Research indicates that more vitamin D has health benefits for the brain as well as the rest of the body. The best source of vitamin D: a few minutes in the sun, without sunscreen. Although too much sun increases the risk of skin cancer, a few minutes allows the body to produce far more vitamin D than is available in foods or supplements. (Image copyright PhotoLibrary.com / Juice Images)
Tuesday, April 07, 2009

Vitamin D and the Brain: More Good News

By: R. Douglas ShytlePh.D., and Paula . BickfordPh.D.

Vitamin D, long ago established as important for healthy bones, is also significant in the brain during development and as we age.

Vitamin D has many roles in regulating brain health, from aiding the development of the brain and nervous system to postponing decline toward the end of life, according to a growing body of research. R. Douglas Shytle and Paula C. Bickford review the field and argue that while it is clear that many people worldwide experience vitamin D deficiency, we need to complete much more research to fully understand the consequences of this deficiency for brain health.

Interest in vitamin D has surged recently for two reasons: so many people do not have enough in their bodies that vitamin D deficiency is now recognized as a worldwide health problem, and at least 100 reports suggest that the nutrient can prevent or treat an array of chronic medical conditions.1 However, in light of the recent controversies surrounding the efficacy—and even safety—of other vitamins (in particular, vitamin E), it is important to evaluate the current research carefully, avoiding the temptation to be polarized by another popular frenzy, whether in support for or against the use of a particular supplement.

While the current controversy regarding the use of vitamin E is beyond the scope of this article, we must remember that much of the confusion surrounding its use stems from the conflation of the large body of evidence supporting the preventive health benefits of eating foods rich in diverse natural forms of vitamin E, known as tocopherols, and the recent short-term studies investigating the use of a single synthetic form, known as alpha-tocopherol, to treat people with chronic medical conditions. We hope that everyone will learn from the mistakes made during the vitamin E craze and avoid promoting premature conclusions regarding the health benefits of vitamin D or any single synthetic form of it.

Vitamins, by definition, are not synthesized by our bodies, but are small natural substances that must be acquired through the foods that we eat. Vitamin D, famously known as “the sunshine vitamin,” is not really a vitamin but a hormone, since most of it is produced by our body as the result of exposing our skin to the sun. While it is well known that vitamin D deficiency causes rickets in children and can lead to osteoporosis and bone fractures in adults, recent research suggests that such a shortage is associated with an increased risk of various types of common cancers, diabetes, autoimmune diseases, hypertension, stroke, infectious diseases and psychiatric illness. It is rapidly becoming clear that vitamin D plays various roles in regulating optimal brain health, both during development of the brain and the nervous system and throughout our lives.

Vitamin D and Early Brain Development

Until recently, it was thought that only certain peripheral organs could synthesize the final active form of vitamin D. But we now know that human and rodent brains do express the protein necessary for the conversion of vitamin D to its final active form, and also that the nutrient binds to sites on brain cells in a similar pattern in both species. This evidence suggests that vitamin D’s roles during normal brain development are so important that they have been preserved through evolutionary change and that we might learn more about humans by observing the rodent brain.

Growing evidence from a group of studies in both rats and mice indicates that vitamin D is involved in normal structural brain development, though it is not clear yet if that is the case in humans.2 Mice born to mothers that were deficient in vitamin D before and during pregnancy had longer, thinner brains, with enlarged ventricles (brain fluid canals). These offspring grew more new brain cells than normal during early brain development and had less “pruning” (death) of excess cells, a necessary process for forming effective brain cell connections. Unfortunately, these effects may be permanent: Some studies report that vitamin D supplementation after birth does not reverse these alterations.

In another series of studies, mice genetically engineered to lack cellular vitamin D binding sites, so that brain cells do not receive the nutrient, appear to have an impaired response to novel environments, similar to that seen in people with autism or schizophrenia. While this is only a first step toward characterizing the behavioral and brain abnormalities of offspring born to vitamin D–deficient mothers, it is an important finding: Studies of populations (epidemiological research) suggest an increased risk of schizophrenia and autism in populations with less sun exposure and vitamin D production, such as those living at higher latitudes or babies exposed to less sun because they were born during winter months.

