There are some elements that we know are required for life: Carbon, oxygen, hydrogen, nitrogen, phosphorus. Others are critical side players: Iron, calcium, potassium and sodium. For a long time, lithium seemed like it was in a third category of elements—like titanium or radium—better left outside the body unless something has gone wrong.
Lithium powers batteries and many of our other technologies, and at the same time, doctors have prescribed it for years as an effective treatment for bipolar disorder and some kinds of major depression. But “up until recently, we did not think about lithium as something that’s physiologically necessary,” says Tomas Hajek, a psychiatrist at Dalhousie University in Nova Scotia.
Now, studies are suggesting that low doses of the element might halt—and even reverse—the ravages of Alzheimer’s disease and cognitive decline. While scientists are still trying to understand how lithium exerts its effects, they are coming to realize that the metal might join the list of key elements our bodies—and especially our brains—need to thrive.
The lithium lift
After lithium’s discovery in 1817, scientists began to investigate the light, silvery metal as a treatment for mental illnesses like “general nervousness.” In the early 20th century, lithium products began to pop up, literally. An early recipe for 7-Up contained lithium, and it’s one explanation for the soda’s name (another is the original number of ingredients in the drink). “The ‘up’ was presumably the psychological effects of lithium, and the seven was the molecular weight,” says Bruce Yankner, a neuroscientist at Harvard Medical School in Boston. As with many patent medicines and tonics during this era, the doses were high, the effects were toxic, and 7-Up now contains no “up” with a molecular weight of seven.
(Can drinking Coke really help with migraines?)
After a bit of a lithium lull, Australian doctor John Cade began successfully treating bipolar disorder patients with lithium in 1949, and it was approved in the United States in 1970. “Lithium became kind of the gold standard in mood-stabilizing treatments,” explains Hajek.
No one is quite sure how lithium lessens mania and eases depression. But how it works is secondary. It saves lives. “It may sound controversial,” Hajek says. “But things can work without me understanding why they work…if we wanted to know the mechanisms of action, we probably would not have essentially any treatments in psychiatry.”
Lithium is given to people with bipolar disorder in the form of lithium carbonate at fairly high doses, and patients are closely monitored to make sure the drug isn’t having negative effects on their kidneys, thyroid, and more.
Lithium’s potential brain benefits
The first clues that lithium’s effects might also prove neuroprotective came from bipolar patients. People with severe mood disorders have a three times higher risk for cognitive impairment as they age, explains Paul Vöhringer, a psychiatrist at the University of Chile in Santiago. But in 2007, scientists in Switzerland showed that bipolar patients treated with lithium “had [the] general population rate of dementia or Alzheimer’s disease when compared with these other patients without lithium treatment.” The treatment appeared to reduce their increased risk back down to the population level.
Then in 2012, Hajek scanned patients’ brains and found differences in the hippocampus—an area of the brain important for memory that is also important in major depressive disorder and bipolar disorder. “Hippocampal volumes are usually smaller in people who have major depressive disorders,” he explains. But patients treated with lithium showed hippocampal volumes that looked normal. “Their brains were essentially intact, despite the fact that they had a very long history of illness,” Hajek says.
Even trace amounts of lithium—those found in some people’s drinking water, for example—have been associated with lower population rates of aggression, suicide risk, and cognitive decline. “This was very puzzling, because there’s a several orders of magnitude difference between the doses of the kind that people would get from the drinking water, and the doses that we use clinically,” Hajek says.
(The unexpected ways Ozempic-like drugs might fight dementia)
The lithium Alzheimer’s link
By coincidence, Yankner’s lab was using lithium in their own studies of Alzheimer’s disease to look at neuroprotective factors activated by a signaling pathway known as wnt. “The classic way to experimentally activate wnt is to use high concentrations of lithium,” he says. In animal models, “these high concentrations lithium could reverse many, if not all, the pathological manifestations” of Alzheimer’s. They began to wonder “whether lithium itself could be part of the disease mechanism.”
