Folate Deficency and Toxicity

Folate Deficency and Toxicity

While folate deficiency is a more likely result than toxicity, either condition can create serious health problems. If a folate deficiency is suspected or detected, it is extremely important not to self-medicate, but let a doctor who specializes in the treatment of nutritional deficiencies determine the appropriate therapeutic dose. Otherwise, overzealous treatment could result in what was a state of deficiency turning into a new problem of toxicity.



Not only inadequate dietary intake of folate itself but insufficient intake of other B vitamins can contribute to a folate deficiency. Vitamins B1, B2, and B3, B6, and B12 are all involved in the folate recycling process. Adequate protein in the diet is also necessary to prevent folate deficiency because folate binding protein is required for optimal absorption of folate from the intestines. Also, certain amino acids directly participate in the recycling of folate so a deficiency in those amino acids can also cause a folate deficiency.
People for whom a folate deficiency is most likely to be a problem include the following:  
  • The elderly
  • Alcoholics
  • Those with liver or kidney disease
  • Psychiatric patients
  • Epileptics
  • Pregnant and lactating women
  • Women taking birth control pills
  • Patients taking certain antibiotics like sulfa drugs and tetracyclines which deplete folic acid producing bacteria in the colon
On the other hand, simply eating a diet that is high in meat and fats and processed foods like white flour, white sugar, and desserts, particularly if the diet is lacking in fresh or lightly cooked vegetables, can also put a person at increased risk for a folate deficiency.
Worldwide, folate deficiency is still a major problem, but at least in the United States, it is not as big a problem as it used to be, largely because so many convenience food products are now fortified with folate. Folate deficiency in this country is now most often seen in alcoholics, those with intestinal disorders, and in other vulnerable groups like the elderly and any other persons taking certain medications which interact with folate and inhibit its absorption. There are also genetic differences in an individual’s ability to absorb and metabolize folate.


Symptoms of folate deficiency vary with the degree of severity. Even mild deficiency can produce the following symptoms:  
  • Fatigue (both physical and mental)
  • Weakness and lack of energy
  • Irregular heartbeat
  • Headaches
  • Insomnia
  • Irritability
  • Loss of appetite
  • Pallor
  • Glossitis (Sore, red tongue)
  • Cheilitis (cracks or scaling of lips and corners of the mouth)
  • Skin disorders
  • Diarrhea
  • Gingivitis and periodontal disease
  • Poor memory
  • Confusion
  • Depression
  • Decreased growth (in children)
  • More rapid graying of the hair (in adults)
Clearly, a folate deficiency can affect every aspect of functioning, while interfering with both physical and mental well-being. For example, the symptoms of diarrhea and dental decay relate to the role of folate in protecting the lining of the body cavities. Other symptoms such as muscle fatigue and mental fatigue and impaired memory stem from the red blood cells not being able to supply the body’s tissues with an adequate supply of oxygen.
Severe folate deficiency also causes a condition called macrocytic anemia. Because folate is essential for cell maturation, a severe deficiency will cause many cells, including red blood cells, to remain in an immature state. Immature red blood cells are larger than mature ones, cannot divide properly, and still have nuclei, which the mature red blood cells do not.
A deficiency of vitamin B12 has the same inhibitory effect on cell maturation and, therefore, can also cause macrocytic megaloblastic anemia. It is also possible for there to be a simultaneous deficiency in both of these B complex vitamins.
The following are the four stages of folate deficiency.  
  • Stage 1: Early negative folate balance (serum depletion)
During this initial stage, serum folate levels drop to less than three ng/ml.  
  • Stage 2: Negative folate balance (cell depletion)
During this stage erythrocyte, folate levels drop to less than 160 ng/ml.  
  • Stage 3: Damaged folate metabolism, with folate-deficient erythropoiesis
This stage is characterized by impaired DNA synthesis along with changes in the appearance of the red blood cells.  
  • Stage 4: Clinical folate deficiency anemia
This final stage is characterized by greater mean corpuscular volume and macrocytic megaloblastic anemia.

