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Sep 02, 2023

Vitamin D Supplements Probably Won't Prevent Mental Illness After All

Despite the stream of “good news” about vitamin D, the supplement’s prospects to

Despite the stream of "good news" about vitamin D, the supplement's prospects to prevent mental health disorders in adults remain dim

In February scientists reported that vitamin D was associated with a reduced risk of suicide attempts among U.S. veterans. The study compared more than 600,000 veterans who took various doses of vitamin D with an equal number of those who did not ingest the supplements. Taking vitamin D, they concluded, was linked with a 45 to 48 percent overall reduction in the risk of visiting a hospital for a suicide attempt or intentional self-harm. The higher the dose, the greater the reduction in risk, particularly for those with the lowest blood levels of the vitamin. "In general, those who had lower blood levels and received higher doses [of vitamin D] had the largest response, which is what you would expect to see if there were an actual treatment effect," says study co-author Jason Gibbons, a postdoctoral fellow and health economist at Johns Hopkins University.

The study adds to a deluge of data from recent decades linking low levels of vitamin D to mental health problems such as depression, schizophrenia and poor cognition. And it showcases the enduring enthusiasm among many scientists for the vitamin's potential as an aid to mental wellness, a message that some doctors relay to patients. "Imagine if getting a little vitamin D pill would reduce the mental health burden around the world. That would be incredible, right? That's the kind of pipe dream I think people are chasing with this research," says Brian Lee, an epidemiologist at Drexel University's Dornsife School of Public Health, who has studied the vitamin's connection with autism.

Vitamin D has important biological effects on the brain. It can cross the blood-brain barrier and enter neurons, and receptors for the vitamin populate many human brain regions. Studies in rodents suggest that vitamin D undergirds the cellular basis of learning and memory, for one, and the brain's balance of signals that stimulate or inhibit neural activity, which is thought to be askew in autism and schizophrenia. Vitamin D is also a steroid hormone with powerful anti-inflammatory qualities, and various lines of evidence suggest that inflammation plays a role in depression.

Still, even well-done observational studies cannot definitively prove that a person's blood level of vitamin D contributes to their mental status or stability. Vitamin D status may instead simply tag along with some other behavior or genetic factor that is more influential. Although researchers try to match the people who took vitamin D with virtually identical controls, there is no way to be sure that there isn't some other difference between the groups that could account for the findings, experts say. "It's possible that other kinds of behaviors could maybe somewhat explain our effect," Gibbons says.

To sort out causal relationships, many researchers place their bets on randomized clinical trials in which some people are assigned to take vitamin D and others are not, and the outcomes are later compared. In a 2020 trial, researchers gave 2,000 international units (IU) of vitamin D supplements or a placebo daily to more than 18,000 men and women aged 50 years or older with no signs of clinical depression. For more than five years the researchers assessed the incidence of depression and mood scores of both groups. They found no significant differences. Two smaller 2019 trials of 800 or 1,200 IU of vitamin D showed no benefit for populations at risk for depression. Not all trials have been so disappointing, but the overall picture is not promising. "We’re not finding in the clinical trial evidence that vitamin D supplementation significantly reduced risk of depression," says Olivia Okereke, an associate professor of psychiatry at Harvard Medical School, who led the 2020 depression trial.

Vitamin D has also lacked luster in trials of other psychiatric disorders. In a 2021 trial testing whether vitamin D can improve health outcomes in people with psychosis, researchers gave a large monthly dose to 149 young people who had experienced a first episode of psychosis, many of whom had had low blood levels of the vitamin. "We randomized the vitamin D supplements versus placebo, and we followed them up for a while, and we found no effect at all" of vitamin D on mental health, says John McGrath, a psychiatrist and epidemiologist at the University of Queensland in Australia and senior author of the study. "So I don't think that adult low vitamin D is a major cause of schizophrenia."

Low vitamin D is more likely to be a marker for illness than a cause of it, he and others say. That's because low vitamin D levels are common in people with any health condition that dissuades them from spending time outdoors—the sun is an important source of vitamin D—or from eating a vitamin-rich diet. "If you have an illness like depression or maybe vulnerability to suicide, and then you change your behaviors, you get less vitamin D because of your changed behavior," McGrath says. "Low [vitamin] D may be one of those bystander or proxy markers that just goes along with your behavior."

Some genetic evidence supports this argument. In a study of more than 400,000 people, McGrath and his colleagues showed that the genetic variants linked to low vitamin D—enzymes that make the vitamin, say, or help determine skin color—are not associated with the presence of psychiatric disorders. The genetic correlates of these disorders are associated with low vitamin D levels, however, likely through behavior. "For example, we found that the genes that link to hours watching television lead to low vitamin D," McGrath says. "Low vitamin D doesn't cause you to watch more TV."

Vitamin D has also fallen short in randomized clinical trials that have tested its mettle against "a very long list of health outcomes," including heart disease, stroke and total cancer incidence, says JoAnn Manson, a professor of medicine at Harvard Medical School and a principal investigator of the Vitamin D and Omega-3 Trial (VITAL), the largest randomized trial of vitamin D in the world. (Okereke's depression trial was part of VITAL.) In July the team added a new null finding: vitamin D did not reduce the risk of bone fractures, which was thought to be its best established benefit, Manson says. The outcomes for which vitamin D has proved beneficial in VITAL have been limited: it has been found to reduce the risk of cancer death and the incidence of advanced cancers and autoimmune diseases.

