Lithium (medication)

Based on Wikipedia: Lithium (medication)

The Lightest Metal That Steadies the Mind

Here's something strange: one of the simplest elements on the periodic table—lithium, atomic number three, light enough to float on water—turns out to be one of the most effective treatments we have for one of the most devastating psychiatric conditions. Bipolar disorder can destroy lives, careers, and families. And the treatment? A salt made from an element that sits just two spots away from hydrogen.

Nobody fully understands why it works.

This isn't some minor gap in our knowledge. Lithium has been used to treat mental illness since the 1870s. It was formally approved by the United States Food and Drug Administration (FDA) in 1970. Doctors prescribe it millions of times each year. And yet, as of today, the exact mechanisms by which lithium stabilizes mood remain only partially understood. We know it does something to telomeres—those protective caps on the ends of chromosomes that shorten as we age. We know it affects mitochondria, the power plants of our cells. We know it interferes with certain enzymes. But the full picture? Still fuzzy.

This is humbling. Modern medicine can sequence the entire human genome and develop mRNA vaccines in under a year, but we still can't fully explain why a simple lithium salt calms the storms of mania.

A Discovery Born from Gout and Guinea Pigs

The story of lithium as a psychiatric medication begins with a scientific wrong turn. In the nineteenth century, doctors used lithium to treat gout—a painful form of arthritis caused by uric acid crystals building up in joints. The logic seemed reasonable at the time: lithium could dissolve uric acid crystals in laboratory settings, so perhaps it would do the same in the body.

This led to a peculiar chain of reasoning. Some physicians noticed that patients with gout often seemed to have mental disturbances. Meanwhile, they observed that patients with mania had elevated uric acid in their urine. Connecting these dots—incorrectly, as it turned out—doctors began giving lithium to manic patients in the 1870s.

The two pioneers were Carl Lange in Denmark and William Alexander Hammond in New York City. Their theoretical justification was completely wrong. Uric acid has nothing meaningful to do with mania. But lithium worked anyway.

Then, for reasons that remain somewhat mysterious, lithium fell out of favor. It wasn't until 1948 that an Australian psychiatrist named John Cade rediscovered its potential. Cade was investigating a different theory—he thought urea from manic patients might be toxic—and he was using lithium urate in his experiments because it was the most soluble form of urate available. He injected it into guinea pigs.

The guinea pigs became remarkably calm.

Cade, being a careful scientist, realized the calming effect might be from the lithium rather than the urate. He tested lithium carbonate by itself. Same result. Then he tried it on his most severely manic patient, a man who had been institutionalized for years. The transformation was dramatic enough that the patient eventually returned to his home and his job.

Walking the Tightrope: Therapeutic Index

Here's the catch with lithium, and it's a significant one: the dose that helps you is uncomfortably close to the dose that harms you.

Pharmacologists have a term for this—"therapeutic index"—which is essentially the ratio between an effective dose and a toxic dose. Aspirin has a wide therapeutic index; you'd have to take many times the normal dose before running into serious trouble. Lithium has a narrow therapeutic index. The blood levels that treat mania effectively hover around 1.0 to 1.5 milliequivalents per liter. Toxicity can begin appearing at levels not much higher than 1.8.

This is why lithium requires something unusual in psychiatric treatment: regular blood tests. Most psychiatric medications don't need this kind of monitoring. With lithium, it's essential. When you start taking it, your doctor might check your levels every week or two. Once you're stable, the checks become less frequent—every six months to a year—but they never stop entirely.

The narrow margin also means that seemingly minor things can tip you into trouble. Dehydration concentrates lithium in your blood. Heat causes dehydration. So does diarrhea, or not drinking enough water, or taking certain other medications. A patient who's been stable on lithium for years can develop toxicity simply by getting a stomach bug or spending too much time in the sun without hydrating.

What Toxicity Looks Like

Mild lithium toxicity announces itself with symptoms that might seem unremarkable at first: diarrhea, vomiting, shaky hands, feeling uncoordinated. These can be easy to dismiss or attribute to something else.

But there's one symptom that's particularly telling: ringing in the ears. If you're taking lithium and you start hearing a persistent tone that isn't there, that's your body sending an alarm.

Severe toxicity is much more serious—confusion, seizures, kidney failure, even death. This is why doctors emphasize the blood monitoring so strongly. It's also why patients on lithium need to understand their medication in a way that patients on many other drugs don't. You need to know that a hot summer day, a bout of food poisoning, or starting a new blood pressure medication could all affect your lithium levels.

The Body's Complicated Responses

Taking lithium is a bit like hiring a houseguest who helps with some chores but also rearranges your furniture in ways you didn't ask for.

