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Potential Lithium Orotate Benefits & Uses (incl. for Anxiety)

Written by Mathew Eng, PharmD | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:
Jonathan Ritter
Puya Yazdi
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Puya Yazdi, MD | Written by Mathew Eng, PharmD | Reviewed by Ana Aleksic, MSc (Pharmacy) | Last updated:

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Lithium Orotate

Trace amounts of lithium seem to make people more peaceful and friendly. Lithium helps with bipolar, anxiety, and depression. It also appears to support the immune system and protect the brain. But what’s the difference between lithium carbonate and lithium orotate? How effective are high doses, low doses, and microdoses? Read on to get to the bottom of the lithium controversy.

What is Lithium?

Overview

Lithium is classified as an essential micronutrient, which means that all humans require it in small doses for good health [1].

Lithium carbonate is typically used at high doses and requires a doctor’s prescription and careful monitoring of blood lithium levels.

Popular blogs claim that lithium has a number of benefits unrelated to its use as a high-dose pharmaceutical. But what does the science say?

Despite the hype, there is insufficient evidence to determine the effectiveness of lower lithium doses. However, early research shows some promise.

Also, lithium orotate is poorly researched and its safety has not been determined. Its alleged benefits and better bioavailability in the brain have never been proven in clinical trials [2, 3].

Additionally, lithium orotate supplements have not been approved by the FDA for medical use. Supplements generally lack solid clinical research. Regulations set manufacturing standards for them but don’t guarantee that they’re safe or effective. Speak with your doctor before supplementing.

In this post, we’ll focus on lithium orotate and the purported benefits of low-dose lithium in general, but we’ll still go over the main uses of high-dose, prescription lithium (lithium carbonate).

Lithium is classified as an essential nutrient and some of its salts are naturally found in food. Lithium orotate is not found in nature and its safety is unknown.

Snapshot

Proponents

  • Prescription lithium is effective for bipolar and possibly effective for depression, ADHD, and schizophrenia
  • Lithium allegedly protects the brain
  • Trace amounts hypothesized to prevent mental disorders and reduce aggression and impulsiveness
  • Low doses are somewhat researched in depression
  • Emerging research exploring its effects on cellular repair and lifespan

CONs

  • Safety and effectiveness of lithium orotate unknown
  • Effectiveness of low-dose lithium unknown
  • May cause mild side effects

Uses of High-Dose Lithium Carbonate

Before we go over the research behind lithium orotate and low-dose lithium, let’s review what high-dose, prescription lithium carbonate is used for.

Remember, mental disorders are thought to exist on a spectrum. Similarly, some scientists think that the effects of lithium also arise on a dosage spectrum. We know a lot about the high-dose spectrum of lithium since it has been used for many decades. Numerous clinical trials and analysis about therapeutic lithium carbonate doses have been published.

On the other hand, we know very little about low-dose lithium and even less about lithium orotate/lithium microdoses.

So, we decided to present lithium science in an unbiased, evidence-based manner–from the highest level of evidence to the lowest.

Effective For:

1) Bipolar Disorder

Doctors have long known that lithium is a mood stabilizer. It is one of the oldest drugs for treating bipolar disorder–and is still the preferred treatment to this day [4, 5].

Lithium is FDA-approved for use in the treatment of bipolar disorder. It is used to treat acute mania or depression in patients with bipolar disorder, as well as to prevent the recurrence of manic episodes [6].

If you have bipolar disorder, your doctor will target a very specific lithium blood level. This “normal level” of lithium (better known as the “therapeutic level“) should provide symptom relief while minimizing side effects [4].

Possibly Effective For:

2) Depression

Lithium is used off-label for depression. Although it’s not FDA-approved for this indication, some evidence suggests that it is effective in some patients with depression. However, other antidepressants are prescribed before lithium is trialed.

However, the data on adding lithium to antidepressants are mixed.

One meta-analysis of clinical trials concluded that prescription lithium does not prevent suicide in in patients with bipolar disorder or depression when compared with placebo. Once the authors revised the data and excluded a low-quality study, they suggested that lithium does reduce suicide risk better than placebo [7, 8].

