Vitamin B3- Niacin or Nicotinamide

Ball-and-stick model of the niacin molecule, a...

niacin molecule, also known as Vitamin B 3 and nicotinic acid

Vitamin B3 is another one of the water-soluble B vitamins. It was first discovered in 1873 by Hugo Weidel during his studies of nicotine. Vitamin B3 is essential in multiple steps in metabolism and is needed for good adrenal gland and nervous system function. It is mostly obtained in the diet from animal sources such as chicken, beef, and fish. Liver and kidney and heart have the highest amounts. The best plant sources include shiitake mushrooms, nuts, whole grains, beans, avocados and dates. The body can also synthesize Vitamin B3 using the amino acid tryptophan.  Interestingly vitamin B3 deficiency became epidemic when corn started being adopted by Europeans as a food source after the discovery of the Americas (corn is native to central america and therefore was unknown in Europe until the 1500s). The Mayans and other native americans that ate corn did not have vitamin B3 deficiency. This was because they cooked the corn using a process called nixtamalization where they cook it in a limewater (calcium oxide lime, not the fruit) making it very alkaline. This made the corn more easy to grind and improved the flavor. However, it also released the Vitamin B3 which is otherwise bound and not bioavailable in corn and allowed it to be absorbed by the body, hence preventing vitamin B3 deficency in Mayans and other native americans. However, the Europeans who adopted corn did not understand the benefit of nixtamalization and therefore did not use this process, and an epidemic of vitamin B3 deficiency ensued.

The recommended daily allowance is approximately 14 to 16 mg/day. The upper tolerable limits is about 35 mg/day but the only side effect to this is skin flushing. Not until doses as high as 2000 mg or more are significant side effects seen, and even then are rare. Some liver toxicity, skin irritation or eczema, heart arrhythmias, increased blood glucose, eye problems, birth defects if given to pregnant women, and indigestion have all been reported. Supplements of Vitamin B3 come in two forms. Niacin is what is used most commonly by physicians to decrease cholesterol. It is used at very high doses (sometimes as much as 3000 mg) and can cause significant side effects at those doses and almost always causes flushing. Nicotinamide is what is used in most dietary supplements found in stores without a prescription. Niacin is converted into nicotinamide by the body so it has the same nutritional value. However that conversion plays a key role in lowering the cholesterol and causing flushing so nicotinamide does neither of these. Nicotinamide has much lower risk for toxicity as well.

Mild niacin deficiency can slow the metabolism causing fatigue and intolerance to cold. Severe deficiency causes what is referred to as pellagra. Pellagra causes a constellation of symptoms including diarrhea, skin irritation and darkening, inflammation of the mouth, dementia and other mental disturbances, and eventually death if not treated.

Niacin has been used since the 1950s as a cholesterol drug. Many studies have been done on the topic the best of which is likely the multicenter placebo controlled trial by Canner et al. With 3 grams of niacin a day subjects saw a 27% reduction in heart attack and 26% reduction in stroke and the cholesterol panel improved significantly as compared to placebo. 9 year follow-up of subjects showed an 11% reduction in mortality as compared to placebo. Overall the benefits seem clear but its role in combination with other cholesterol lowering drugs, more specifically with statins such as Lipitor,Zocor, and Crestor, is still being worked out. Also, the very high doses needed for cholesterol lowering does cause significant flushing which decreases compliance. However, it has not been looked at yet to see if lower doses that may not have as dramatic effect on cholesterol levels may still show stroke and heart attack prevention by other mechanisms. I feel this is an open question that should be addressed.

Test tube studies are showing evidence that vitamin B3 deficiency may increase the risk for cancer. Vitamin B3 deficiency seems to be associated with instability of genes which is a first step to forming cancer. A 1999 study by Jacobson et al from the University of Kentucky showed that one part of this may be vitamin B3’s role in supporting the tumor suppressor gene p53. They also showed a clear correlation of low vitamin B3 in tissues of people who had increased skin tumors such as squamous cell carcinoma. Kirkland from the University of Guelph in Canada also further explained how Vitamin B3 may decrease the risk for cancer (see link below).  A study done by Dr. Yong with OSHA (the national institute of occupational safety and health) in 2011 of 81 pilots who were exposed routinely to ionizing radiation due to their work found that those with the higher intake of Vitamin B3 had a significantly lower rate of DNA damage. However this was merely observation and not a randomized controlled trial so the effect cannot be definitively linked to Vitamin B3. Similar studies looking at Vitamin B3 intake in those with esophageal and throat cancer found a 40% reduction in risk in those eating 5 to 6 mg more per day.