These findings are “associations,” not cause and effect. More research should aim at clarifying these correlations, especially since roughly half of all pregnant women and newborns in the world currently have insufficient blood levels of vitamin D, even among populations with normal sun exposure. In particular, more research should be directed at investigating the hypothesis that vitamin D deficiency may contribute to the apparent increase in autism, as measured by the increase in diagnosis of the disease among children. The increasing numbers of autism diagnoses in the past 20 years appear to correspond with the increasing use of sunscreens and sun avoidance, which may have led to lower vitamin D levels in developing brains.

While we still have much to learn about how vitamin D acts in early brain development, a likely hypothesis is that it does so through its regulation of substances known as bone morphogenetic proteins (BMP). These proteins are important in triggering stem cells to become (or differentiate into) many types of cells, including brain cells. Evidence suggests that vitamin D increases the production of these proteins. In addition, the proteins’ signaling pathways may serve an essential purpose during brain development, blocking brain cell division.3 This process appears to be missing in vitamin D–deficient mice. However, no research group has yet conducted the pivotal experiments in animals or humans that would connect these dots with assurance.

Vitamin D and the Adult and Aging Brain

Recent epidemiological studies report that too-low levels of vitamin D appear to raise people’s risk for fatal stroke, dementia and multiple sclerosis (MS). For example, in a recent study, Thomas Wang of Harvard Medical School in Boston followed 1,739 people (average age 59) for 5 years.4 Those with low vitamin D levels had about a 60 percent higher risk of a cardiovascular event such as heart attack or stroke than did those with higher levels of the nutrient, even after accounting for other well-known cardiovascular risk factors such as diabetes, high cholesterol and high blood pressure. The risk for heart attack, heart failure or stroke was double in people with both high blood pressure and vitamin D deficiency.

Investigators at the University of Heidelberg in Germany reported similar results.5 Of 3,316 people referred for evaluation of their heart arteries, those with low levels of vitamin D were more likely to have a fatal stroke in the next seven years (the median follow-up period), even after accounting for other cardiovascular risk factors. These authors noted that vitamin D thins the blood and seems to protect neurons in animal studies; the researchers’ findings suggested that people who have had strokes or are at high risk for stroke should take vitamin D supplements. Findings from a number of studies in which researchers induced strokes in animals also support the idea that a certain level of vitamin D can prevent or treat stroke.

The results of these studies are consistent with psychiatric research investigating the cognitive and mental impairment associated with the age-related decline in vitamin D levels referred to as hypovitaminosis D (HVD). At least 40 percent—one study indicated 90 percent—of older adults, including people who live in sunny areas such as Florida, have HVD.6,7 Because vitamin D is fat soluble, many elderly people (who often have a higher fat-to-muscle ratio) may retain more of the nutrient in fatty tissue and have less of it available in the blood to maintain proper health. In addition, as we age, our skin becomes less efficient at making vitamin D from the sun.8

A recent review of the research on vitamin D deficiency and mental disorders by Paul Cherniack’s group at the University of Miami found five studies reporting an association between HVD and dementia, four studies linking it to mood disorders such as depression and bipolar disorder and four studies linking it to schizophrenia.9 Only two studies to date found no relationship between HVD and mental illness: one study of depression and one study of dementia.

The bulk of the evidence so far suggests that people who have HVD are at greater risk for conditions such as stroke, dementia, and mood disorders than those who do not. What is not clear is whether short-term oral vitamin D supplements would reverse these conditions in people who already have them. Again, more research is needed.

A critical issue in designing future clinical studies is defining the optimal dosage of oral vitamin D. For example, Reinhold Vieth, a prominent vitamin D researcher from the University of Toronto, has argued persuasively that clinical trials should use oral vitamin D doses equal to or higher than 800 IU/day (an International Unit, or IU, is a measurement based on a vitamin’s biological effect), since most previous studies reporting clinical benefits of vitamin D for bone health used doses that exceeded this level. Already one trial using supplements to treat people with depression that used only 400 IU/day (the current U.S. recommended daily allowance for adults, also described as 5 micrograms) failed to show any benefit from the treatment.