Two other meta-analyses suggested that adding lithium to certain types of antidepressants (tricyclics and second generation antidepressants) improves symptoms of depression [9, 10].

3) ADHD

Some early clinical research suggests that prescription lithium might improve impulsive-aggressive behavior associated with ADHD. The researchers pointed out that it should be used after other medications fail to work. Additional, large-scale studies are needed [11].

4) Schizophrenia

Lithium is sometimes added (augmented) to antipsychotic drugs for schizophrenia. It should not be used as the only medication in these patients [12].

Some clinical studies suggest that this add-on approach might improve symptoms in people prescribed first-generation antipsychotics. Additional studies suggest that lithium should no be added to second-generation antipsychotics [12, 13, R].

The available studies about lithium augmentation have several limitations. Larger, better-designed clinical trials are warranted.

Potential Benefits of Low-Dose Lithium

Insufficient Evidence For:

The following purported benefits are only supported by limited, low-quality clinical studies.

There is insufficient evidence to support the use of low-dose lithium for any of the below listed uses.

Remember that low-dose/subtherapeutic lithium refers to lithium carbonate doses of 150-200 mg/day. It requires a doctor’s prescription.

1) Depression

Prescription lithium is sometimes added to antidepressants in people who don’t respond to conventional antidepressants [14].

Early studies suggest that adding low doses of lithium may also have an effect, though proper trials are lacking.

One study examined 51 patients with depression who did not respond to treatment with venlafaxine (a commonly prescribed antidepressant). When low dose lithium was added to their normal venlafaxine treatment, about half of the patients saw improvement. Further studies are needed [15].

2) Dementia Prevention

After testing microdoses, a Brazilian team investigated subtherapeutic lithium in a randomized, controlled, double-blind trial on 45 people with mild cognitive impairment (MCI). Subtherapeutic lithium delayed the progression of MCI into dementia, given over one year [16].

The patients received 150 to 600 mg of lithium carbonate daily. The dose was titrated to subtherapeutic blood levels (0.25–0.5 mmol/l) [16].

However, these findings have never been replicated. Large-scale, multi-center trials are warranted.

3) Headaches

Despite some promising findings, no large studies have investigated the effects of low-dose lithium on headaches. Its effectiveness for this indication is still unknown.

A review of small studies revealed that lithium may reduce the severity of cluster headaches, a rare, but severe type of headache. Subtherapeutic levels of lithium (0.4 to 1.0 mmol/L in the blood) seemed to improve symptoms in many patients [17].

According to one theory, lithium may also help in hypnic headache (sometimes called “alarm clock headache”). This rare type of headache usually affects the elderly, waking them from sleep at around the same time each night [18].

4) Huntington’s Disease

Some doctors prescribe low doses of lithium off-label in Huntington’s disease, but there’s no clinical data to support this practice. It mostly relies on clinical experience. Human studies are needed.

A case series including 3 patients with Huntington’s describes that low dose lithium (150 mg) improved movement and behavioral symptoms. However, we can’t draw any conclusions about effectiveness or safety from a couple of limited cases. Clinical trials are needed [19].

A low-dose lithium formulation is currently in development for the treatment of Huntington’s. Preliminary animal studies show that this new drug may improve motor function and prevent brain cell death, but clinical data are still lacking [20].

Purported Benefits of Lithium Microdoses/Lithium Orotate

Insufficient Evidence For:

The following purported benefits are only supported by limited, low-quality human studies. Most of the studies on trace amounts of lithium were epidemiological association studies. There types of studies can’t establish a cause-and-effect relationship.

Therefore, there is insufficient evidence to support the use of lithium microdoses for any of the below listed uses.

Additionally, clinical data on lithium orotate are completely lacking. Its safety profile is unknown and its use relies on a couple of old animal studies. We recommend against using this form of lithium. Lithium citrate and carbonate are much better researched.

Remember to speak with a doctor before taking lithium supplements. Lithium supplements should never be used as a replacement for prescription lithium or other approved medical therapies.

