly established in the clinical data (lithium carbonate), is it not possible that it could be established in alternative sources, such as LO?

What are the reported benefits from taking LO? The reported benefits of taking LO are as follows: feeling calmer; experiencing fewer or less intense depressive, hypomanic or mixed affective symptoms; being less impulsive; experiencing less frequent and less intense suicidal thoughts or aggressive impulses; reduced consumption of alcohol and not getting as easily upset by stressors. It is interesting to note that the reported benefits of LO are similar to the known benefits of lithium carbonate, albeit in an attenuated form.

High-dose inorganic lithium compounds (lithium carbonate) versus low-dose organic lithium compounds (LO) The ideal lithium supplement would be one where you would only need to consume micro-doses of elemental lithium, and yet still benefit from it. Advocates argue that this is where LO comes into the picture. The theory is that when the lithium ion is combined with the orotate molecule, it acts as a targeted delivery system and transports the lithium ion efficiently through the cell membrane to its various sites of action within the cell (Nieper, 1973). In comparison, according to Nieper and his supporters, with lithium carbonate, you need high doses to ‘force’ lithium into the body’s cells via a crude concentration gradient. Thus theoretically, you can achieve the same clinical effect with a lower dose of (elemental) lithium, with less side effects, when lithium is taken in the orotate form compared to the carbonate form. Unfortunately, Nieper’s study was never replicated. Nevertheless, a quick Google search will reveal studies of other metals, e.g., with iron, showing that organic mineral supplements typically have superior efficacy and less side effects and require much lower doses of the elemental metal, compared to inorganic mineral supplements. To further illustrate the differences in the daily doses of elemental lithium between the orotate and carbonate forms, a single 120 mg tablet of LO contains about 5 mg of elemental lithium. This is only 10% of the dose of elemental lithium that you would find in a single 250 mg tablet of lithium carbonate, which would have about 50 mg of elemental lithium. There are no established (medical) guidelines for the daily dose of LO. However, the standard dose prescribed by alternative health practitioners is a single tablet of 120 mg of LO a day (which is equivalent to 5 mg of elemental lithium).

Human trials There have only been a few small trials done in humans, and they showed that LO was effective, safe and generally well tolerated. The most recent trial was by Schrauzer and de Vroey (1994). There have been no randomised controlled trials done to date. In conclusion, There is mounting evidence that a higher, incidental oral intake of lithium via environmental sources is neuroprotective. Nieper’s study that LO has significantly different pharmacokinetics to lithium carbonate requires replication, particularly the assertion that LO is more efficient at entering the cell compared to lithium carbonate. There is no definitive evidence for the long-term safety of LO. It is, however, reassuring that there have been no reported cases of death or serious side effects in more than 40 years of LO use in the United States and Europe. Nevertheless, the issues of safety would be paramount to consider especially in vulnerable populations, e.g., the elderly, people who have had previous kidney or thyroid problems and individuals who have ‘normal’ kidney and thyroid function but with an underlying pharmacogenetic susceptibility to lithium-induced renal or thyroid impairment.

Acknowledgements The author would like to thank Drs Adam Burgess and Christian Heim for providing valuable feedback on the original draft.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. Funding

The author(s) received no financial support for the research, authorship and/or publication of this article.

References