Early data did show promise for Vitamin B3 to possibly treat and/or prevent type 1 diabetes. However this was followed up with good randomized trials including by Lampeter et al. and Greenbaum et al and unfortunately they found no benefit. The data when taken together show that it is possible that Vitamin B3 actually does help prevent destruction pancreatic insulin secreting cells that leads to diabetes type 1. However Greenbaum’s study showed that this effect may be offset by an increase in insulin resistance caused by high dose Vitamin B3. Basically you may be trading type 1 diabetes for type 2. This is still an open question.

The association of mental issues with pellagra has led some to look into niacin and mental conditions such as schizophrenia. Interestingly it was found that Schizophrenics do show less tendency to flushing when treated with niacin. Messamore from the Portland VA in a 2012 study showed that severity of schizophrenia correlated well with less tendency to flushing with niacin. Dr Puri in 2001 showed that this reaction has a 90% sensitivity and 75% specificity to schizophrenia and it has actually been proposed to use it as a diagnostic tool for schizophrenia. A randomized controlled trial of Vitamin B3 supplementation by Dr. Ramsay et al in 1970 was done with newly admitted schizophrenic patients and found no benefit, however I found no mention of the number of patients. Conversely, Hoffer et al in 1957 did a trial of 30 schizophrenics and found a 80% recovery in the vitamin B3 group vs 30% recovery with placebo. In a follow-up study by Dr. Hoffer he found 79.5% vs 41.9% recovery in the niacin group vs placebo group respectively. Morris et al in a 2004 study also showed that higher dietary intake of Vitamin B3 decreased the risk for Alzheimer’s disease dramatically. And studies as far back as 1953 and one in the 1970s showed some benefit of nicotinamide on depression but have never been followed up with any good randomized controlled trials.

A study by Dr. Melton all the way back in 1943 also showed a dramatic improvement in asthma is subjects treated with niacin. However, to the best of my knowledge this study was never followed up with a randomized controlled trial. In fact the only other trial I can find exploring the matter was a 1974 study by Dr. Bekier that showed a decreased allergic response in guinea pigs treated with nicotinamide.

Also a 2006 study out of the University of Pittsburg laid out the benefits of nicotinamide for inflammatory skin conditions such as acne and rosacea.

Overall vitamin B3 shows a lot of promise. I feel one main issue may be our overemphasis on niacin while neglecting the less toxic nicotinamide. I feel we need to investigate to see if we can get the same heart attack and stroke prevention (our real goal) from nicotinamide as we do with niacin. And nicotinamide’s role in the treatment of Alzheimer’s, schizophrenia, depression, bipolar disorder and other common psychiatric disorders needs to be determined. Lastly, vitamin B3’s role in treating acne and rosacea is definitely needs to be investigated further.

References

Vitamin B3 and tumor suppressor gene p53

Kirkland study on Vitamin B3 and cancer formation

OSHA pilot study

Vitamin B3  and throat cancer

Vitamin B3 and esophageal cancer

1998 Lampeter Diabetes type 1 and vitamin B3 study

Greenbaum study showing increased insulin resistance with Vitamin B3 high dose

Schizophrenia and skin flushing from Vitamin B3

Schizophrenia skin flushing Dr. Puri study

Vitamin B3 and Alzheimer’s

Dr. Melton 1943 study on Asthma and niacin

Guinea pig asthma and Vitamin B3 study

Article on Dr. Hoffer’s studies on Vitamin B3 and schizophrenia

Nicotinamide for acne and rosacea

Vitamin B1- Thiamine

Next up is one of the B vitamins, Vitamin B1, otherwise known as thiamine. All living things need thiamine. However, plants, bacteria and fungi can produce their own. Animals such as ourselves have to obtain it in our diet. Thiamine was the first water-soluble vitamin discovered. It was first recognized in 1884 when a surgeon general in the Japanese Navy Kanehiro Takaki noticed health benefits when a more varied diet was used on Navy ships instead of just the standard white rice predominant diet. This change in diet helped to alleviate many of the nerve and heart problems seen in the sailors. Unfortunately the Japanese navy did not feel it was worth the expense of the more varied diet.