1) Reducing Suicide Risk

Lithium may have unique effects on suicidal behavior. Limited evidence suggests that prescription lithium reduces suicide risk in people with mood disorders better than some antidepressant and antipsychotic medications [21, 22].

Some scientists think that low doses of lithium may also reduce suicides, but proper clinical trials are lacking. Nonetheless, some studies found a link between trace amounts of lithium found in groundwater and lower suicide rates [23].

Higher lithium levels in public drinking water were linked to lower suicide rates, according to a study looking at water samples from 226 counties in Texas [23].

A similar association between lithium levels and suicide rates has been brought up in multiple countries, including Japan, Italy, Lithuania, and Greece [24, 25, 26, 27].

However, a 22-year long study following close to 4 million adults in Denmark did not find a link between lithium and suicide risk. The authors proposed that this may be explained by Denmark’s low average level of lithium in drinking water, which was about 12 micrograms per liter. More large-scale studies are needed [28].

Lliving in areas with higher concentrations of lithium in the drinking water has been linked to lower suicide rates in some studies, but the findings have been inconsitent.

2) Reducing Criminal Behavior

Here’s the most intriguing part: lithium seems to make people more mellow and easygoing–that is, scientists suspect it makes people less likely to engage in behavior that might put them in jail. Lithium deficiency, on the other hand, has been linked to aggression and violence [29, 30].

However, the link between lithium and aggression is still purely hypothetical. It hasn’t been proven in proper human studies.

This makes people wonder: do communities of more peaceful, less aggressive, less impulsive, and happier people around the world all have more lithium in their water and food? Of course, we know that it can’t be as simple… but lithium might turn out to be a part of the equation [29, 30].

It may sound silly to some people, but studies do point to a potential connection between lithium and criminal behavior.

Some researchers claim that areas with higher concentrations of lithium in the drinking water have lower rates of homicide, rape, and theft. This is according to a study looking at 9 years worth of data from 27 counties in Texas [31].

A study performed in Greece found similar results. Cities with higher lithium levels in the public water supply had lower incidences of homicide, rape, and drug abuse [32].

What could explain this link?

The connection between low lithium and criminal behavior is not totally understood, but scientists hypothesize that lithium’s ability to improve impulse control might play a major role. More research is needed [29].

Some scientists think that lithium might improve impulse control and make people less aggressive, but this hypothesis remains unproven.

3) Cognition & Dementia Prevention

There is insufficient evidence to confirm a link between higher lithium levels and lower rates of dementia, though early findings are intriguing. Nonetheless, clinical trials are needed.

A massive study performed in Denmark compared drinking water samples from over 800k people. They found that people drinking water with higher amounts of lithium had lower rates of dementia [33].

Higher lithium levels in drinking water were also linked with a lower risk of death in Alzheimer’s patients, according to a study looking at water samples from 234 counties in Texas [34].

The first study of Brazilian team of scientists interested in the cognitive effects of lithium found investigated microdoses of lithium. They used 300 micrograms per day of elemental lithium over 15 months, which is about 1.5 mg of lithium carbonate–that’s 100 times less than low-dose lithium. They found that this microdose helps prevent cognitive loss in Alzheimer’s patients [35].

People have criticized this study, calling it “sketchy” and dismissing it as unreliable. This study had no major flaws: it was placebo-controlled and double blinded. However, it did have some less notable limitations.

Thus, the scientific community was weary of their results. This Brazilian research team had to go “back” and pinpoint potential dementia-preventive mechanisms of lithium microdoses in animals [36].

To date, no other clinical studies have been conducted.

Larger, multi-center trials are warranted.

Small doses of lithium were researched for improving cognition and slowing mental decline, but proper clinical data are lacking.

4) Alcoholism

One old study, published in 1982, treated 42 alcoholic patients with 150 mg lithium orotate daily for at least 6 months. The authors claimed that about a third of the patients went 1 to 3 years without relapse and that a quarter went 3 to 10 years without relapse. Their findings were never replicated [37].

