According to a few controversial studies, trace amounts of lithium seem to make people more peaceful and friendly. Relatively high doses of lithium carbonate are commonly used to treat mental health conditions such as bipolar disorder, anxiety, and depression. Lithium 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 “micro-doses”? Read on to get to the bottom of the lithium controversy!
What is Lithium?
Lithium is classified as an essential micronutrient, which means that all humans require it in small doses for good health .
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 currently insufficient evidence to determine the effectiveness and safety of lithium when used at lower doses. However, early research shows some promise.
Also, lithium orotate is relatively poorly-researched, and its safety (both in the short and long term) has not been determined. Its alleged health benefits and supposedly enhanced bioavailability in the brain have never been directly proven by clinical trials [2, 3].
Additionally, lithium orotate supplements have not been officially approved by the FDA for any medical use or other health application. Supplements generally lack solid clinical research: regulations set manufacturing standards for them, but don’t guarantee that they’re safe or effective. Always make sure to speak with your doctor before supplementing with any new compounds.
With those important points in mind, in this post we’ll be focusing 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).
- Prescription lithium (lithium carbonate) is effective for bipolar and possibly effective for depression, ADHD, and schizophrenia
- Lithium allegedly protects the brain
- Trace amounts of lithium have been hypothesized to potentially help prevent mental disorders, and reduce aggression and impulsiveness
- Low doses are somewhat researched in depression, and some early evidence suggests potential effectiveness
- Ongoing research is currently exploring lithium’s potential effects on cellular repair, neurogenesis, and overall lifespan
- Safety and effectiveness of lithium orotate is currently unknown
- Effectiveness of low-dose lithium is currently unknown
- May have the potential to cause adverse 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, psychiatric disorders are generally believed to exist on a spectrum. Similarly, some scientists think that the effects of lithium also arise on a dosage spectrum. We know relatively much more about the “high-dose” spectrum of lithium, since it has been used by medical practitioners for many decades: numerous clinical trials and analyses on therapeutic lithium carbonate doses have been published.
On the other hand, we know very little about “low-dose” lithium treatments — and even less about supplemental lithium orotate / lithium “micro-doses”.
So, we decided to present lithium science in an unbiased, evidence-based manner — from the highest level of evidence to the lowest.
1) Bipolar Disorder
Doctors have long known that lithium acts as a mood stabilizer. It is one of the oldest drugs for treating bipolar disorder, and is still the preferred medical treatment for this condition 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 .
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“) is carefully determined and calculated by doctors to provide relief from symptoms, while also minimizing the possibility of negative side-effects .
Possibly Effective For…
Lithium is used “off-label” for depression. Although it’s not officially FDA-approved for this medical application, some evidence suggests that it is effective in some patients with certain forms of depression. However, other antidepressants are typically prescribed before lithium treatment is tried (in other words, lithium is only used for patients who haven’t successfully responded to more conventional forms of antidepressant treatment).
Additionally, lithium is sometimes “added on” to treatment alongside more conventional antidepressants (such as SSRIs). However, the evidence in support of these “combined uses” is mixed.
One meta-analysis of clinical trials concluded that prescription lithium did not significantly help in preventing suicide in in patients with bipolar disorder or depression, when compared to a placebo. However, once the authors revised the data to exclude one especially low-quality study, they suggested that lithium may reduce suicide risk better than placebo after all [7, 8].
Two other meta-analyses have suggested that adding lithium to certain types of antidepressants (“tricyclics” and “second-generation” antidepressants, such as desipramine, venlafaxine, trazodone, and bupropion) may help improve symptoms of depression in some patients [9, 10].
Some early clinical research suggests that prescription lithium might reduce impulsive-aggressive behaviors associated with ADHD. However, the researchers took care to point out that lithium should only be used after other medications have been tried and failed to work. Additional, large-scale studies are needed .
Lithium is sometimes added to antipsychotic drugs for treating schizophrenia (also known as “add-on” or “augmented” treatment).
While some evidence supports this application, it is also widely believed that lithium should not be used as the only medication in these patients .
Some clinical studies suggest that this add-on approach might improve symptoms in people prescribed “first-generation” antipsychotics (such as chlorpromazine, haloperidol, and fluphenazine). Additional studies suggest that lithium should not be added to second-generation antipsychotics (such as risperidone, olanzapine, and clozapine) [12, 13].
The available studies about lithium augmentation have several limitations. Larger, better-designed clinical trials are warranted.