Thiamine and other B vitamins are important for breaking down starch, sugars and carbohydrates to use as energy and also play a key role in nerve signal transmission. These functions make thiamine important for energy levels, the nervous system, muscle health and the digestive system.

Thiamine is found in a wide variety of foods but the highest concentration is in yeast, pork, and beans. The main source of thiamine in the diet is from grains. However, yet another reason to eat whole grains rather than highly processed ones is that thiamine is mostly found in the outer layers and germ of the grains that are removed during processing. In the US thiamine is added back in to processed flour. Thiamine is not stored by the body so symptoms of thiamine deficiency can form after even short periods of not eating enough (in as little as 2 weeks).

The recommended daily allowance for Thiamine is 1.4 mg. However some studies have shown benefits to higher doses up to 50 mg. It is likely the lower limit for ideal health lies somewhere around 5 mg or greater as it has been observed that the bodies absorption of thiamine decreases above this level. There are no adverse effects to excess thiamine as it is a water-soluble vitamin and excess amounts are easily excreted by the body in the urine.

Thiamine deficiency causes two main well know syndromes. The first one is Beriberi. Dry beriberi is a disease mostly of the peripheral nerves (those nerves further down than the spinal cord). This causes what is called a peripheral neuropathy where these nerves are damaged causing numbness, tingling, weakness, difficulties walking, and abnormalities in the reflexes. Wet beriberi has all of these symptoms from peripheral neuropathy but also leads to heart failure as well. It is called wet because the heart failure leads to a back up of fluid into the lungs and lower extremities causing swelling/edema. When treated the heart failure can improve rapidly but peripheral nerves can regenerate themselves (unlike central nerves like those in the spinal cord and brain) but this process takes months to correct.

Thiamine deficiency causes central nerve problems in the brain as well. In developed countries this usually happens in alcoholics as alcohol interferes with thiamine uptake by the body and displaces food in the diet that is normally the source of thiamine. It causes two conditions referred to as Wernicke encephalopathy and Korsakoff syndrome. But they so commonly happen together that they are often referred to as a blanket term Wernicke-Korsakoff syndrome. The Wernicke encephalopathy is a constellation of problems with eye movements, altered mental status, and difficulties walking. Kosackoff is a thiamine deficiency induced severe impairment in memory. Thiamine deficiency can also lead to visual disturbances.

Thiamine is mostly only used in medical practice whenever a person struggling with alcoholism is admitted to the hospital. They are routinely given thiamine to help prevent Wernicke-Korsakoff syndrome. Other than that thiamine is rarely used in medical practice.

Some studies have looked at the role of thiamine in Alzheimer’s disease. This article described some of the results showing that thiamine supplementation does show benefit in the cognition of those with Alzheimer’s disease. As this study showed there is an issue with many of the studies done with thiamine as they will often use doses as low as 3 mg per day which is likely lower than what the average person should be eating a day. The elderly absorb thiamine even less effectively than younger people so treatment doses should likely be well in excess of 10 mg but studies rarely do this. Giving IV is another option but this limits using the results for the general public as outpatients. However, what studies have been done show little or no benefit and studies looking at thiamine levels in the cerebrospinal fluid (CSF) showed no correlation with the level and risk for Alzheimer’s. Therefore it seems unlikely that thiamine will play a major role in the treatment of Alzheimer’s. However supplementation or increased intake in the diet may help a little. (however studies do show that Vitamin A may play a role in the treatment of Alzheimer’s Dementia. Please see my previous post and this study.)