One of the most active areas of vitamin D research is its potential connection to multiple sclerosis (MS). As is the case with autism, the number of people with MS is higher in northern latitudes. Since vitamin D is produced primarily by exposure to sunlight, and high serum levels of vitamin D have been reported to correlate with a reduced risk of MS, researchers hypothesize that vitamin D may help protect people from the disease.

A recent study conducted by scientists at the University of Oxford and the University of British Columbia is being hailed by many as a major step in proof of this hypothesis because it links the environmental risk factor of low vitamin D levels with a previously known genetic abnormality common to many people with MS. These researchers discovered that if a person has low levels of vitamin D, this gene does not function properly, which sets up vulnerability to environmental triggers suspected in MS.10 At least two clinical trials are under way to investigate the potential benefits of using vitamin D supplements as a treatment for MS.

We find compelling the scientific evidence from animal studies that vitamin D supports healthy brain function in general throughout life. Vitamin D appears to be a “multi-potent” brain-cell-protective hormone, working through diverse and complex mechanisms including brain calcium regulation, antioxidative properties, immune system regulation and enhanced brain cell signaling.11

More May Be Better 

Between 20 and 80 percent of the population worldwide have insufficient vitamin D levels, and what this means for their brains and bodies is not yet clear. Why such a deficiency? Likely because we have hidden from the sun—the major source of vitamin D for most people. Very few foods naturally contain vitamin D, and foods fortified with the nutrient often do not have enough of it to satisfy our daily requirements. For example, a fair-skinned young adult wearing a bathing suit who spends 5–15 minutes in the midday summer sun can produce around 10,000 IU of vitamin D. To obtain the equivalent amount from our diet, we would need to drink 100 glasses of milk (at 100 IU per 8-ounce glass) or take 25 vitamin tablets containing the current recommended daily allowance (400 IU/tablet).

Considering that vitamin D supplements are low in cost and in known risks, and that research suggests that vitamin D may benefit early brain development and ongoing functioning, we would like to see doctors advising their healthy patients to optimize vitamin D production via the skin during summer months and use vitamin D supplements and eating more foods rich in vitamin D, such as fish, in the winter months (or year-round for those living in the higher latitudes).

Humans require 5–15 minutes of unprotected daily summer sun exposure (depending on skin type and proximity to the equator) to optimize vitamin D synthesis from the skin, according to the available evidence. We might consider 5–15 minutes of unprotected summer sun exposure, then applying a sunscreen for the rest of the day to help mitigate the bad effects of prolonged exposure, such as the risk of skin cancer and premature skin aging. (Sun exposure also provides other health benefits for the brain that may not be directly related to vitamin D production, including the positive effects of sunlight on mood regulation, that are important but are topics for another paper.)

While daily oral vitamin D supplements can completely compensate for lack of vitamin D production from the sun, especially during winter months or at high latitudes, most studies suggest that the recommended daily allowance of this vitamin should be increased to somewhere between 800 IU and 2,000 IU per day in order to be beneficial for most age groups—and even higher doses for those with extremely low vitamin D blood levels.12

Several randomized, prospective, controlled trials among frail elderly people strongly suggest that they benefit from daily oral supplements of 800 IU or more of vitamin D, which enhances muscle strength and decreases risk of bone fractures. The current recommended daily allowance for elderly people, 600 IU, is not enough, the research suggests; increasing the dosage in these individuals, particularly those who are inactive (housebound or institutionalized) may prevent or ease some symptoms of frailty. Also, it appears that there is a wide safety margin in dosage—doubling or even tripling the standard vitamin D supplement doses or fortifying more foods with vitamin D would be very safe—recent research has detected signs of vitamin D toxicity only after daily doses exceed 50,000 IU for several days or weeks.13

Such proposals may sound alarmingly similar to the sort of thing that was all over the media when the vitamin E craze started. As with other new findings, people should discuss this new research on vitamin D with their health care provider before beginning to take large doses (>2000 IU/day) of vitamin D on their own, especially if they have a medical condition or are on other medications that may interact with the nutrient. Another good source of information is pharmacists, who are often more aware of new preventive health guidelines, drug-supplement interactions and what dietary supplement products have the best quality standards.