Potential Benefits of Low-Dose Lithium
The following purported benefits are only supported by limited, low-quality clinical studies. There is currently insufficient evidence to support the use of low-dose lithium for any of the uses discussed below.
Remember that “low-dose” (“sub-therapeutic“) lithium refers to lithium carbonate doses of between 150-200 mg/day. While these doses are considerably lower than those used in other medical applications of lithium carbonate, “low-dose” lithium still requires a doctor’s prescription.
Insufficient Evidence For…
Prescription lithium is sometimes added to antidepressants when treating patients who haven’t successfully responded to conventional antidepressants (such as SSRIs) .
Some early research suggests that adding “low” doses of lithium may also have an effect in depression treatment, though proper full-scale clinical trials are currently lacking.
One study examined 51 patients with depression who did not respond to treatment with venlafaxine (a commonly-prescribed antidepressant medication). When low-dose lithium was added to their normal venlafaxine treatment, about half of the patients reported improvements in their symptoms .
While this early finding is promising, much more research will still be needed to verify and extend these early reports.
2) Dementia Prevention
After testing “micro-doses” of lithium, a Brazilian research team investigated sub-therapeutic lithium in a randomized, controlled, double-blind trial in 45 patients with mild cognitive impairment (MCI). Sub-therapeutic lithium was reported to delay the progression of MCI into dementia over the one-year course of the tested treatment .
The patients received 150-600 mg of lithium carbonate daily. The dose was adjusted (“titrated“) to cause “sub-therapeutic” blood levels of lithium (0.25–0.5 mmol/L) .
However, these findings have never been replicated. Large-scale, multi-center trials are warranted.
Despite some promising findings, no large-scale studies have investigated the effects of low-dose lithium on headaches. Its effectiveness for this indication is still unknown.
One review of multiple preliminary small-scale studies has reported 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) were reported to improve symptoms in many of the tested patients .
According to one theory, lithium may also help in hypnic headache (sometimes called “alarm-clock headaches”). This rare type of headache usually affects the elderly, waking them from sleep at around the same time each night .
4) Huntington’s Disease
Some doctors prescribe low doses of lithium “off-label” in Huntington’s disease, although there is currently insufficient clinical data to support this practice. It mostly relies on clinical experience. Human studies are needed.
One series of case studies has reported that low-dose lithium (150 mg) improved movement and behavioral symptoms in 3 patients with Huntington’s disease. However, we can’t draw any conclusions about effectiveness or safety from a couple of limited cases: large-scale clinical trials are needed .
One low-dose lithium formulation is currently in development for the treatment of Huntington’s. Preliminary animal studies suggest that this new drug may improve motor function and prevent brain cell death, although clinical data are still lacking .
Purported Benefits of Lithium “Micro-doses” / Lithium Orotate
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. These types of studies can suggest a potential connection, but cannot establish a direct cause-and-effect relationship.
Therefore, there is insufficient evidence to support the use of lithium micro-doses for any of the uses listed below.
Additionally, clinical data on lithium orotate are completely lacking. Its safety profile is unknown, and proponents of these applications typically rely just on a couple of old animal studies to make their claims. Therefore, we currently recommend against using this form of lithium.
Always remember to speak with your doctor before taking lithium supplements. Lithium supplements and other “complementary health strategies” should never be used as a replacement for conventional medical care, or for prescription lithium or any other treatments your doctor has recommended.
Insufficient Evidence For…
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 epidemiological studies have reported a potential link between trace amounts of lithium in ground-water and lower suicide rates .
Higher lithium levels in public drinking water have also been linked to lower suicide rates, according to one other study looking at water samples from 226 counties in Texas .
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 .
2) Reducing Criminal Behavior
Here’s the most intriguing part: lithium seems to make people more “mellow” and “easy-going” — 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 increased aggression and violent behavior [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 as that: but lithium still may turn out to be at least 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 .
A study performed in Greece reported similar results. Cities with higher levels of lithium in the public water supply also seemed to have lower incidence rates of homicide, rape, and drug abuse .
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 may play a role .
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, additional large-scale clinical trials will still be needed.
A very large-scale study performed in Denmark compared drinking water samples from over 800,000 people. This study reported that people drinking water with higher amounts of lithium appeared to show relatively lower rates of dementia (compared to people whose drinking water contained less lithium) .
Higher lithium levels in drinking water have also been linked with a lower risk of death in Alzheimer’s patients, according to one other study looking at water samples from 234 counties in Texas .
