What Medications Decrease Folate Levels and How to Manage It

Certain medications can significantly lower the body's supply of folate (vitamin B9), a crucial nutrient for DNA synthesis and cell growth [1.3.4, 1.5.2]. This article explores what medications decrease folate levels and the mechanisms behind this common drug-induced nutrient depletion.

Quick Summary

A variety of common prescription drugs can lead to folate deficiency by interfering with its absorption or metabolism. Key culprits include methotrexate, certain antiepileptics, and antibiotics like trimethoprim.

Key Points

• Folate's Role: Folate (Vitamin B9) is crucial for DNA synthesis, red blood cell formation, and preventing birth defects [1.5.2, 1.10.2].

• Folate Antagonists: Methotrexate and the antibiotic trimethoprim directly block the enzyme dihydrofolate reductase (DHFR), preventing folate activation [1.4.1, 1.6.2].

• Anticonvulsant Effects: Older antiepileptic drugs like phenytoin and carbamazepine can lower folate by increasing its metabolic breakdown in the liver [1.2.1, 1.3.3].

• Absorption Blockers: Medications such as sulfasalazine and cholestyramine interfere with the intestinal absorption of dietary folate [1.8.2, 1.9.1].

• Other Key Drugs: Metformin, a common diabetes drug, is also associated with reduced folate and vitamin B12 levels over time [1.7.3].

• Deficiency Symptoms: Low folate can cause fatigue, megaloblastic anemia, a sore tongue, and neurological symptoms [1.10.3, 1.10.4].

• Management is Key: Prevention and management strategies include monitoring, dietary changes, and targeted folic acid supplementation as advised by a healthcare provider [1.11.1].

The Critical Role of Folate in the Body

Folate, also known as vitamin B9, is a water-soluble vitamin that plays a fundamental role in numerous bodily functions. It is essential for the synthesis, repair, and methylation of DNA, making it critical for cell division and growth [1.4.1, 1.5.2]. Folate is also vital for the formation of red blood cells, and a deficiency can lead to a condition called megaloblastic anemia, characterized by large, immature red blood cells [1.3.5, 1.10.2]. In pregnant women, adequate folate levels are crucial to prevent neural tube defects in the developing fetus [1.10.2, 1.10.4]. Given its importance, a deficiency—whether from dietary insufficiency or other factors like medication use—can have significant health consequences [1.10.3].

Medications That Interfere with Folate Metabolism

Several classes of drugs are known to interfere with the body's ability to absorb or utilize folate. This interference, or antagonism, can lead to clinically significant low folate levels. The mechanisms vary, from direct inhibition of key enzymes to impaired absorption in the gut [1.2.3, 1.8.2].

Folate Antagonists: Methotrexate and Trimethoprim

This class of drugs directly inhibits the action of dihydrofolate reductase (DHFR), an enzyme essential for converting dietary folate into its active form, tetrahydrofolate [1.4.1, 1.6.4]. Without this conversion, cells are starved of the building blocks needed for DNA and RNA synthesis.

• Methotrexate: Used to treat cancer and autoimmune diseases like rheumatoid arthritis, methotrexate is a powerful folate antagonist [1.4.3]. It binds much more tightly to DHFR than folate itself, effectively shutting down the pathway [1.4.1]. This action is what makes it effective against rapidly dividing cancer cells, but it also affects healthy, proliferating cells in the body, leading to side effects associated with folate deficiency [1.4.1, 1.4.5]. Patients on methotrexate are often prescribed a specific form of folic acid (leucovorin or folinic acid) to help mitigate these effects without compromising the drug's efficacy [1.3.4].
• Trimethoprim: This antibiotic, often combined with sulfamethoxazole, also works by inhibiting DHFR [1.6.2, 1.6.5]. While its affinity for bacterial DHFR is much higher than for human DHFR, it can still affect human folate metabolism, especially with high doses or prolonged use [1.6.1, 1.6.2]. This can increase the risk of hematologic side effects like megaloblastic anemia, particularly in individuals who are already at risk for folate deficiency [1.6.3].

Anticonvulsant (Antiepileptic) Drugs

Some of the most widely prescribed medications for epilepsy have been linked to reduced folate levels for decades [1.5.5]. Up to 90% of patients receiving older, enzyme-inducing antiepileptics may show reduced folate levels [1.5.2].

• Phenytoin, Phenobarbital, and Carbamazepine: The exact mechanism is still debated, but it's believed these drugs induce liver enzymes that increase the breakdown and metabolism of folate [1.2.1, 1.3.3]. They may also impair the intestinal absorption of folate [1.3.5]. This depletion is concerning, especially for women of childbearing age, due to the increased risk of fetal birth defects [1.5.1, 1.5.2]. Routine folic acid supplementation is often recommended for patients on these medications [1.5.2].

Other Notable Medications

Several other common drugs can impact folate status through various mechanisms:

• Sulfasalazine: Used for inflammatory bowel disease (like ulcerative colitis) and rheumatoid arthritis, sulfasalazine inhibits the intestinal absorption of folate [1.2.2, 1.8.2]. It interferes with enzymes responsible for processing dietary folate into an absorbable form [1.8.2, 1.8.3]. This effect can increase the risk of folate deficiency in patients who already have malabsorption issues due to their underlying condition [1.8.4].
• Metformin: This first-line medication for type 2 diabetes has been shown to reduce serum levels of both vitamin B12 and folate, particularly with long-term use [1.7.2, 1.7.3, 1.7.4]. The mechanism is not fully understood but may be related to altered absorption in the intestines [1.7.3].
• Cholestyramine: This cholesterol-lowering medication works by binding bile acids in the intestine. Unfortunately, it can also bind to dietary folate, preventing its absorption and leading to depletion over time [1.9.1, 1.9.2]. It's recommended to take folic acid supplements at a different time than cholestyramine to avoid this interaction [1.9.4].
• Oral Contraceptives: Some studies suggest that oral contraceptives can inhibit folate absorption, contributing to lower levels [1.2.1, 1.2.3].

