B vitamins Archives - Health Tips From The Professor

Do Supplements Interfere With Chemotherapy?

February 2, 2021 by Dr. Steve Chaney

Should You Avoid Supplement Use During Chemotherapy?

Since much of my research career was devoted to cancer research, specifically developing new chemotherapeutic drugs for treating cancer, many of you have asked me the question: “Do food supplements interfere with chemotherapy?”

My answer has always been that it is theoretically possible, but that we don’t really know the answer because the necessary studies have not been done.

However, I do know that most cancer drugs are retained in the body for a short period of time. So, my pragmatic advice has always been to avoid supplementation for a day or two before to a day or two after each round of chemotherapy. That is a strategy designed to minimize the possibility that supplementation would interfere with chemotherapy and maximize the possibility that supplementation might aid in recovery between rounds of chemotherapy.

That is why I was interested when I saw the recent headlines claiming certain supplements may interfere with chemotherapy for breast cancer. I wanted to find out if someone had finally done a definitive study on the effect of supplementation on chemotherapy.

So, I have reviewed the study (CB Ambrosone et al, Journal of Clinical Oncology, 38, 804-815, 2020) behind the headlines and will share what I discovered.

How Was The Study Done?

This study was an offshoot of a much larger Phase III clinical trial designed to determine the best schedule for administering three drugs (doxorubicin, cyclophosphamide, and paclitaxel) to patients with high-risk early-stage breast cancer.

The 1,134 patients enrolled in this study were given questionnaires on their use of supplements when they registered for the study to determine supplement use prior to the study. They were also given questionnaires when they completed chemotherapy to determine supplement use during chemotherapy.

The questionnaires documented use of:

Multivitamins

The antioxidants vitamin C, vitamin A, vitamin E, carotenoids, and coenzyme Q10.

Vitamin D.

The B vitamins vitamin B6, vitamin B12, and folic acid.

The minerals iron and calcium.

Omega-3 fatty acids.

Glucosamine, melatonin, and acidophilus.

Recurrence of the breast cancer and death from breast cancer were measured 6 months after chemotherapy ended.

Do Supplements Interfere With Chemotherapy?

The study reported:

The number of patients using individual antioxidant supplements was too low to determine whether individual antioxidants had any effect on treatment outcomes.

When the patients using any antioxidant supplement were pooled into a single group, there was a nonsignificant association between antioxidant supplement use during chemotherapy and an increased risk of breast cancer recurrence and death from breast cancer.

Iron use during chemotherapy was significant associated with an increased risk of breast cancer recurrence.

Vitamin B12 use during chemotherapy was significantly associated with increased risk of breast cancer recurrence and death from breast cancer.

Multivitamin use was not associated with either recurrence or death from breast cancer.

The number of patients using the other supplements was too low to determine whether those supplements had any effect on treatment outcomes.

The authors concluded: “Associations between survival outcomes and use of antioxidant and other dietary supplements are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.”

This is the conclusion that generated the headlines you may have seen.

However, in their discussion the authors conceded that a previous review concluded that, “…insufficient evidence existed with regard to the safety of dietary supplements [during chemotherapy] to make recommendations, and that still may be the case.”

I will discuss the reasons for their disclaimer below. However, I will point out that disclaimers like this never seem to make it into the headlines you read.

What Are The Strengths And Weaknesses Of This Study?

The only strength of this study is that it was performed in the context of an ongoing clinical trial, with surveys conducted before chemotherapy and during chemotherapy to assess supplement use.

However, the study had multiple weaknesses that limit the ability to draw any firm conclusions from the study.

#1: The number of people using supplements in this study was very small. For example:

Only 200 people took any antioxidants during chemotherapy.

Only 137 people took a vitamin B12 supplement during chemotherapy.

Only 109 people took an iron supplement during chemotherapy.

To put this into perspective, if a drug company were submitting a new drug for approval to the FDA, they would be required to submit data from ~50-100-fold more cancer patients to prove that the drug was effective.

With this small number of supplement users, even “statistically significant” observations are questionable.

In contrast, the number of people taking a multivitamin during chemotherapy was 497. Thus, those data were a little stronger than the data for individual supplements.

#2: They did not ask why people were taking supplements. It turns out that the patients who used supplements were older and sicker. They were more likely to be overweight and to have type 2 diabetes.