The first study of a Brazilian team of scientists interested in the cognitive effects of lithium investigated “micro-doses” 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 treatments. They reported that this micro-dose may be associated with reduced cognitive impairments in Alzheimer’s patients .
However, many people have criticized this study, calling it “sketchy” and dismissing it as unreliable. However, the basis for some of these criticisms are unclear. This study does not appear to have any major methodological flaws: for example, it was placebo-controlled, and double-blinded. However, it did have some more minor and subtle limitations, which have caused other scientists to be skeptical of its reported findings.
Due to this skepticism, the Brazilian research team had to go back and pinpoint potential dementia-preventive mechanisms of lithium microdoses in animals. According to this research, they proposed that lithium may act by protecting brain cells from damage, as well as by possibly increasing BDNF levels .
However, these mechanisms were only shown in animals, and so it remains unclear whether these effects or mechanisms would be similar in human patients.
To date, no other clinical studies have been conducted, and so much more additional research will be needed to confirm whether lithium has any significant potential therapeutic effects in neurodegenerative disorders.
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 1/3rd of the patients went 1-3 years without relapsing, and that a quarter of them went 3-10 years without relapse .
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 .
However, these early findings were never replicated by any follow-up studies, so no firm conclusions can be made until much more additional research is available.
5) Preventing Mental Disorders
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. However, no proper, modern-day trials are available .
One curious phenomenon dates over a hundred years back. It’s known as the “crazy waters” of Texas.
However, keep in mind that this story is purely anecdotal:
While many mineral springs contain lithium, the Mineral Wells in Texas became famously known as “crazy waters.” Texas had many mineral water resorts back in the 19th century; and thousands of “crazy” people and those with various chronic health problems used to travel to these springs in order to get the “healing benefits of lithium.” Others reported good health just from living nearby .
There’s also one anecdotal case from France in the 1930’s. The French physician Dr. Reyss-Brion recalls that a preparation called “Dr. Gustin’s Lithium” was especially popular in southern 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 .
Only one recent study provides us with partial clues. According to one survey of over 3,000 Japanese students, those with higher levels of lithium in their local tap water reported fewer symptoms of depression. However, this association was not confirmed by additional follow-up studies, suggesting that this reported finding may not be genuine .
Anecdotes aside, we’re still missing hard evidence about the effects of trace amounts of lithium on preventing mental disorders like depression and bipolar.
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.
1) Increasing Lifespan
The effects of lithium on overall longevity in humans are currently unknown.
One study in Texas found an association between higher trace levels of lithium in tap water and lower rates of death by any cause. However, no other human studies to date have investigated or followed up on this potential link .
According to some scientists, future studies should determine whether lithium can increase the length of telomeres — small proteins that cap DNA-holding chromosomes, and which have been widely implicated in the human aging process [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 more “time” they have left. This is just one hypothesis, though — and it’s still unverified .
Other scientists say that lithium may improve mitochondrial turnover, which maintains healthy mitochondria. However, this effect has only been reported in roundworms. Additionally, mitochondrial health has only been linked to lifespan by a handful of limited studies, so this connection remains unconfirmed [R, R].
2) Brain Protection
Although some online proponents have claimed that low “supplemental” doses of lithium can help protect the brain, direct evidence in support of such effects in humans are completely lacking so far.
Preliminary reports from a few animal studies may suggest that sub-therapeutic lithium could potentially block NMDA receptors, which could theoretically prevent cellular damage caused by excess glutamate activity (excitotoxicity) [47, 48, 49].
However, it remains unknown whether similar mechanisms might apply to humans, and so this effect is still mostly hypothetical.
Scientists are also exploring whether lithium inhibits GSK-3, an enzyme that plays several critical roles in energy metabolism, cell growth, and the immune system. Overactivity of GSK-3 has been tentatively associated with a number of diseases, including bipolar disorder and Alzheimer’s disease. Blocking GSK-3 could theoretically prevent the death of brain cells (apoptosis), although human studies would need to confirm this [50, 51].
3) 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, one animal study in rats has reported that lithium increased the concentration of BDNF, NGF, and GDNF throughout the brain. These compounds are commonly known as neurotrophic factors, meaning that they directly stimulate the growth of the brain and its cells .
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 .
Nonetheless, the potential effect of lithium on neurotrophic factors in humans remains purely speculative, and hasn’t been directly confirmed by any scientific research so far.
