Is Lithium the Drug Different Than the “Natural” Forms?

There’s a lot of misinformation about lithium. A lot of mainstream sources (WebMD, for instance) seem to suggest that lithium prescribed as a treatment for depression or bipolar disorder (as carbonate or chloride salts and in higher doses) works differently than over-the-counter lithium orotate.

All the research I’ve seen talks about the ion lithium, which would make the salt type of lithium not that relevant except for how bioavailable it is and how capable it is in crossing the brain barrier.

Some people say that the over-the-counter version – lithium orotate – passes the brain barrier much more efficiently than the other versions.

Even assuming the possibility of some differences in dosage, studies about one form of lithium can very likely be generalized to others. In this post, we bring down studies on any form of lithium, but if you are not taking the drug with the consent of a doctor, then you should not take more than a few mg of lithium orotate a day.

My Experience

The usual lithium orotate dosage taken is 5 mg, but I decided to take 15 mg to see what would happen. I can say that there’s definitely a subtle cognitive effect. It’s definitely got an anti-depressant and anti-anxiety effect, and it seemed to lengthen the period of my circadian rhythm, as I started to feel tired later on.

On the negative side, it made me more zoned out. It also made me feel less attached to everything. The fact that I felt acute effects at 15 mg suggests me that lithium orotate passes the brain barrier efficiently, perhaps even more so, since a much higher dosage of lithium carbonate is standardly used.

Anyway, I’m glad I did the experiment so that I now know lithium orotate is definitely having an effect and I can use it in my coaching practice.

This suggests that at least some of the benefits of other lithium salts prescribed by doctors can be achieved through the orotate version commonly sold.

Lithium Snapshot


  • Great for emotional balance, including anxiety and depression
  • Improves cognitive performance
  • Increases lifespan
  • Increases bone density
  • Improves mitochondria


  • May increases IL-8 in the gut
  • May cause some fatigue
  • May inhibit thyroid function a bit

Lithium is an alkali metal, naturally present in trace amounts in minerals, water, and soil, and in fruits, vegetables, and other plants that are grown in lithium-rich soil [R].

It plays a role in the proper function of several enzymes, hormones, vitamins, growth factors, and the immune and nervous systems [R].

Aside from helping patients with mental health issues, lithium has a wide and ever-growing list of health benefits.

The Health Benefits of Lithium

1) Lithium Is Neuroprotective

Chronic lithium treatment was found to robustly reduce glutamate-induced excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors. This effect was at least partly due to lithium’s ability to inhibit the influx of calcium, which mediates NMDA receptor activity. [R].

Therefore, it can help mood disorders, Alzheimer’s, diabetes, cancer, and inflammatory and autoimmune diseases [R].

2) Lithium Inhibits Apoptosis

Lithium increases Heat Shock Proteins (HSPs), which promote folding of proteins, refolding of misfolded proteins, and disposal of abnormal proteins [R].

Among HSPs, HSP70 exerts a wide variety of neuroprotective effects against apoptosis. These effects are mediated by inhibition of GSK-3 [R].

Lithium also inhibits GSK-3 [R].

Chronic lithium treatment also induces the production of Bcl-2, a protein in the frontal cortex that protects cells from apoptosis [R].

3) Lithium Increases Neurotrophic Factors BDNF, NGF, and GDNF

Long-term treatment of cultured neurons with lithium induces BDNF. [R].

BDNF is a major neurotrophin essential for cognitive development, synaptic plasticity, and neuronal survival with anti-depressants and anti-anxiety effects. [R].

This is likely a result of inhibition of GSK-3. [R].

Lithium also increases Nerve Growth Factor (NGF) and Glial-Derived Neurotrophic Factor (GDNF) in the hippocampus, frontal cortex, occipital cortex, and striatum [R].

NGF and GDNF help increase neuronal survival and plasticity (the ability to regenerate and form new connections) of dopaminergic, cholinergic, and serotonergic neurons in the central nervous system.

4) Lithium Helps Remodel the Brain and Heart (VEGF)

Lithium treatment increases the production of VEGF, which promotes cell growth and remodeling of the blood vessels after stroke [R].

By increasing VEGF, lithium treatment can help people recover more quickly from a stroke or a heart attack [R].

The likely mechanism is by inhibiting GSK-3 [R].

5) Lithium Induces Autophagy

Autophagy or “cellular self-eating” is when the cells degrade and recycle cellular components to reuse the raw materials [R].

It is considered anti-aging, cancer-preventing, and important for neuronal function and survival [R, R].

Lithium can induce autophagy by depleting inositol independently of mTOR inhibition (which typically induces autophagy) [R].

Because lithium induces autophagy, it may be particularly helpful for neurodegenerative disorders – Alzheimer’s, Parkinson’s, ALS, and Huntington’s because these disorders are, in part, characterized by the accumulation of, misfolded disease-causing proteins [R].