The same study reported some mild side effects, including muscle weakness, loss of appetite, and mild apathy. However, these were said to have disappeared when the supplement was given less frequently [37].

This study has several red flags, though. For one, the single author behind this study, H.E. Sartori, is highly controversial. For example, he claimed to kill cancer cells with cesium salts.

5) Preventing Mental Disorders

As a prescription medication, lithium is used to treat several psychiatric conditions, including bipolar disorder, depression, and schizophrenia [4, 14, 38].

The purported benefits of supplemental lithium on mental health, however, are not clear. Old and unreliable reports suggest it might help prevent certain mental disorders. No proper, modern-day trials are available [39].

One curious phenomenon dates over a hundred years back. It’s known as the “crazy waters” of Texas. Have in mind that this story is purely anecdotal.

Many mineral springs contain lithium, but the Mineral Wells in Texas became famous as “crazy waters.” Texas had many mineral water resorts back in the 19th century. Thousands of “crazy” people and those with various chronic health problems used to gush to these springs to get the “healing benefits of lithium.” Others reported good health just from living nearby [40].

There’s also one anecdotal case from the 1930s France. French physician Dr. Reyss-Brion remembers that a preparation called “Dr. Gustin’s Lithium” was popular in the south of France around that time. “It’s quite simply for that reason that you don’t have a lot of manic-depressives in Marseilles,” he said [40].

Only one recent study provides us with partial clues. In over 3k students in Japan, those with higher levels of lithium in tap water had fewer symptoms of depression. This potential association was not confirmed in further studies [41].

Anecdotes aside, we’re still missing hard evidence about the effects of trace amounts of lithium on preventing mental disorders like depression and bipolar.

Future clinical trials should investigate the effects of small amounts of lithium on preventing depression.

Lithium Uses Lacking Evidence

Summary of Animal & Cell-Based Research

No clinical evidence supports the use of lithium for any of the conditions listed in this section.

Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.

Lifespan Extension

The effects of lithium on lifespan in humans are unknown.

A study in Texas found an association between higher trace levels of lithium in tap water and lower rates of death by any cause. No other human studies looked at this potential link [42].

According to some scientists, future studies should determine whether lithium can increase the length of telomeres – small proteins that cap DNA-holding chromosomes [43, 44, 45].

The longer telomeres are, the more leeway cells have to divide. Some researchers have described the length of telomeres as something like the sand in the top part of a lifespan hourglass–the more people have, the better. This is just one hypothesis, though, and it’s still unverified [46].

Other scientists say that lithium may improve mitochondrial turnover, which maintains healthy mitochondria. This has been explored in roundworms only, while mitochondrial health has been linked to lifespan in some limited studies [R, R].

Scientists are investigating whether lithium can extend the length of telomeres, but no human data are available.

Brain Protection

Although some blogs claim that lithium protects the brain at the low doses that supplements provide, human data about such effects are completely lacking.

Animal studies suggest that subtherapeutic lithium blocks NMDA receptors, which may prevent damage caused by excess glutamate [47, 48, 49].

Scientists are also exploring whether lithium inhibits GSK-3, an enzyme that plays a role in metabolism, cell growth, and the immune system. Overactivity of GSK-3 is linked to a number of diseases, including bipolar disorder and Alzheimer’s disease. Blocking GSK-3 might theoretically prevent the death of brain cells (apoptosis), but human studies would need to confirm this [50, 51].

Other research teams are investigating low doses of lithium against the toxic effects of lead exposure [39, 52].

The effects of small doses of lithium against brain toxins and brain damage are unknown.

Cell Growth and Repair

Basic science suggests that cells depend on lithium for proper development and repair, but this hasn’t been confirmed in humans.

For example, a rat study found that lithium increases the concentration of growth factors in the brain, such as BDNF, NGF, and GDNF. These factors are neurotrophic, which means that they are brain food. The term comes from the Greek words neuro for brain and trophic for food or nourishment [53].

However, the effects of lithium on neurotrophic factors in humans remains to be researched.