The most common side effects are increased thirst and increased urination. This isn't coincidental—they're connected. Lithium interferes with how your kidneys concentrate urine. Normally, a hormone called antidiuretic hormone tells your kidneys to reabsorb water and produce concentrated urine. Lithium blocks this signal. The result is diabetes insipidus—not the sugar-related diabetes most people think of, but a condition where you produce large volumes of dilute urine and consequently need to drink more water to compensate.

Then there's the thyroid. Your thyroid gland produces hormones that regulate metabolism, energy, and body temperature. Lithium interferes with thyroid function frequently enough that people taking it are about six times more likely to develop hypothyroidism—an underactive thyroid—than the general population. This means regular thyroid monitoring becomes part of the routine, alongside those lithium blood levels.

Some people develop a goiter—an enlarged thyroid gland—even when their thyroid hormone levels remain normal. It's the gland working harder to compensate for lithium's interference.

Hand tremors affect about a quarter of people taking lithium. For some, this is barely noticeable. For others—surgeons, artists, anyone whose work requires fine motor control—it can be a significant problem. The tremor is usually worse when you're holding your hand out or performing precise movements, less noticeable when your hands are at rest.

Weight gain happens, though recent research suggests it's less dramatic than previously thought. A 2022 analysis found the average gain was less than half a kilogram—about a pound—and lithium actually caused less weight gain than several alternative mood stabilizers. The older reputation for significant weight gain may have been exaggerated.

Pregnancy, Breastfeeding, and Difficult Decisions

Lithium forces some of the most difficult conversations in medicine.

The drug is teratogenic—it can cause birth defects, particularly affecting heart development when exposure occurs during the first trimester. The risk is real but not absolute. Not every exposed pregnancy results in problems. But the FDA categorizes lithium as having positive evidence of risk during pregnancy.

This creates an agonizing dilemma for women with bipolar disorder who want to have children. Stopping lithium risks a manic or depressive episode during pregnancy—itself dangerous for both mother and fetus. Continuing lithium risks birth defects. There's no option that eliminates risk entirely.

Breastfeeding presents similar questions. Lithium passes into breast milk. The American Academy of Pediatrics lists it as contraindicated—meaning they recommend against it—for breastfeeding mothers. Many international health authorities agree. But "contraindicated" isn't the same as "absolutely forbidden," and individual circumstances vary. These are decisions that require careful consultation with doctors who understand both the psychiatric and obstetric implications.

Interestingly, there's a connection to the Substack article that prompted this exploration. Hormonal changes during and after pregnancy—like the testosterone decline mentioned in "For Me, Postpartum Testosterone Decline Has Been Very Real"—can interact in complex ways with psychiatric conditions and their treatments. The postpartum period is already a time of significant mood vulnerability, and medications like lithium add another layer of complexity to an already complicated biological situation.

What Lithium Actually Treats

Bipolar disorder remains lithium's primary territory. The condition involves cycles of mania—periods of elevated mood, decreased need for sleep, racing thoughts, impulsive behavior, sometimes grandiose beliefs—alternating with depression. Some people cycle rapidly between states; others go years between episodes.

Lithium works best as a maintenance treatment, taken daily to prevent episodes rather than to stop them once they've started. Think of it as a mood thermostat, keeping the emotional temperature from swinging too high or too low. For acute mania—an episode that's already underway—lithium helps, but antipsychotic medications often work faster.

For the depressive side of bipolar disorder, the evidence is murkier. Treatment guidelines recommend lithium, but studies comparing it to placebo for acute bipolar depression don't show overwhelming benefits. Atypical antipsychotics may be more effective for treating depressive episodes when they occur.

Beyond bipolar disorder, lithium has found uses in several other conditions, though the FDA hasn't formally approved it for these purposes—making them "off-label" uses. Doctors prescribe lithium as an add-on to antidepressants when those drugs alone don't fully treat major depression. This combination has been studied since the 1980s and seems to help some patients who don't respond to antidepressants alone.

Schizophrenia is another off-label use, though lithium works poorly as a standalone treatment for this condition. It's sometimes combined with antipsychotic medications, with mixed results in clinical studies.

The Suicide Question

Few topics in psychiatry generate as much hope—and controversy—as lithium's potential to prevent suicide.

The hope comes from observational data. People with bipolar disorder face dramatically elevated suicide risk. Studies repeatedly find that those taking lithium seem to attempt and complete suicide less often than those who don't. Some research has even found correlations between lithium levels in drinking water and lower suicide rates in the general population, particularly among men.

The controversy comes from randomized controlled trials—the gold standard for medical evidence. A 2022 systematic review concluded that "evidence from randomised trials is inconclusive and does not support the idea that lithium prevents suicide or suicidal behaviour."

How can both things be true? Observational studies can be confounded by factors that randomized trials control for. Perhaps people who take lithium consistently are also more engaged with treatment generally, more likely to attend therapy, more supported by family. Perhaps the effect is real but too small to detect in studies with limited sample sizes. Perhaps lithium does prevent suicide, but only in specific subgroups that get washed out in overall analyses.