6) Lithium Increases Neurogenesis and Improves Cognitive Function

Lithium was found to stimulate progenitor and stem cells in cultured brain hippocampal neurons (neurons from the memory center). In addition, lithium prevents the loss of proliferation induced by glutamate or cortisol (glucocorticoids). Long-term lithium treatment promotes the conversion of these progenitor cells into neurons. [R].

In addition, chronic lithium treatment not only enhanced neurogenesis in the hippocampus (memory center) of normal mice but also restored neurogenesis in the brain in an animal model of Down syndrome [R].

It also increases neurogenesis in the subventricular zone, the only other place except for the hippocampus (memory center) that it’s been found to occur, causing a sustained increase in gray matter volume in patients [R].

Lithium increases N-acetyl aspartate (NAA), which may be a marker of creativity and is correlated with IQ scores [R, R].

One probable effect is more efficient communication between two sides of the brain, which enhances intellectual performance. [R].

Chronic lithium treatment increases long-term potentiation (LTP) in neurons of the hippocampus, which makes the nerve cells more efficient, and thus helps with learning and memory [R].

7) Lithium Can Calm and Stabilize Mood

In animals, lithium consistently decreased exploratory activity and aggression. [R].

Lithium is known to have a calming and mood-stabilizing effect in people as well and is used to treat depression, bipolar disorder, and schizophrenia.

Lithium carbonate is the drug of choice for control of manic-depressive illness, reducing manic attacks [RRR].

It was also shown to be effective for aggressive behavior in people with attention-deficit hyperactivity disorder (ADHD) [R].

Lithium increases CCK in the brain and this is part of the mechanism by which lithium prevents mania in bipolar.

8) Lithium Combats Depression

Lithium is one of the best-studied strategies for treatment-resistant depression [R].

Lithium increases serotonin 5-HT1A postsynaptic sensitivity, which is in part responsible for its antidepressant activity. [R].

Lithium also elevates BDNF, which combats depression.

Lithium ameliorates depression in animals, in part, by increasing neural stem cells.

9) Lithium May Be a Potential Treatment for Huntington’s Disease

Lithium prevented nerve cell death in animal models of Huntington’s disease [RR].

Lithium decreases excessive NMDA receptor function, which could potentially counteract increased activation of NMDA receptors that occurs in the brain of patients with Huntington’s disease [R].

10) Lithium Decreases Insulin Resistance

Lithium enhances insulin-stimulated glucose transport and glycogen synthesis in insulin-resistant muscle in rats [R].

These effects are dependent on p38 MAPK [R].

It also decreases insulin release [R].

Administration of lithium significantly increased glucose transport into muscle cells in response to insulin by 2.5 fold, and also increased insulin responsiveness [R].

11) Lithium Reduces Autoimmunity and Inflammation

Lithium has potent immune-boosting effects [RR].

By inhibiting GSK-3, lithium is beneficial in animal models of autoimmune conditions. [R].

Lithium suppresses Th1 cells and interferon gamma (but not Th17 cells) [R].

Lithium has anti-inflammatory effects by decreasing the production of IL-1β and TNF-α and increasing the production of IL-2, TGF, IL-1RA, and IL-10 [R, R].

However, studies indicate that under certain experimental conditions, lithium also has pro-inflammatory effects by increasing production of IL-4, IL-6, and TNF-α [R].

Lithium increases the production of IgG and IgM antibodies [R].

Lithium decreases the production and activity of prostaglandins, thus preventing its negative effect on the immune system [R].

Lithium decreased the frequency and duration of recurrent labial and genital herpes infections and reduced the occurrence of common colds [RR].

12) Lithium Supports Bone Health

A study assessed bone mineral density at the hip and lumbar spine in 75 lithium-treated outpatients and 75 normal subjects matched for age, sex, and body mass index. The study found a lower bone turnover state in those receiving lithium. The mean bone density in lithium-treated patients was 4.5% higher at the spine, 5.3% higher at the femoral neck, and 7.5% higher at the trochanter [R].

Lithium is associated with a decrease in the risk of bone fractures, and an increase in bone formation [RRR].

13) Lithium Helps Entrain Circadian Rhythm

Lithium is the drug of choice for treating patients suffering from bipolar disorder, which is characterized by the presence of mania and depression.

One mechanism by which lithium can help bipolar disorder is by lengthening the circadian rhythm. People with bipolar disorder tend to have a shorter circadian rhythm than those without bipolar.

It helps entrain our circadian rhythm more quickly in response to light and darkness.

14) Lithium Improves Mitochondrial Function

Lithium treatment in worms increased lifespan and improved markers of health, including mitochondrial energy output [R].

Lithium may improve mitochondrial function by increasing the turnover of dysfunctional mitochondria [R].