In heart failure some studies have shown that thiamine deficiency may play a role, which is logical given the known syndrome of wet beriberi. However, even in patients with heart failure due to other reasons such as coronary artery disease these patients often receive a diuretic called lasix to help keep fluid levels low in the body. It has been shown that lasix causes increased excretion of thiamine which leads to low levels further worsening heart failure. Finally this was studied in a well designed but disgracefully small study (9 patients). The study showed a 4% improvement in cardiac function (which in heart failure patients is a lot) with thiamine supplementation. There is also a well-known heart failure in alcoholics called alcoholic cardiomyopathy which could easily at least partially be explained by thiamine deficiency yet few of these patients receive thiamine supplementation at home. And then there is a large group of what we call idiopathic cardiomyopathies where patients have heart failure of unknown cause. Despite not being able to find a cause thiamine deficiency is rarely if ever entertained and thiamine is equally rarely given. Given the data I see no reason why every single hear failure patient shouldn’t be given thiamine supplementation. Many of them are on lasix anyway which deplete thiamine and may further worsen their heart failure. And in a small group we may find that thiamine deficiency was the sole cause of their heart failure and they will be cured. The study to look into the effect of thiamine on heart failure would be easy to do with a randomized controlled trial. However, given thiamine’s almost complete lack of risk for toxicity and being very cheap I see no reason not to give all heart failure patients thiamine now with the data we already have.

Early studies are showing too that thiamine may be especially helpful for diabetics especially in preventing damage to peripheral nerves which can cause a condition called diabetic neuropathy, which causes tingling, pain, or numbness in the toes, feet and legs. This article even lays out how thiamine deficiency may play a key role in the damage to blood vessels that lead to heart disease, eye problems and strokes in diabetics.

This placebo controlled trial showed an improvement in energy levels, mental clarity and response times with thiamine supplementation of 50 mg/day. This was in individuals who at baseline had what was considered adequate thiamine intake and levels.

Thiamine and cancer is being actively investigated. It has been shown that thiamine levels are very low in cancer patients. However, this does NOT mean that thiamine deficiency causes or even increases the risk for cancer. It is entirely possible that the thiamine deficiency is caused by the cancer or is actually part of the body’s defense mechanisms against the cancer. One supporting piece of information for this is the observation in one study that cancer growth actually increased at doses a few times higher than the recommended daily allowance. However it has also been shown that thiamine doses thousands of times higher than the RDA dose actually inhibit cancer growth. This is an ongoing area of investigation and will be very interesting to watch going forward. But given the current data giving thiamine to cancer patients without thiamine deficient symptoms would not be advisable as data to date shows no benefit and possible harm.

Overall with the data we have so far the role of thiamine in heart failure and diabetes should be investigated with larger placebo controlled trials. But given its almost complete lack of toxicity and the data we already have so far likely all patients with heart failure and all diabetics should be on a relatively high does of thiamine (about 50 mg) daily.

Thiamine is a prime example of how vitamins can serve as medicine while being far cheaper and safer than modern pharmaceuticals.

References

Thiamine and Alzheimer’s http://www.ncbi.nlm.nih.gov/pubmed/22218733

CSF thiamine levels and Alzheimer’s http://www.ncbi.nlm.nih.gov/pubmed/12111441

Vitamin A and Alzheimer’s – http://www.ncbi.nlm.nih.gov/pubmed/22221326

Lasix, heart failure and thiamine – http://www.ncbi.nlm.nih.gov/pubmed/1867241

Small but well designed thiamine study – http://www.ncbi.nlm.nih.gov/pubmed/22057652

Thiamine and Diabetic neuropathy – http://www.ncbi.nlm.nih.gov/pubmed/21342411, http://www.ncbi.nlm.nih.gov/pubmed/19057893

Article on thiamine and its role in vascular damage in diabetics – http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376872/

 

Vitamin A

Polar Bear (Sow), Arctic National Wildlife Ref...

Vitamin A is actually a group of compounds that include retinol and beta-carotene among others. The science behind it dates back to 1816 when scientists noticed nutrition deprived dogs developed corneal ulcers. It was later found to be a fat soluble vitamin (as opposed to water-soluble) meaning it is stored in the fat (along with vitamins D, E, and K).