You May Also Like
Yankner and his colleagues began by examining the brains of cadavers and found that normal brains had baseline levels of lithium—levels so low that they went undetected in previous studies. Cognitively normal neural tissue has trace amounts of lithium “approximately 1000-fold lower than what are achieved when a bipolar patient is treated with high doses of lithium,” he says. But those trace levels were even lower in people who died with mild cognitive impairment or Alzheimer’s disease.
Where was this lithium going? Yankner and his lab were able to show that lithium “binds pretty tightly” to clusters of the protein amyloid beta, specifically a form made up of 42 amino acids that has been implicated in the development of Alzheimer’s Disease, he explains. The plaques could be sucking up the brain’s stores of lithium.
“We get our lithium from our diet and our water,” Yankner explains. So to find out the role those lithium ions were playing, the lab then deprived mice of 92 percent of the lithium normally present in their water and food. While this decreased lithium levels in blood by 90 percent, Yankner notes, the brain only lost 50 percent of its lithium— suggesting that the brain was protecting its lithium supplies. “It’s clear that there’s a pool of lithium which is very tightly bound in the brain.”
In mouse models of Alzheimer’s disease, even the 50 percent decrease was profound. Amyloid plaques ballooned, as did tangles of tau, another protein implicated in Alzheimer’s. The mice also showed poor memory performance—signs of early cognitive decline, the team reported in the journal Nature earlier this year.
(What are the signs of dementia—and why is it so hard to diagnose?)
Taking out cellular trash
Lithium is an almost ludicrously tiny atom that’s highly electrochemically active, so it’s hard to pinpoint what exact role it’s playing in the brain that impacts Alzheimer’s.
One possible explanation may lie in lithium’s ability to reduce the activity of an enzyme called glycogen synthase kinase-3 beta, or GSK-3 beta. This busy molecule is involved in many things, including regulating the wnt pathways that play a role in protecting the brain and got Yankner interested in lithium. GSK-3 beta also acts on tau—attaching extra phosphorous to the protein and leading it to tangle inside cells during Alzheimer’s disease. Blocking GSK-3 beta can also activate autophagy, when a cell breaks down nonfunctioning parts, Francesco Fornai, a neuroscientist at the University of Pisa and the Candiolo Cancer Institute in Italy.
Autophagy is suppressed in patients with Alzheimer’s, Fornai notes, resulting in buildup of cellular “trash”—amyloid beta plaques and tau tangles. Activate autophagy again, he notes, and the cells restart their sanitation systems, “which [is] accompanied by an improvement of cognitive function.” Lithium, he notes, can activate that autophagy.
Yankner and his lab did this, returning lithium in a low-dose form called lithium orotate. The deposits of amyloid beta plaques and tau buildup ceased. The mice regained their memory function. All of this happened at doses far lower than the ones currently used to treat bipolar disorder.
A clinical element
The results in mice are promising, but no one is popping lithium back in soda just yet. The next step is clinical trials to determine which forms and doses of lithium are safe and effective against dementia declines in humans.
Vöhringer is currently recruiting for a clinical trial in Chile, looking for older adults with mood disorders—people at high risk for cognitive impairment. He hopes to give some participants low doses of lithium for five years, about 50 mg (treatment for bipolar disorder usually starts at 300 mg), to see if it can prevent the development of mild cognitive impairment.
But funding has been hard to come by, Vöhringer notes. “Nobody makes money off of lithium, because lithium is like a natural product,” he says. “It’s like making money out of oxygen, or water, it’s not a drug.” This makes it cheap, but also unprofitable, and big pharmaceutical companies aren’t as motivated to test it. Yankner is also planning more studies, using lithium orotate.
Many questions remain about what this tiny element is doing. “We don’t totally understand everything that physiological lithium is doing in the brain,” Yankner says. It could be involved in beta amyloid, in tau, in GSK-3 beta. “But it is also possible, and I wouldn’t exclude this, that lithium has a direct effect in the electrochemistry of the brain, just like it does in our lithium batteries,” he says. “Maybe we weren’t the first to discover and use that unique electrochemistry, maybe evolution found it before we did.”
While further studies will be key to understanding, to psychiatrists like Vöhringer, clinical practicality comes first. “I’m not going to be waiting to have the whole picture to start treating patients,” he says. “If we are giving this to patients and they are doing better, let’s go for it.”