Also, lithium inhibits mir-34a, which in turn inhibits NAMPT, the enzyme that makes NAD+ [R].

Therefore, lithium probably increases NAD+.

15) Low Dose Lithium Increases Longevity

Researchers have found a positive correlation between lifespan and lithium levels in drinking water. There was a decreased risk for all causes of death in Japanese neighborhoods with higher lithium levels.

This was also the case in worms. Long-term low-dose exposure to lithium may exert anti-aging capabilities, decreasing mortality in evolutionary distinct species [R].

The improvements in health were accompanied by improved mitochondrial function. [R].

16) Lithium May Improve Symptoms of Tourette’s Syndrome

Tourette’s syndrome is a neurological disorder, characterized by involuntary muscle movements and uncontrollable vocal sounds.

In a small study involving 3 patients, lithium had a better outcome than haloperidol, a commonly prescribed drug for Tourette’s. Patients who were taking lithium experienced a significant decrease in the number of tics and involuntary vocal sounds. Patients experienced no side effects and were symptom free months later [R].

17) Lithium May Help with Tardive Dyskinesia

Tardive dyskinesia is a neurological disorder characterized by involuntary, sudden, and jerky movements of the face and/or body, caused by the long-term use of antipsychotic drugs [R].

Studies showed that lithium significantly reduced the severity of tardive dyskinesia [R, R, R].

It decreased agitation and aggression and improved involuntary movements [R, R].

However, 2 large studies failed to report consistent effects of lithium on tardive dyskinesia [R, R].

18) Lithium Helps with Obsessive-Compulsive Behaviors

Obsessive-compulsive disorder (OCD) is a mental disorder characterized by obsessive thoughts and behaviors [R].

Lithium supplementation is associated with a decrease in symptoms of OCD that are resistant to standard therapy [R].

Compulsive and pathological gamblers also had a good response to lithium supplementation, possibly by regulating dopamine imbalances in the brain [R].

19) Lithium May Relieve Headache

Lithium may reduce the severity of both chronic and episodic cluster headaches [R].

Lithium carbonate given before sleep helped with “alarm clock headache” (a headache that affects the elderly, waking them from sleep at the same time of night) [R, R, R].

20) Lithium May Be Effective in Anorexia Nervosa

Patients suffering from anorexia nervosa for many years were treated successfully with lithium carbonate [R, R].

One patient gained 12 kg and the other 9 kg within 6 weeks, and the weight gain was maintained for a year with lithium therapy [R].

21) Lithium May Be Effective for Treating Alcoholism

Lithium orotate is useful in the treatment of alcoholism.

In a study of 42 alcoholic patients, lithium was safely tolerated, with minor side effects, such as muscle weakness, loss of appetite, or mild apathy [R].

Lithium carbonate promotes abstinence from alcohol, diminishes subjective symptoms of withdrawal, and delays the time to first drink [RR].

Patients treated with lithium were much less likely to be re-hospitalized for alcoholism rehabilitation during the 18-month followup [R].

22) Lithium May Reduce Seizures

The effect of lithium on seizure disorders is still controversial [R].

Some epileptic patients show a statistically significant decrease in seizure frequency as well as improved behavior when treated with lithium [R].

However, a few epileptic patients experienced an increased number of seizures while on lithium [R, R, R].

23) Lithium May Relieve Symptoms of Meniere’s Disease

Meniere’s disease is a disorder of the ear that causes severe dizziness, ringing in the ears, hearing loss, and a feeling of fullness in the ear.

Seventy percent of patients with Meniere’s disease experienced less frequent and severe attacks when on lithium treatment [R].

However, a study with patients given 6 months of lithium and 6 months of placebo showed no difference between the 2 treatments [R].


Genetic Factors That Affect Responses to Lithium

5-HTTLPR (SLC6A4) Serotonin Transporter

Subjects with 2 copies of the short form of this gene show a worse response to lithium than those with the long form [R].

Relevant SNPs: The presence of rs25531 (not in 23andme) may indicate the long form.

GSK3beta -50T/C

This SNP is a source of variability between responses to lithium in bipolar patients, although the results are mixed [R, R, R].

The C allele is associated with better response to antidepressants than with lithium augmentation [R].

Potential Risks/Negatives

Lithium has numerous side effects and can be toxic at high doses.

The severity of symptoms is generally proportional to the degree of elevation of blood lithium levels [R].