Randomized trials are not foolproof. Some, such as McGrath's, may not have lasted long enough to show effects. In other cases, the trial might simply have missed the window for when supplementation is critical, Lee says. "[Randomized controlled trials] are the gold standard of evidence, but you could do something at the completely wrong time point, and it won't matter," Lee says. In addition, the vitamin D of a placebo group is difficult to control because people can easily pick up extra vitamin D from sunlight or food. Still, these trial results have soured many researchers in the field on the idea that vitamin D has a significant influence on mental health in adults. "You’re an adult, and you get low vitamin D: Does it increase the risk of depression or suicide or schizophrenia? I think the evidence is not very strong," McGrath says. (Because vitamin D requirements vary by individual, and no specific level is critical for health, the U.S. Preventive Services Task Force concluded in 2021 that there was insufficient evidence to assess the benefits and harms of screening the population at large for vitamin D deficiency.)

But even if vitamin D blood levels have little impact on the adult brain, they could still be critical during development. A wealth of data in animals and cell culture support this idea. The production of factors that spur neuronal growth depends on vitamin D, which has also proved critical to brain cell maturation, says Darryl Eyles, a developmental neurobiologist at the University of Queensland. When a pregnant rat is deficient in vitamin D, the brain of its fetus has more dividing cells than mature cells, suggesting a delay in brain maturation. "The addition of vitamin D differentiates brain cells—be they glia, be they neurons—and will push them down various lineages. If there is an absence of this vitamin, you will dedifferentiate the brain," Eyles says.

Other studies show that vitamin D shepherds certain neurons in the midbrain—those that use the neurotransmitter dopamine and are abnormal in schizophrenia—to their correct brain locales during development. A deficiency can perturb the proper formation of those circuits, Eyles and his colleagues have found. And when pregnant rats are deprived of vitamin D during gestation, their offspring show cognitive deficits and diminished sociality, among other behaviors reminiscent of people with schizophrenia. (That condition is thought to have developmental origins.) "We have heaps of animal experimental evidence which shows that this is a biologically plausible candidate," McGrath says.

None of this means that vitamin D deficiency in the womb is a risk factor for schizophrenia. But several observational studies hint that it could be. In a 2018 study, McGrath and his colleagues measured vitamin D levels in 2,602 blood samples from newborns from a repository in Denmark. (The blood came from heel pricks used to screen for conditions such as phenylketonuria and hypothyroidism.) Some of these children later developed schizophrenia, and the researchers found that low vitamin D was associated with an increased risk of that illness. The work replicated results that McGrath and his colleagues published in 2010.

Several studies of a similar design have shown the same association between vitamin D and autism. In a 2021 study, researchers measured the vitamin in blood collected from more than 3,000 women in Finland during the first and second trimesters of pregnancy. They compared vitamin D levels from the 1,558 pregnancies that led to a child who was later diagnosed with autism with an equal number of pregnancies that did not result in an autistic child. Two other studies of similar size, published in 2017 and 2019, linked increased autism odds to low levels of vitamin D in newborn blood samples from a Swedish registry or maternal blood collected in the Netherlands. Not every study of vitamin D and autism has showed a link, however. And giving children a high dose of the vitamin after birth does not confer additional benefits for neurodevelopment by age six, compared with a standard dose, according to one trial conducted in Finland.

Despite the mixture of findings and lack of clinical trials, the idea that prenatal vitamin D may be important is still very much alive. Reverse causality does not apply, after all, because there are no fetal behaviors that could explain low vitamin D in the womb. "In a healthy pregnancy that just has low vitamin D, the fetus is not changing its behavior," Eyles says. "It's something about the developing system." It is possible that low vitamin D in a pregnant person accompanies a genetic propensity for mental or other illnesses that they then pass to their fetus, however. "I still can't put my hand on my heart and say we’ve proven pregnant women should take vitamin D supplements to stop their kids from getting schizophrenia," McGrath says. But "I have not been able to reject the hypothesis yet."

The randomized trials that would help settle the issue are probably not imminent. Such trials are tricky to conduct in pregnant people. They also present logistical problems for a condition such as schizophrenia that manifests decades later, McGrath says. So researchers continue to work on the circumstantial case.

Meanwhile Okereke's team has done another analysis of data from its clinical depression trial in adults that yielded negative results to examine the impact of vitamin D on certain groups within the larger populations studied. This subgroup analysis opens up the possibility that vitamin D could benefit certain individuals. To confirm those benefits would require additional clinical trials, Okereke says.

The results of the recent suicide study call for similar confirmation, its authors say. "We should be looking potentially at vitamins in randomized controlled trials and vitamins D2 and D3 in particular as potential interventions for suicide prevention," says study investigator Jill Lavigne, an epidemiologist at the U.S. Department of Veterans Affairs’ Center of Excellence for Suicide Prevention in Canandaigua, N.Y.

Fully evaluating that potential, Lee says, would require a very large trial whose participants are diverse geographically, racially and ethnically. Even a small reduction in the odds of suicide would be important, he adds. "Let's say taking a vitamin D pill reduces your risk of depression or suicide by—forget 50 percent—5 percent. That, over the entire population, would be a huge public health benefit," he says. "That's the kind of work that needs to be done, quantifying the actual effect, if there is any."

Until then, there is no harm in supplementing at reasonable doses, Lee says. (Large doses can be toxic.) But unless you have a vitamin D deficiency, he adds, there is also no compelling reason to do it. "I don't supplement myself," he says.

Ingrid Wickelgren is a freelance science journalist based in New Jersey.

Melinda Wenner Moyer