These are patients who are also more likely to have poor outcomes from chemotherapy. The authors tried to correct for that, but it is virtually impossible to make these corrections when the number of patients taking supplements is so low.

#3: They did not ask about the dose of supplements people were taking.

Multivitamins typically contain RDA levels of antioxidants and vitamin B12, so it would be safe to assume that RDA levels of antioxidants and vitamin B12 are safe during chemotherapy.

Approximately 50% of the women in the study were premenopausal, so it is likely that they were taking a multivitamin with iron. That suggests that RDA levels of iron are safe during chemotherapy for premenopausal women.

In short, the association between supplement use and poorer outcomes from chemotherapy is tenuous. If there is any association, it is likely with high dose individual supplements rather the lower levels of the same nutrients found in a multivitamin.

Is An Effect Of Supplement Use On Chemotherapy Plausible?

As a biochemist, the next question I ask is whether there is a plausible mechanism for an effect of any of these supplements on chemotherapy outcomes.

For two of the drugs in the regimen (paclitaxel and cyclophosphamide), free radical formation may contribute to their effectiveness, but it is not their main mechanism of action. Thus, it is plausible that high dose antioxidant supplements could make these drugs less effective, but the effect should be relatively small.

Tumors require high amounts of iron for proliferation, so it is plausible that excess iron could make tumors more resistant to chemotherapy. However, for premenopausal women, multivitamins with iron did not interfere with the drugs used in this study. Thus, it appears likely that RDA levels of iron, where appropriate, do not interfere with chemotherapy.

The authors said that the reason for the observed effects of vitamin B12 on chemotherapy in their study “remains to be understood”. However, the answer might be found in the dosage of vitamin B12. A previous study reported that doses of vitamin B12 that were greater than 20 times the RDA increased the risk of lung cancer.

If people in this study were taking doses of vitamin B12 in excess of 20 times the RDA, it would provide a plausible explanation for B12 interfering with chemotherapy. If not, there is no known explanation. In any case, I do not recommend taking such high doses of any supplement.

Should You Avoid Supplement Use During Chemotherapy?

Now, let’s get back to the original question: “Should you avoid supplement use during chemotherapy?” If you read the headlines saying, “Supplement Use During Chemotherapy May Be Risky”, you might think that the answer is an unqualified yes. That is also what your doctor is likely to think.

However, when you analyze the study behind the headlines you realize that the evidence supporting the headlines is very weak.

So, that puts us back to where we were before the study was published. Simply put:

It is theoretically possible that supplements interfere with chemotherapy, but we don’t know for sure.

A pragmatic approach is to avoid supplementation for a day or two before to a day or two after each round of chemotherapy. This is a strategy designed to minimize the possibility that supplementation would interfere with chemotherapy and maximize the possibility that supplementation might aid in recovery between rounds of chemotherapy.

Note: This is generic advice. I am not a medical doctor, so it would be unethical for me to provide individualized advice on how to minimize interactions between supplements and chemotherapy. What I recommend is that you ask your doctor whether my generic recommendations make sense for your cancer and your drug regimen.

If this study advanced our knowledge at all, it would be that:

The supplements most likely to interfere with chemotherapy appear to be high dose antioxidants, vitamin B12, and iron supplements.

Multivitamins, even multivitamins with iron when appropriate, are unlikely to interfere with chemotherapy.

The Bottom Line

Recent headlines have warned, “Supplement Use During Chemotherapy May Be Risky”. Is that true?

However, when you analyze the study behind the headlines you realize that the evidence supporting the headlines is very weak.

So, that puts us back to where we were before the study was published. Simply put:

It is theoretically possible that supplements interfere with chemotherapy, but we don’t know for sure.

A pragmatic approach is to avoid supplementation for a day or two before to a day or two after each round of chemotherapy. This is a strategy designed to minimize the possibility that supplementation would interfere with chemotherapy and maximize the possibility that supplementation might aid in recovery between rounds of chemotherapy.

Note: This is generic advice. I am not a medical doctor, so it would be unethical for me to provide individualized advice on how to minimize interactions between supplements and the chemotherapy drugs you are on. What I recommend is that you ask your doctor whether my generic recommendations make sense for your cancer and your drug regimen.

If this study advanced our knowledge at all, it would be that:

The supplements most likely to interfere with chemotherapy appear to be high dose antioxidants, vitamin B12, and iron supplements.