Most Common Side Effects of Lithium

The most common side effects of lithium therapy include [R]:

  • Headaches
  • Lethargy and fatigue – this may be a result of a significant reduction in orexin-producing cells and through reducing thyroid function
  • Drowsiness
  • Hand tremors
  • Muscle weakness
  • Nausea/vomiting
  • Diarrhea

Symptoms of Moderate Lithium Toxicity

Moderate toxicity (serum lithium concentration = 2.0 to 2.5 mmol/L) is characterized by [R]:

  • Confusion
  • Dysarthria (speech motor problem)
  • Nystagmus (eye twitch)
  • Ataxia
  • Muscle twitches
  • ECG changes (flat or inverted T waves)

Symptoms of Severe Lithium Toxicity

Symptoms of severe toxicity (serum lithium concentration> 2.5 mmol/L) include [R]:

  • Impaired consciousness
  • Seizures
  • Syncope
  • Kidney insufficiency
  • Coma and death

Lithium May Lower Thyroid Function

Lithium decreases production and release of thyroid hormones, thus hypothyroidism is very prevalent among patients on lithium therapy [RRRR].

Studies reported that goiter (enlargement of the thyroid gland) occurred in 50 to 60% of patients treated with lithium [R, RRR].

Hyperthyroidism occurs rarely, and it is characterized by transient and painless inflammation of the thyroid gland (thyroiditis), due to a possible toxic effect of lithium on the thyroid gland [RRR].

Lithium induces thyroid autoimmunity by increasing B cell activity and decreasing ratios of suppressor to cytotoxic T cells [R].

As a result, 20% of lithium-treated patients have thyroid auto-antibodies.

It may also be useful in combination with radioactive iodine in the treatment of thyroid cancer [R].

Other Negative Effects of Lithium

  • Lithium is a competitive inhibitor of magnesium, which is part of its mechanism of action [R].
  • Lithium may increase inflammation in the intestines- IL-8 and Nf-kB. If you have colitis or Crohn’s, I would not take this. Colitis is caused in part by IL-8 and this increases IL-8 [R, R].

Special Precautions

  • Pregnancy and breastfeeding: Lithium can be toxic to a developing baby and increase the risk of birth defects. It can enter breast milk and cause side effects in a nursing infant.
  • Heart disease: Lithium should be carefully used in patients with preexisting heart disease because it may cause irregular heart rhythms.
  • Kidney disease: Lithium removal from the body by the kidneys is decreased in patients with kidney disease, and the risk of lithium intoxication increases considerably in this setting.
  • Thyroid disease: Lithium may make thyroid problems worse.

Lithium Deficiency

Lithium deficiency caused by low dietary intakes, or due to certain diseases (kidney disease, especially in dialysis patients) is unlikely to happen in humans.

If a deficiency occurs, symptoms are mild and manifest primarily as behavioral problems [R].

Lithium Drug Interactions

Antidepressant drugs (such as Prozac®, Zoloft®, Elavil®, Anafranil®, Tofranil®), and lithium increase serotonin. Taking lithium with these medications could cause serious side effects such as heart problems, shivering, and anxiety [RR].

In patients treated with both lithium and an antipsychotic (haloperidol, thioridazine, chlorpromazine, clozapine, and risperidone), toxicity to the brain ranges from extrapyramidal symptoms (continuous muscle spasms or jerky movements) to neuroleptic malignant syndrome [RRRR].

Taking lithium along with anticonvulsant medications used to prevent seizures, such as phenobarbital, valproic acid, and carbamazepine may increase the risk of toxic effects from these drugs [R].

Medications for high blood pressure (ACE inhibitors – Capoten®, Vasotec®, and Prinivil®; and calcium channel blockers – Adalat®, Calan®, Cardizem®, and DynaCirc®) can increase lithium levels in the body, thus increasing its side effects [RRRR].

Diuretics, like water pills, and hydrochlorothiazide, chlorothiazide, and furosemide increase blood lithium concentrations by reducing lithium removal by the kidneys [RR].

Non-Steroidal Anti-inflammatory Drugs (ibuprofen, naproxen, and diclofenac) decrease lithium removal by the kidneys and thus increase blood lithium concentrations [RRR].

Taking lithium along with muscle relaxants (pancuronium, succinylcholine) might prolong muscle relaxation [RR].

Taking lithium along with dextromethorphan (Robitussin DM®), meperidine (Demerol®), or tramadol (Ultram®) may increase serotonin in the brain, and cause serious side effects including heart problems, shivering, and anxiety [R].

Acetazolamide, theophylline, and sodium bicarbonate can lower blood lithium concentrations by increasing lithium excretion in urine.

Dietary Sources of Lithium

Primary dietary sources of lithium are grains and vegetables, which may contribute from 66% to more than 90% of the total lithium intake [R].

Cacao, oats, seafood (shrimp, lobster, oysters, and scallops), seaweed, beef liver, goji berries, various fruits and vegetables (depending on the soil in which they are grown), and egg yolks are significant sources of lithium.


If you’re completely healthy, I recommend 1 to 2 mg a day in the long term. There is an association with low doses of lithium (1 to 2 mg) and longevity [R].

However, I wouldn’t expect to feel anything at that dosage. I’ve been taking 1 mg for quite a few months, with no noticeable effect. I’ve recently upped it to 5 mg.

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