Comparison of Medications Affecting Folate

Medication	Drug Class	Primary Mechanism of Folate Depletion	Management Recommendation
Methotrexate	Folate Antagonist	Inhibits dihydrofolate reductase (DHFR) enzyme [1.4.1]	Supplementation with folinic acid (leucovorin) [1.3.4]
Trimethoprim	Antibiotic/Folate Antagonist	Inhibits bacterial and, to a lesser extent, human DHFR [1.6.2]	Caution in at-risk patients; monitor blood counts [1.6.1]
Phenytoin	Anticonvulsant	Increases folate metabolism via liver enzyme induction [1.2.1, 1.3.3]	Routine folic acid supplementation [1.5.2]
Carbamazepine	Anticonvulsant	Increases folate metabolism via liver enzyme induction [1.5.2]	Routine folic acid supplementation [1.5.2]
Sulfasalazine	Anti-inflammatory	Inhibits intestinal absorption of folate [1.8.2]	Folic acid supplementation is often advised [1.8.1]
Metformin	Antidiabetic	May impair intestinal absorption of folate [1.7.3]	Monitor levels, especially with long-term use [1.7.3]
Cholestyramine	Bile Acid Sequestrant	Binds to folate in the intestine, preventing absorption [1.9.1]	Take folic acid supplements at a different time [1.9.4]

Symptoms and Risks of Folate Deficiency

A mild deficiency may not have obvious symptoms, but as it worsens, it can cause a range of issues [1.10.4]. The most common signs include:

• Fatigue and lack of energy [1.10.3]
• Megaloblastic anemia [1.10.2]
• Pale skin [1.10.2]
• A sore, red tongue and mouth ulcers [1.10.3, 1.10.4]
• Irritability and confusion [1.10.4]
• Muscle weakness and pins and needles (paresthesia) [1.10.3]

Beyond these symptoms, chronic folate deficiency poses serious health risks, including an increased risk of birth defects during pregnancy and potential nervous system problems [1.10.2, 1.10.3].

Managing and Preventing Drug-Induced Folate Deficiency

Awareness and proactive management are key to preventing the consequences of drug-induced folate depletion. Strategies include:

1. Patient Education: Healthcare providers should inform patients about the risk of nutrient depletion associated with their medications [1.11.1].
2. Monitoring: Regular blood tests can detect falling folate levels before they become a serious problem [1.11.1].
3. Supplementation: For many of these drugs, particularly methotrexate and certain anticonvulsants, prophylactic folic acid supplementation is a standard part of care [1.5.2, 1.11.4]. The dosage and form of folic acid can vary depending on the medication, so it's crucial to follow a doctor's advice.
4. Dietary Adjustments: Increasing the intake of folate-rich foods like leafy green vegetables (spinach, broccoli), legumes, asparagus, and fortified grains can help support folate levels, though supplementation is often necessary to overcome the drug's effect [1.2.2].

Conclusion

Many commonly used medications can significantly decrease folate levels, putting patients at risk for anemia, fatigue, and other serious health issues. Understanding which drugs pose a risk—from direct antagonists like methotrexate and trimethoprim to those that impair absorption like sulfasalazine and cholestyramine—is the first step toward effective management. Through patient education, diligent monitoring, and appropriate supplementation, healthcare providers and patients can work together to mitigate the risks of drug-induced folate deficiency and ensure both therapeutic success and overall well-being. For more detailed information on folate, consider visiting the NIH Office of Dietary Supplements.

Frequently Asked Questions

What are the most common medications that lower folate levels?

The most well-known medications include methotrexate, certain antiepileptic drugs (like phenytoin and carbamazepine), the antibiotic trimethoprim, sulfasalazine, and metformin [1.2.3, 1.5.2, 1.7.3].

How does methotrexate cause folate deficiency?

Methotrexate is a folate antagonist. It works by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for converting folate to its active form, which is needed for DNA synthesis and cell replication [1.4.1, 1.4.3].

Can I prevent folate deficiency while on these medications by eating more leafy greens?

While a diet rich in folate from sources like leafy greens is beneficial, it is often not sufficient to counteract the potent effects of medications that block folate absorption or metabolism. Supplementation with folic acid is typically required, as advised by a doctor [1.11.1, 1.11.4].

What are the symptoms of low folate?

Symptoms can include extreme fatigue, lack of energy, pale skin, a sore and red tongue, mouth ulcers, muscle weakness, and psychological issues like depression or confusion [1.10.3, 1.10.4].

Why is it important for women on anticonvulsants to monitor their folate levels?

Certain anticonvulsants can significantly lower folate levels. This is a major concern for women of childbearing age because folate deficiency dramatically increases the risk of having a baby with serious neural tube defects, such as spina bifida [1.5.1, 1.5.2].

Does taking folic acid make my medication less effective?

For some medications, like methotrexate used for autoimmune conditions, taking standard folic acid helps reduce side effects without impacting effectiveness [1.4.5]. However, for others, the type and timing of supplementation are critical. Always consult your healthcare provider before starting any supplement [1.2.4, 1.9.4].

Can metformin for diabetes affect my folate levels?

Yes, long-term use of metformin has been shown to reduce levels of both vitamin B12 and folate. It's recommended that patients on long-term metformin therapy have their levels monitored periodically [1.7.2, 1.7.3].