Neurotrophic factors increase the birth of new neurons to, theoretically, help “regrow” the brain and repair brain damage. The birth of new brain cells is called neurogenesis, and some researchers believe it’s important for recovering from mental illness [54].

These factors might also increase neuroplasticity, which is the brain’s ability to make new connections and adapt throughout life [55].

Research on human cells is investigating whether subtherapeutic levels of lithium (0.2 mmol/L) increase VEGF, another type of growth factor that affects blood vessels. This could hypothetically help with blood vessel repair after a stroke [56].

Growth factors aren’t the only area of research. Several studies are looking at whether lithium stimulates stem cells in the blood, brain, and bones, potentially implicated in tissue repair after injury [57, 58].

There are also some research teams looking at how lithium impacts autophagy [59].

Autophagy translates to “self-eating” and it’s equivalent to a “detox” from a cellular perspective. Autophagy takes old cell material, recycles it, and re-uses the components. This process regenerates aging cells, prevents diseases, and it’s key to lifespan extension [60, 61].

Scientists are investigating whether lithium increases growth factors and stem cells in animals and test tubes.

Insulin Resistance

Lithium might improves glucose transport and glycogen synthesis in insulin-resistant rats, according to one study. Its effects on insulin resistance in humans are unknown [62].

The researchers of the study suggest that lithium should be further studied in patients with diabetes and insulin resistance [63].

Bone Health

Research in animals suggests that lithium may decrease the risk of bone fractures and promote bone growth. The effects of supplemental doses on bone health in humans have not been explored [64, 65].

Limited human studies have revealed some benefits to bone health with prescription doses of lithium. More research is needed [66, 67].

Autoimmunity and Inflammation

Lithium may interact with the immune system through several mechanisms. Scientists are investigating hw lithium might affect the following pathways in cells or animals:

  • Inhibiting GSK-3, which might theoretically reduce autoimmunity (conditions where the immune system attacks its own body) [68].
  • Suppressing Th1 cells and interferon-gamma (but not Th17 cells) [68].
  • Increasing the production of IgG and IgM antibodies while decreasing the activity of inflammatory prostaglandins [69, 70].

These mechanisms have not been confirmed in humans.

Sleep

Based on animal and cell studies, some scientists think that lithium might have interesting effects on the circadian rhythm.

It seems to lengthen the circadian rhythm period, which can theoretically help with desynchronization from a normal 24-hour cycle [71, 72].

Some researchers are investigating whether lithium can help activate the genes and proteins involved in the sleep-wake cycle, which can help the body be in better sync with day and night cycles. This might make lithium a sort of sensitizer to zeitgebers–biological cues for the time of day, but much more research is needed [71, 72].

Clinical trials show that lithium medications can improve sleep in bipolar patients. However, the effects of lower lithium doses on sleep are unknown [73, 74].

Limitations

Research on lithium orotate is very limited and most studies are decades old.

Many of the purported benefits of lithium orotate are erroneously inferred from studies that look at low-dose prescription lithium (also known as subtherapeutic or microdose lithium).

Studies examining the trace amounts of lithium found in drinking water offer no information about the potential benefits of lithium supplements. Clinical trials are needed.

Read More

Takeaway

The human body needs tiny amounts of lithium to function properly.

High-dose lithium carbonate is an effective treatment for bipolar disorder. Solid research shows that it likely also helps with some symptoms of depression, ADHD, and schizophrenia.

Controversial studies suggest that people who get a bit more lithium might be less suicidal and more peaceful, but solid data are lacking to back up this hypothesis.

Despite some promising early findings, there is insufficient evidence to support the use of supplemental (micro) doses or low lithium doses for any condition. Future research should determine the effects of varying low lithium doses on brain health, cognition, and autoimmunity.

About the Author

Mathew Eng

Mathew Eng

PharmD
Mathew received his PharmD from the University of Hawaii and an undergraduate degree in Biology from the University of Washington.
Mathew is a licensed pharmacist with clinical experience in oncology, infectious disease, and diabetes management. He has a passion for personalized patient care and believes that education is essential to living a healthy life. His goal is to motivate individuals to find ways to manage their chronic conditions.

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