People Who May Benefit from Additional Amounts of Folate

Even though the Institute of Medicine has established guidelines for the recommended daily allowance of folate, there can be special circumstances in which additional folate might be beneficial. Age, diet, pregnancy or lactation, overall health and what medications the person is taking, and the presence of a condition or illness that may interfere with folate utilization all need to be taken into consideration. If you have reason to be concerned, your doctor would be the appropriate person to ask how much folate is the optimal amount for you.
As a general guide, people in the following groups might benefit from additional folate.  
  • Those with inadequate caloric or nutritional intake or increased nutritional requirements, especially a diet that is low in protein and lacking in fresh fruits and vegetables. Both the elderly (since absorption efficiency decreases with age) and teenagers who eat a lot of junk food are particularly vulnerable.
  • Those who are 55 and older with the inadequate dietary intake.
  • Pregnant and lactating women and women who are capable of becoming pregnant.
  • Women using oral contraceptives. (Birth control pills may reduce folic acid absorption by up to 50%.)
  • Those who are abusing alcohol or drugs. (Excessive consumption of alcohol inhibits folate digestion and absorption.)
  • Those with malabsorption disorders or other serious intestinal problems.
  • Those with loss of adrenal gland function
  • Epileptics and others taking certain prescription drugs that may interact with folate
  • Those with HIV or another chronic wasting illness
  • Anyone who has had recent gastrointestinal surgery
  • Those with recent severe burns or injuries
  • Anyone who is under extreme stress for prolonged periods


Folic acid in dosages over 1,000-2,000 mcg can produce toxicity and trigger some of the same symptoms as deficiency--insomnia, malaise, irritability, and intestinal disorders. So while too little of this nutrient is clearly harmful to your health, too much is not good for you either.


The reason for assigning a UL for folic acid relates to the possibility that rather than there being a folate deficiency or a folate deficiency exclusively, the individual has a vitamin B12 deficiency that produces similar symptoms. If that is the case, a high dose of folic acid will clear up the megaloblastic anemia associated with the vitamin B12 deficiency. However, not only might a state of folate toxicity be induced if there was not a deficiency in this nutrient to begin with, but the neurological damage caused by the vitamin B12 deficiency, which if left to progress, becomes irreversible, would remain undetected and untreated.
Therefore, tablets containing more than 400 mcg of folic acid are now available by prescription only. In order to ensure appropriate treatment and not over medicate with folic acid, the blood levels of both folate and vitamin B12 should be assessed, after which a qualified physician would be better able to determine how much, if any, folic acid supplementation (and/or vitamin B12 supplementation) is necessary.
Otherwise, toxicity can and does occur in people who decide on their own, for whatever reason to take folic acid supplements, and in higher than the recommended doses, without consulting a doctor beforehand. The first thing you should do if you have reason to believe your folate intake is inadequate or you have a problem absorbing dietary folate is to discuss your concerns with your doctor. He or she will then order the appropriate tests to make certain supplementation is necessary and, if so, how much to take.


Prolonged high dosages of folic acid can cause folacin crystals in the kidneys. Dosage over 1,500 mcg/day can cause a variety of other symptoms, such as the following:  
  • Loss of appetite
  • Bitter taste
  • Nausea
  • Flatulence
  • Abdominal distention
  • Upset stomach
  • Diarrhea
  • Insomnia
  • Altered sleep patterns, including vivid dreams
  • Allergic skin reactions
  • Neuropathy
  • Irritability and excitability
  • Hyperactivity
  • Confusion
  • Impaired judgment
  • Possible increased cognitive deficits in elderly patients
  • Exacerbation of seizure frequency
  • Psychotic behavior
  • Zinc deficiency
Another possibility is increased the risk of certain types of cancer. To be on the safe side, do not take folic acid supplements except as prescribed by your doctor, do not take more than your doctor prescribes or recommends, and do not exceed the Upper Tolerable Limit of 1,000 mcg/day.