Multivitamins, even multivitamins with iron when appropriate, are unlikely to interfere with chemotherapy.

For more details read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

How Much DHA Is Needed To Prevent Alzheimer’s

September 8, 2020 by Dr. Steve Chaney

What Are We Missing?

We are an aging population. As such, issues like cognitive decline, dementia, and Alzheimer’s Disease are of increasing concern. After all, what is the good of reaching your “Golden Years” with a healthy body if you lose your mind?

The ability of the omega-3 fatty acids DHA and EPA to reduce the risk of cognitive decline, dementia, and Alzheimer’s Disease is controversial. Some studies say yes. Others say no.

When studies are conflicting most experts simply conclude the treatment is unproven. I am sympathetic to that viewpoint, but I first like to ask the questions: “Why are the studies conflicting? What are we missing?”

I start by evaluating the strengths and weaknesses of the individual studies.

If the studies claiming the treatment works are weak, I am content to “join the chorus” and consider the treatment unproven.

If the studies claiming the treatment doesn’t work are weak, I am a strong advocate for more well-designed studies before we conclude that the treatment doesn’t work.

If both the “pro” and “con” studies are strong, I want to ask, “What are we missing?”

This is the situation with studies asking whether DHA reduces the risk of Alzheimer’s Disease and other forms of cognitive decline as we age.

Association studies show that greater intake and higher blood levels of the omega-3 fatty acids EPA and DHA are associated with lower risk of Alzheimer’s Disease.

However, most placebo-controlled clinical trials with either DHA alone or DHA + EPA have come up negative. Of course, one can always argue that most of the placebo-controlled clinical trials were too short or too small to show a statistically significant effect. But, my question remains, “What else are we missing?”

One recent study has provided an interesting clue. The authors of the study postulated that B vitamins were required to deliver omega-3 fatty acids to the brain, and their study showed that omega-3 fatty acids were only effective at decreasing the risk of cognitive decline in subjects who also had optimal B vitamin status.

In other words, this study suggested that studies on the effect of omega-3 supplementation and risk of developing Alzheimer’s are doomed to failure if a significant percentage of the subjects have sub-optimal B vitamin status.

The authors of the current study ( IC Arellanes et al, EBioMedicine, doi.org/10.1016/j.ebiom.2020.102883) proposed two additional hypotheses for the negative results of previous clinical trials and designed an experiment to test their hypotheses. Their hypotheses were:

Uptake of DHA and EPA by the brain is very inefficient, and previous studies have not used sufficient doses of DHA or DHA plus EPA to see a significant effect on cognitive impairment.

The APOE4 gene further decreases the uptake of DHA and EPA by the brain.

Before I describe how the study was done, I should probably provide some context by describing how DHA and EPA reach the brain and the role of the apoE protein in the process. It’s time for my favorite topic: “Biochemistry 101”.

Biochemistry 101: What Does The ApoE Protein Do?

If you have ever tried to mix oil and water, it should come as no surprise to you that fats, including DHA and EPA, and cholesterol are not water soluble. That leaves our bodies with a dilemma. How do they get the fat and cholesterol we eat to pass through our bloodstream and get to our cells, where they are needed?

Our body’s solution is to incorporate the fat and cholesterol into particles called lipoproteins. Lipoprotein particles sequester the fat and cholesterol in their interior and surround them with water soluble phospholipids and proteins. Lipoproteins allow our bodies to transport fat and cholesterol through our bloodstream to the tissues that need them.

The next question, of course, is how the lipoproteins know which cells need the fat and cholesterol. This is where apoproteins like apoE come into play. We can think of the apoE protein as a zip code that directs lipoproteins to cells with an apoE receptor.

Our nervous system contains lots of apoE receptors, and binding of the apoE protein to its receptor is instrumental in the delivery of DHA, EPA, and cholesterol to our nervous system.

DHA and cholesterol are both important for brain health. That is because they are major components of the myelin sheath that wraps around our neurons and protects them. EPA may also be important for brain health because its anti-inflammatory effects are thought to prevent the accumulation of the amyloid plaques that are the hallmark of late-onset Alzheimer’s Disease.

There are three major versions of the APOE gene, APOE2, APOE3, and APOE4. Each of them plays slightly different roles in our body. However, it is the APOE4 version that is of interest to us. About 25% of us have the APOE4 version of the APOE gene and it increases our risk of developing Alzheimer’s Disease by a factor of two.

