A toxicological evaluation of lithium orotate

The scientific paper A Toxicological Evaluation of Lithium Orotate by Murbach et al. investigates the safety of lithium orotate (LO), a compound used as a dietary supplement for its potential calming and stress-relief effects. Despite decades of use, concerns about the safety of LO and its components, lithium and orotic acid, prompted this preclinical evaluation. Unlike pharmaceutical lithium salts, which are prescribed for psychiatric conditions and carry a risk of significant toxicity, LO is available over the counter at much lower doses. The authors conducted genetic toxicity tests and a 28-day oral toxicity study to provide a comprehensive assessment of LO’s safety profile, focusing on its potential impacts on DNA and overall toxicity in animals. This study addresses a critical gap in understanding the safety of LO, given its growing popularity and lack of prior formal evaluations.

Lithium orotate (LO) is a compound made by combining lithium and orotic acid. It has been marketed for decades as a dietary supplement, often touted for its calming effects and ability to help manage stress and impulsivity. People frequently compare LO to pharmaceutical lithium carbonate (LC), but the doses in supplements are significantly lower than those in prescription lithium treatments.

In the study, the authors noted that while LO has been used worldwide, there is limited evidence on its safety. Concerns arise because pharmaceutical lithium salts can cause serious side effects, even at therapeutic doses. There are some potential risks associated with orotic acid. This scientific paper aimed to evaluate the safety of LO through a series of preclinical tests, providing much-needed clarity for its users.

The study used rigorous scientific methods to evaluate the safety of lithium orotate (LO). Researchers conducted two types of experiments: genotoxicity tests and a repeated-dose toxicity study, adhering to Good Laboratory Practices (GLP ) and internationally recognized guidelines like those from the Organisation for Economic Co-operation and Development (OECD).

These tests assessed whether LO could damage DNA or cause genetic mutations, which could increase the risk of cancer or other genetic disorders.

• Bacterial Reverse Mutation Test: Using Salmonella typhimurium and Escherichia coli strains, this test looked for mutations caused by LO at various concentrations. The highest tested concentration was 5000 µg/plate, the limit for soluble, non-toxic substances.
• In vitro Mammalian Chromosomal Aberration Test: Researchers exposed hamster lung cells to LO to check for structural chromosome changes. Short- and long-term experiments used concentrations up to 2500 µg/mL, designed to assess cytotoxicity and chromosomal integrity.
• In vivo Mammalian Micronucleus Test: Mice received oral doses of LO up to 2000 mg/kg body weight twice in 24 hours. Bone marrow cells were analyzed under a microscope to detect micronuclei and small DNA fragments indicating chromosomal damage.

• Male and female rats were given oral doses of LO at 0, 100, 200, or 400 mg/kg body weight/day for 28 days. The highest dose represented the study's No Observed Adverse Effect Level (NOAEL).
• The study assessed weight gain, food intake, organ weights, blood and urine tests, and tissue health through clinical pathology and detailed histopathological examinations. Special attention was given to organs like the liver and kidneys, commonly affected by lithium toxicity in pharmaceutical forms.

This methodology ensured a comprehensive evaluation of LO’s potential toxic effects across multiple biological systems.

The research provided detailed insights into LO's safety profile:

• LO did not cause mutations in bacterial or mammalian cells, even at maximum test concentrations.
• Chromosomal studies found no structural changes or evidence of clastogenic effects, confirming that LO does not damage genetic material.
• The absence of micronuclei in bone marrow cells from mice further validated LO’s non-genotoxic nature.

• Rats in all dosage groups remained healthy, with no deaths or major signs of toxicity.
• Minor changes, such as a slight increase in liver weight and ALT levels, were observed in the highest dose group. However, these were considered non-harmful adaptive changes, as no corresponding tissue damage or inflammation existed.
• Notably, the highest dose tested, 400 mg/kg/day, was established as the NOAEL. This means no adverse effects were observed at this level.

The researchers highlighted that while pharmaceutical lithium salts often target organs like the kidneys and thyroid, no such effects were seen with LO, even at high doses in this study.

This study offers significant reassurance for people using LO as a dietary supplement. It supports the idea that LO is safe for short-term use at doses within the tested range. The lack of genotoxicity or significant toxic effects aligns with the compound’s history of safe use.

However, the authors stressed the importance of monitoring chronic or excessive use. As LO is widely available without a prescription, individuals may use it in ways that deviate from recommended doses. This lack of supervision could lead to cumulative effects over time, which have not yet been studied.

The study's findings provide a starting point for further research. Future studies could explore the long-term effects of LO, its impact on specific populations, and potential benefits compared to pharmaceutical lithium salts.

The study provides strong evidence that lithium orotate is safe at recommended doses. In short-term animal studies, it does not cause DNA damage, mutations, or major toxicity. These results reinforce LO’s reputation as a low-risk supplement and support its use for individuals seeking its calming and stress-relief benefits.

That said, caution is key. While LO appears safe, long-term effects remain unknown, and dosage matters significantly. If you’re considering LO, consulting with a healthcare provider is the best way to ensure it fits your health needs. Continued research will help clarify its role in supplement regimens, making it a promising area of study for both safety and potential benefits.