To confirm the nutrient’s benefits in humans, we would like to see well-controlled clinical trials of vitamin D supplementation in people who have clinically low vitamin D blood levels, a measure that seems likely to have low risk and high return on investment to prevent disease and promote health.

A long-term social goal should be to validate optimal levels of vitamin D, especially in women before pregnancy, and work to maintain appropriate levels throughout everyone’s life span. We should not rely only on the potential short-term benefits of using vitamin D supplementation or, worse, synthetic vitamin D analogues (as we did with vitamin E) only after the damage is done.

References

1. M. F. Holick and T. C. Chen, “Vitamin D Deficiency: A Worldwide Problem with Health Consequences,” American Journal of Clinical Nutrition 87, no. 4 (2008):1080S–1086S.

2. R. M. Lucas, A. L. Ponsonby, J. A. Pasco, and R. Morley, “Future Health Implications of Prenatal and Early-Life Vitamin D Status,” Nutrition Reviews 66, no. 12 (2008): 710–720.

3. H. L. Chen and D. M. Panchision, “Concise Review: Bone Morphogenetic Protein Pleiotropism in Neural Stem Cells and Their Derivatives: Alternative Pathways, Convergent Signals,” Stem Cells 25, no. 1 (2007): 63–68.

4. T. J. Wang, M. J. Pencina, S. L. Booth, P. F. Jacques, E. Ingelsson, K. Lanier, E. J. Benjamin, R. B. D'Agostino, M. Wolf, and R. S. Vasan, “Vitamin D Deficiency and Risk of Cardiovascular Disease,” Circulation 117, no. 4 (2008): 503–511.

5. S. Pilz, H. Dobnig, J. E. Fischer, B. Wellnitz, U. Seelhorst, B. O. Boehm, and W. März, “Low Vitamin D Levels Predict Stroke in Patients Referred to Coronary Angiography,” Stroke 39, no. 9 (2008): 2611–2613.

6. M. L. Melamed, E. D. Michos, W. Post, and B. Astor. “25-hydroxyvitamin D Levels and the Risk of Mortality in the General Population.” Archives of Internal Medicine 168, no. 15 (2008): 1629–1637.

7. E. P. Cherniack, H. Florez, B. A. Roos, B. R. Troen, and S. Levis. “Hypovitaminosis D in the Elderly: From Bone to Brain.” The Journal of Nutrition, Health and Aging 12, no. 6 (2008): 366–373.

8. M. F. Holick. McCollum Award Lecture, 1994: “Vitamin D—New Horizons for the 21st Century.” The American Journal of Clinical Nutrition 60, no. 4 (1994): 619–630.

9. E. P. Cherniack, B. R. Troen, H. J. Florez, B. A. Roos, and S. Levis, “Some New Food for Thought: The Role of Vitamin D in the Mental Health of Older Adults,” Current Psychiatry Reports 11, no. 1 (2009): 12–19.

10. S. V. Ramagopalan, N. J. Maugeri, L. Handunnetthi, M. R. Lincoln, S.-M. Orton, D. A. Dyment, G. C. DeLuca, B. M. Herrera, M. J. Chao, A. D. Sadovnick, G. C. Ebers, and J. C. Knight, “Expression of the Multiple Sclerosis–Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D,” PLoS Genetics 5, no. 2 (2009): e1000369.

11. S. J. Kiraly, M. A. Kiraly, R. D. Hawe, and N. Makhani, “Vitamin D as a Neuroactive Substance: Review,” Scientific World Journal 6 (2006): 125–139.

12. J. J. Cannell and B. W. Hollis, “Use of Vitamin D in Clinical Practice,” Alternative Medicine Review 13, no. 1 (2008): 6–20.

13. Ibid.



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Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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