We do not know why this is, but one hypothesis is that lipoproteins with the apoE4 protein have more difficultly delivering much needed DHA, EPA, and cholesterol to the brain. This is one of the hypotheses that the authors set out to study.

How Was The Study Done?

There are two things you should know about this study.

This was a pilot study designed to test the author’s hypotheses and allow them to choose the correct dose of DHA to use for a subsequent study designed to test whether high-dose DHA can reduce the risk of developing Alzheimer’s Disease.

This was a very small study. That’s because the only way to determine how much DHA and EPA reaches the nervous tissue is to perform a lumbar puncture and obtain cerebrospinal fluid at baseline and again at the end of the study. Lumbar punctures are both painful and a bit risky. They were lucky to find 26 individuals who consented to the lumbar punctures.

This was a double-blind, placebo controlled clinical study.

Half the subjects were given 2,152 mg/day of DHA for 6 months, and half were given a daily placebo consisting of corn and soybean oil for 6 months.

Because previous studies have suggested that B vitamins were important for DHA and EPA uptake by nervous tissue, all subjects received a B vitamin supplement.

Levels of DHA and EPA were measured in both plasma and cerebrospinal fluid at baseline and again at the end of 6 months. Note: The subjects were only supplemented with DHA. The investigators were relying on the body’s ability to convert DHA into EPA.

All subjects were screened for APOE4

Other important characteristics of the study subjects were:

Average age was 69. They were 80% female.

All of them had a close family member who had previously been diagnosed with dementia, but none of them had been diagnosed with cognitive impairment at the time of entry into the study.

Around 45% of them had the APOE4 version of the APOE.

In other words, none of them currently had dementia, but most were at high risk of developing dementia.

How Much DHA Is Needed To Prevent Alzheimer’s?

After 6 months of supplementing with over 2,000 mg/day of DHA:

DHA levels in the blood had increased by 200%.

However, DHA levels in cerebrospinal fluid had increased by only 28%.

Moreover, DHA levels in cerebrospinal fluid were 40% lower in subjects who had the APOE4 gene compared to subjects with the APOE2 and APOE3

EPA levels in cerebrospinal fluid averaged about 15-fold lower than DHA levels. When they looked at the effect of DHA supplementation on EPA levels.

EPA levels in plasma had increased by 50%.

EPA levels in cerebrospinal fluid had increased by 43%.

EPA levels in cerebrospinal fluid were 3-fold lower in subjects who had the APOE4 gene compared to subjects with the APOE2 and APOE3

The authors concluded:

“We observed only a modest (28%) increase in cerebrospinal fluid DHA levels with 2152 mg per day of DHA supplementation. This finding has implications for past clinical trials that have used lower doses (e.g. 1 g daily of DHA supplements or less) and were overwhelmingly negative. Using lower doses of omega-3 supplements may have resulted in limited omega-3 brain delivery.”

“Another aspect affecting the response to DHA supplementation is APOE4 status. Subjects with the APOE4 gene showed lower DHA levels and significantly lower EPA levels than subjects with other APOE genes”.

“In summary, our study suggests that higher doses of omega-3 fatty acids (2 or more g of DHA) are needed to ensure adequate brain delivery, particularly in APOE4 carriers…Past low dose (1 g per day or less) omega-3 supplementation trials in dementia prevention may not have provided adequate brain levels to fully evaluate the efficacy of omega-3 supplementation on cognitive outcomes.”

Based on the results from this study the authors are currently testing the effect of B vitamins and high dose DHA supplementation on cerebrospinal fluid fatty acid levels, brain imaging, and cognitive outcomes in a larger ongoing clinical trial.

What Does This Study Mean For You?

The ability of the omega-3 fatty acids DHA and EPA to reduce the risk of cognitive decline, dementia, and Alzheimer’s Disease is confusing. Studies disagree.

In situations like this, most experts dismiss the hypothesis as “unproven”. However, I like to ask, “What are we missing?”

One recent study provided a clue. It suggested that omega-3s and B vitamins were interdependent. We need both to reduce cognitive decline. However, that might not be the complete answer.

This study gave both DHA and B vitamins to subjects and discovered another interesting clue. The study suggests we may not have been giving subjects enough omega-3s to see a significant effect on cognitive decline.