Vitamin A is indeed important in maintaining good vision. It is also important for cell growth and differentiation, skin health, and the immune system. For women the recommended daily allowance (RDA) is 700 mcg and 900 for men. The widely considered upper safe limit is considered to be 3000 mcg.

Animal sources of vitamin A include cheddar cheese, eggs, butter, and liver. Plant source include carrots, broccoli, kale and spinach. Dandelion greens have a particularly high amount of vitamin A and are used in natural medicine.

Worldwide Vitamin A deficiency is a huge problem. Approximately one-third of children are estimated to be vitamin A deficient. Nearly a half a million children a year go blind each year due to vitamin A deficiency. It often presents first with night blindness. Also early on a condition called xerophthalmia occurs where the eye is unable to produce tears. This leads to eye dryness, then plaques and eventually ulcerations. Other symptoms include increased infections due to an impaired immune system and poor forming of tooth enamel.

Vitamin A overdose is a significant risk as it is fat soluble, which means the body stores it in fat cells so excess amounts cannot be cleared easily. Excess vitamin A in pregnant women has been shown to cause birth defects in their offspring (however vitamin A deficiency also causes issues for the fetus as well). Toxic levels can cause nausea, vomiting, hair loss, weakness, and headaches and can lead to osteoporosis. Liver damage has also been seen at high doses. However, it is interesting to note that these toxicities and teratogenicity (damage to unborn fetuses) are only seen with preformed vitamin A (retinoid) as found in animal sources of Vitamin A such as in liver or supplements with retinol or retinoic acid. It is not seen with carotenoid forms (such as beta-carotene) which are found in plant sources such as carrots and are molecules that have to be converted into vitamin A by the body. Carotenoids are water-soluble and not stored by the body hence they are rarely if ever toxic. Beta-carotene is the most common carotenoid in supplements but there are many more (approximately 500 known so far) but only about 10% of those are made into vitamin A. Therefore if one is going to supplement vitamin A levels they should avoid retinol or retinoid acid and instead try to get a supplement with a mixture of carotenoids.

Vitamin A research is severely limited due to its overblown risks for toxicity. Most people I know during medical school were told of a group of arctic explorers that died due to Vitamin A toxicity from eating polar bear livers. Of course liver is the richest possible source of vitamin A in the diet. It is also all in the preformed retinoid form which is the most toxic. I personally have never, not once, seen a case of vitamin A toxicity. And that is in spite of the fact that I live within a short drive of Herbalife headquarters and in southern California where people take supplements galore.

Vitamin A is most commonly used to treat Acne most commonly in the form of isotretinoin (Accutane). It is effective but does come with significant side effects and very high risk for birth defects if a woman becomes pregnant on it. Therefore women have to pledge to use contraception while using it.

Vitamin A is also used rarely for cancer in the retinoid form which is the active metabolite of vitamin A. Mostly it is used in rare pediatric tumors such as acute promyelocytic leukemia and neuroblastoma. The role of Vitamin A and cancer is still being evaluated as described in this study. Vitamin A may also play a role in cancer prevention.

Research has also shown that Vitamin A can dramatically decrease the complications and death rate from measles. It has also been shown since the 1990s that vitamin A helps to decrease morbidity and mortality from HIV, however this has not been adequately looked at and few if any doctors given Vitamin A to their HIV patients despite these results.

Vitamin A is still plagued with incomplete research due to a variety of reasons. Lack of profit of course is one, but also Vitamin A’s multiple forms and knowing which one to use for trials is not clear. Also complicating the matter is its risk for toxicity and teratogenicity. However, the risk is quite low for toxicity if given in reasonable doses and I feel naturopathic doctors could give us a lot of guidance as to what forms to use for supplementation as they have been using them for centuries.

There are many possible exciting avenues for research for vitamin A. The pharmaceutical industry is already trying to form more patentable versions for cancer treatment. It would be interesting to see if traditional vitamin A supplements (particularly mixed carotinoids) would help with cancer treatment.

However, I feel given the dramatic results from HIV and measles research that has already been done, the most promising avenues of research would be those for viral illnesses. Hepatitis C and HIV are two of the most devastating and costly viral illnesses we struggle with. Hepatitis C has a very high treatment failure rate and it would be fascinating to see if treatment with Vitamin A supplements in addition to normal treatment for Hepatitis C increased the treatment success rate. It would also be great to see if Vitamin A supplements decrease viral load levels in HIV patients on medication. Preliminary research already points to the fact that it likely does.