Many clinicians continue prescribing lithium partly based on its believed suicide-prevention effects. The evidence isn't settled, but when the stakes are life and death, "probably helps" can be enough.

Lithium and the Aging Brain

Some of the most intriguing recent research on lithium has nothing to do with bipolar disorder. Scientists are investigating whether this simple salt might help with Alzheimer's disease.

Alzheimer's affects forty-five million people worldwide and ranks as the fifth leading cause of death among those over sixty-five. There's no cure. Available treatments modestly slow decline at best.

The Alzheimer's brain shows several characteristic changes. One involves the tau protein, which normally helps stabilize the internal scaffolding of neurons. In Alzheimer's, an enzyme called glycogen synthase kinase-3 (GSK-3) adds too many phosphate groups to tau, causing it to malfunction and clump together.

Lithium inhibits GSK-3.

This caught researchers' attention. If lithium blocks the enzyme that misbehaves in Alzheimer's, might it slow the disease? Early studies have been provocative. In 2009, researchers gave low-dose lithium to Alzheimer's patients for three months and found significant slowing of cognitive decline, with the greatest benefits in patients who hadn't yet progressed far into the disease.

Population studies have added another piece to the puzzle. In 2017, researchers found that areas with higher lithium levels in drinking water had fewer deaths attributed to dementia. This echoes the suicide findings—correlations in water supplies suggesting that tiny doses might have population-level effects.

A 2025 study pushed further. Researchers examined twenty-seven different metals in the brains of people with Alzheimer's and found that lithium levels were significantly reduced compared to healthy brains. When they gave lithium orotate—a different lithium salt—to mice engineered to develop Alzheimer's-like symptoms, it prevented cognitive defects.

None of this proves lithium treats Alzheimer's in humans. The leap from mouse studies to clinical practice is notoriously treacherous. But the convergence of multiple lines of evidence—the enzyme inhibition, the population studies, the animal experiments—suggests this is worth continued investigation.

How Lithium Might Protect Neurons

If lithium does help with brain aging, the mechanisms probably go beyond GSK-3 inhibition.

Lithium stimulates neurogenesis—the birth of new brain cells—particularly in the hippocampus, the seahorse-shaped structure critical for memory formation. Brain imaging shows that the hippocampus actually becomes thicker in people taking lithium.

The drug also increases production of brain-derived neurotrophic factor (BDNF), a protein that supports neuron survival and growth. Think of BDNF as fertilizer for brain cells. In the 2009 Alzheimer's study, patients who improved showed increased BDNF markers in their blood.

Calcium regulation offers another potential mechanism. Brain cells depend on precisely controlled calcium levels—too much or too little calcium can trigger cell death. Alzheimer's involves dysregulated calcium signaling. Lithium appears to help restore calcium balance by affecting how calcium flows into and out of cells.

None of these mechanisms is fully understood. But together they paint a picture of lithium as something like a general neuroprotective agent—not targeting any single pathway, but supporting brain cell health through multiple simultaneous effects.

Stopping Lithium

If you've taken lithium for a long time and achieved stable remission, you might wonder about stopping. This needs to happen gradually and under medical supervision.

Abrupt discontinuation can trigger symptoms within the first week: irritability, restlessness, dizziness, vertigo. These are usually mild and resolve on their own within weeks. But there's also the risk of relapse into mania or depression, which is why the decision to stop lithium requires careful consideration of the individual's history and risk factors.

For some people, lithium is a lifelong medication. For others, it might be a bridge through a particularly unstable period. The decision depends on factors like how severe your episodes were, how long you've been stable, what triggered your episodes in the past, and what other supports you have in place.

The Paradox of an Ancient Treatment

There's something almost embarrassing about lithium's place in modern psychiatry.

We live in an era of targeted therapies, precision medicine, drugs designed in computers and refined through understanding of specific molecular pathways. And one of our most effective psychiatric treatments is a naturally occurring salt that we discovered works through a combination of serendipity, wrong theories, and guinea pigs.

Nobody patented lithium. It's been generic from the start. This means no pharmaceutical company has much incentive to fund large studies—there's no money to be made. It means lithium doesn't get marketed the way newer drugs do. Some researchers believe it's actually underused, particularly in older patients and in certain countries, partly because of this lack of commercial promotion.

In 2023, lithium carbonate was the 187th most commonly prescribed medication in the United States, with over two million prescriptions. That's a lot of people trusting their mental stability to element number three on the periodic table.

The World Health Organization includes lithium carbonate on its List of Essential Medicines—the drugs considered most important for a basic healthcare system. Alongside antibiotics and cancer treatments and vaccines, there's a simple salt that keeps millions of people from the devastating extremes of bipolar disorder.

We still don't fully understand why it works. Maybe we never will. But for over 150 years now, it has kept working anyway.