Let me start by saying this study did not test whether or not DHA supplementation prevents cognitive decline, dementia, and Alzheimer’s Disease. Nor does it tell us how much DHA is needed to prevent Alzheimer’s Disease, other than to show that anything less than 2 g per day is likely to be inadequate.

However, the study did make two important advances:

#1: It showed just how difficult it is to deliver adequate amounts of DHA and EPA to the brain. This is important because it shows:

Most previous studies have not used high enough doses of DHA or DHA plus EPA to evaluate the effect of omega-3 fatty acids on cognitive decline. Those studies were not simply negative. They were doomed to failure. The studies were worthless.

That means we should stop saying that the ability of omega-3s to prevent cognitive decline and diseases like Alzheimer’s is unproven. Instead, we should say that hypothesis has not adequately been tested.

That also means future studies of the ability of DHA to reduce the risk of cognitive decline, dementia, and/or Alzheimer’s will need to use much higher doses or a better delivery system to get adequate amounts of DHA and EPA into the brain.

#2: It showed that the APOE4 gene significantly decreases the ability of the brain to accumulate DHA and EPA. This has several important implications.

Because both DHA and EPA are vital for brain health, this may explain why the APOE4 gene increases the risk of Alzheimer’s Disease.

It also means those at highest risk for Alzheimer’s Disease are the ones who are most likely to have difficulties accumulating DHA and EPA in their brain.

Once again, it means future studies of the ability of supplemental DHA to reduce the risk of Alzheimer’s Disease will need to use much higher doses of DHA.

The Bottom Line

The ability of the omega-3 fatty acids DHA and EPA to reduce the risk of cognitive decline, dementia, and Alzheimer’s Disease is controversial.

Association studies show that greater intake and higher blood levels of the omega-3 fatty acids EPA and DHA are associated with lower risk of Alzheimer’s Disease.

However, most placebo-controlled clinical trials with either DHA alone or DHA + EPA have come up negative.

In situations like this, most experts dismiss the hypothesis as “unproven”. However, I like to ask, “What are we missing?”

One recent study provided a clue. It suggested that omega-3s and B vitamins were interdependent. We need optimal amounts of both to reduce dementia. However, that might not be the complete answer.

This study gave both DHA and B vitamins to participants and discovered another interesting clue. The study suggests we may not have been giving subjects enough omega-3s to see a significant effect on cognitive decline.

The authors of the study hypothesized:

Uptake of DHA and EPA by the brain is very inefficient, and previous studies have not used sufficient doses of DHA or DHA plus EPA to see a significant effect on cognitive impairment.

The APOE4 gene, which is known to increase the risk of Alzheimer’s Disease, further decreases the uptake of DHA and EPA by the brain.

Their study confirmed their hypotheses and made two important advancements:

#1: It showed just how difficult it is to deliver adequate amounts of DHA and EPA to the brain. This is important because it shows:

Most previous studies have not used high enough doses of DHA or DHA plus EPA to evaluate the effect of omega-3 fatty acids on cognitive decline. Those studies were not simply negative. They were doomed to failure. The studies were worthless.

That means we should stop saying that the ability of omega-3s to prevent cognitive decline and diseases like Alzheimer’s is unproven. Instead, we should say that hypothesis has not adequately been tested.

That also means future studies of the ability of DHA to reduce the risk of cognitive decline, dementia, and/or Alzheimer’s will need to use much higher doses or a better delivery system to get adequate amounts of DHA and EPA into the brain.

#2: It showed that the APOE4 gene significantly decreases the ability of the brain to accumulate DHA and EPA. This has several important implications.

Because both DHA and EPA are vital for brain health, this may explain why the APOE4 gene increases the risk of Alzheimer’s Disease.

It also means those at highest risk for Alzheimer’s Disease are the ones who are most likely to have difficulties accumulating DHA and EPA in their brain.

Once again, it means future studies of the ability of supplemental DHA to reduce the risk of Alzheimer’s Disease will need to use much higher doses of DHA.

Based on the results from this study the authors are currently testing the effect of B vitamins and high dose DHA supplementation on DHA and EPA levels in the brain, brain imaging, and cognitive outcomes in a larger ongoing clinical trial.

For more details, read the article above. For a better understanding of the roles of DHA, EPA, and the APOE gene in brain health, you may want to read my “Biochemistry 101” section above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.