One main issue with the studies done so far is that they are often done with the active forms (retinoids) which carry the high risk for toxicity. It is possible carotenoids may not have the same effects as the body may regulate the conversion by the body to levels not high enough to see the effects achieved with direct supplementation with active retinol vitamin A. However, studies would be much easier, safer, and more generalizable to medical practice if carotenoids were used. Many studies have been done with beta-carotene but this is likely flawed. This is only one of over 50 carotenoids the body makes into Vitamin A and when you eat Vitamin A naturally you get many of these all at once. They do not come in isolation. Studies are showing that likely this mixture of carotenoids is what leads to the beneficial effects of Vitamin A, so supplementing one carotenoid in isolation may have little or no effect or may even been detrimental. If one is to supplement vitamin A the best way of course is with Vitamin A rich foods such as carrots or spinach. But for studies to allow for a placebo they would have to be given as pills to allow for a placebo. So mixed carotenoids would be best to allow for a good chance of beneficial effect while avoiding the toxicity seen with retinol or retinoic acid.

It is time we stop fearing this Vitamin and start using it to our advantage. It could end up being one of our most powerful weapons against viruses and maybe even cancer.

References

Vitamin A in cancer study – http://www.ncbi.nlm.nih.gov/pubmed/21073338

Vitamin A and breast cancer – http://www.ncbi.nlm.nih.gov/pubmed/12452454

Vitamin A and cancer prevention – http://www.ncbi.nlm.nih.gov/pubmed/15134535

Vitamin A and measles – http://www.ncbi.nlm.nih.gov/pubmed/12521271

Vitamin A and multivitamin in HIV – http://www.ncbi.nlm.nih.gov/pubmed/17368322

Beta Carotene and HIV – http://www.ncbi.nlm.nih.gov/pubmed/8450402

Vitamin A and Hepatitis C – http://www.ncbi.nlm.nih.gov/pubmed/23213086

Vitamin C and Cancer

106. colon cancer chemotherapy

One of the best examples of a natural remedy not being fully explored that I know of is intravenous vitamin C and cancer. As far back as 1976 Dr. Linus Pauling did a study with 100 terminal cancer patients and gave them IV vitamin C and compared them to 1000 controls who received usual chemotherapy treatment. The Vitamin C group lived on average 4 times longer. There were some questioning as to randomization of the patient’s and how advanced each patient was.

A follow-up study done at the Mayo clinic that was randomized and controlled showed no benefit to vitamin C therapy and that pretty much killed interest in vitamin C for cancer for the coming decades. However, there was one glaring problem with the study. The patients only received ORAL vitamin C. None of them got intravenous vitamin C.

This makes the Mayo Clinic study useless. We have since learned that Vitamin C although normally thought of as an antioxidant can act as a pro-oxidant at very high doses, doses that can only be achieved through IV administration. And it is believed that this pro-oxidant effect at high IV doses is what can cause cancer cell death while the normal antioxidant properties of your body allow normal cells to have little or no damage.

Dr. Riordan pioneered much of the research into IV vitamin C and through his clinic treated many patients and has had multiple well documented case reports of cancer response to IV Vitamin C alone. He also showed that extremely high doses of IV vitamin C (many of which he even tested on himself) are well tolerated and have little or no side effects. In fact a toxic dose of vitamin C has yet to be found.

Despite pharmacological reasons why intravenous Vitamin C would work to kill cancer cells, case reports and studies showing it to be effective, and its complete lack of toxicity large-scale medical research still has not been done.

Currently there are about five studies actively enrolling patients to evaluate the effect of IV vitamin C on cancer. But this has been done in the past only to have studies that used already known to be ineffective doses of Vitamin C or failing to enroll enough patients. It has been almost 40 years since this therapy suggested and given its promise, very low-cost, and lack of toxicity it is time we stand up and demand that a proper study be done so we can either start using this therapy or learn from its failure and move on.