Research on human cells is also currently investigating whether sub-therapeutic levels of lithium (0.2 mmol/L) may help increase VEGF, another type of growth factor that affects blood vessels. This could hypothetically help with the repairing of blood vessels after a brain injury, such as a stroke, although much more research will be needed to confirm this potential effect .
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, which have been implicated in tissue repair after injury [57, 58].
There are also some research teams looking at how lithium impacts autophagy . “Autophagy” translates to “self-eating,” and it’s biologically equivalent to a “detox” from a cellular perspective. Autophagy takes old cell material, recycles it, and re-uses the components. This process is believed to play a key role in regenerating aging cells and preventing diseases — and it’s this process is therefore believed to be a key player in determining overall lifespan and longevity [60, 61].
4) Insulin Resistance
According to some highly preliminary research, lithium may improve glucose transport and glycogen synthesis in insulin-resistant rats. Based on these preliminary findings, the authors of the above study have suggested that lithium should be further studied in patients with diabetes and insulin resistance .
Nonetheless, lithium’s potential effects on insulin resistance in humans currently remains unknown and unconfirmed.
5) Bone Health
Some early research in animals suggests that lithium may decrease the risk of bone fractures and promote bone growth. However, the effects of supplemental doses of lithium on bone health in humans have not yet been explored further, and more research will be needed before this effect can be confirmed [63, 64].
6) Autoimmunity and Inflammation
Lithium may interact with the immune system through several different potential mechanisms. Scientists are currently investigating how lithium might affect the following pathways in cells or animals:
- Inhibiting GSK-3, which might theoretically reduce autoimmunity (conditions in which the immune system “attacks” the body’s own tissues and organs) .
- Increasing the production of IgG and IgM antibodies, while also potentially decreasing the activity of inflammatory prostaglandins [68, 69].
- Suppressing Th1 cells and interferon-gamma (but not Th17 cells) .
Nonetheless, these mechanisms have so far only been studied in animals and cells, and have not yet been investigated or confirmed in humans.
Based on a handful of preliminary animal and cell studies, some scientists have proposed that lithium may have some notable effects on the circadian rhythm (the body’s “master clock” that helps regulate sleep, digestion, and other important daily activities and processes).
Specifically, lithium has been suggested to “lengthen” the circadian rhythm period, which could theoretically help treat some of the sleep issues and other problems that arise when the circadian rhythm is “desynchronized” from its normal 24-hour cycle [70, 71].
Relatedly, some other researchers are currently investigating whether lithium may help activate the various genes and proteins involved in the sleep-wake cycle, which could therefore potentially help the body stay “in sync” with day- and night cycles. In short, this could point to a potential role of lithium in making the body and brain more sensitive to “zeitgebers,” or biological cues for the time of day. However, these early findings have not yet been confirmed in humans, and so much more research will still be needed to verify and extend them [70, 71].
Finally, a few clinical trials have reported that lithium medications may improve sleep in bipolar patients. However, these findings pertain only to “high-dose” pharmaceutical forms of lithium — and whether they might also apply to lower-dose, “supplemental” forms of lithium remains unknown [72, 73].
Research on lithium orotate is very limited, and many studies are decades old.
Additionally, many of the purported benefits of lithium orotate are erroneously inferred from studies that actually looked at low-dose prescription lithium carbonate (also known as “sub-therapeutic” or “micro-dose” lithium). Therefore, these findings and effects don’t necessarily translate to “supplemental” forms of lithium, and much more research would be needed to firmly establish these so-called “benefits” in healthy human users.
Studies examining the trace amounts of lithium found in drinking water offer no information about the potential benefits of lithium supplements. Proper long-term, large-scale clinical trials will be needed to follow up on these associational findings.
The human body needs tiny amounts of lithium to function properly.
High-dose lithium carbonate is an effective and officially-approved treatment for bipolar disorder and some other psychiatric conditions. Solid research shows that it likely also helps with some symptoms of depression, ADHD, and schizophrenia.
A few limited and highly-controversial studies have suggested that people who get a bit more dietary lithium may be less suicidal and more peaceful, but these findings have only reported associations, and do not establish a direct casual effect of lithium on complex human behavior. Solid data are lacking to back up this hypothesis.
Despite some promising early findings, there is currently insufficient evidence to support the use of supplemental (“micro-” or “low-“) doses of lithium for any condition or other health benefit. Much more additional research will be needed in order to determine the effects of low-dose lithium on brain health, cognition, and autoimmunity.