Can Methylfolate Cause Diarrhea and Other Digestive Issues?

October 8, 2025 •

4 min read

In the U.S., up to 40% of white and Hispanic people have a common MTHFR gene mutation that impairs the body's ability to use folic acid [1.8.3]. This leads many to use L-methylfolate, but a key question arises: can methylfolate cause diarrhea?

Quick Summary

While not the most common side effect, methylfolate can lead to gastrointestinal issues, including diarrhea, especially at high doses or due to underlying digestive problems. This overview explains the connection and management strategies.

Key Points

Diarrhea is a possible side effect: While not the most common reaction, methylfolate can cause diarrhea, especially in cases of overdose or when starting supplementation [1.2.3, 1.3.2].
Dosage is critical: Side effects are often dose-dependent. Starting with a low dose and increasing it slowly is recommended to improve tolerance [1.10.1].
Underlying gut health matters: Digestive issues like SIBO may be the root cause of symptoms, as pathogenic bacteria can feed on B vitamins [1.3.1, 1.11.4].
Methylfolate vs. Folic Acid: Methylfolate is a bioavailable form of B9 that bypasses the need for MTHFR enzyme conversion, unlike synthetic folic acid [1.6.3].
Other ingredients can be culprits: Combination supplements, such as those containing iron, may cause GI side effects like diarrhea that are not from the methylfolate itself [1.2.1].
Management strategies exist: Taking methylfolate with food, adjusting the timing, and ensuring adequate levels of cofactors like B6 and B12 can help minimize side effects [1.5.1, 1.5.2].
Consult a professional: Always speak with a healthcare provider to determine the right dosage and approach for your specific needs, especially if you have an MTHFR mutation [1.10.1].

Understanding Methylfolate and Its Importance

Methylfolate, or L-5-methyltetrahydrofolate (L-5-MTHF), is the active, bioavailable form of vitamin B9 [1.6.3]. Unlike synthetic folic acid, which the body must convert, methylfolate is ready for immediate use. This is crucial for individuals with a common genetic variation in the MTHFR (methylenetetrahydrofolate reductase) gene [1.6.1]. This gene provides instructions for making the MTHFR enzyme, which is essential for converting folic acid into methylfolate. Up to 60-70% of the general population has at least one variant in this gene, which can limit this conversion process [1.8.2].

Methylfolate plays a vital role in numerous bodily processes, including:

Neurotransmitter Production: It is essential for synthesizing serotonin, dopamine, and norepinephrine, which regulate mood [1.6.1, 1.6.3]. This is why it's often used as an adjunctive therapy for depression [1.6.4].
Homocysteine Regulation: It helps convert the amino acid homocysteine into methionine. High levels of homocysteine are linked to cardiovascular risks [1.6.3].
DNA Synthesis and Repair: Folate is critical for creating and repairing DNA, making it a cornerstone of cellular health [1.6.3].
Red Blood Cell Formation: The body needs folate to produce red blood cells, and a deficiency can lead to certain types of anemia [1.6.2].

Can Methylfolate Cause Diarrhea? A Closer Look

While many people tolerate methylfolate well, gastrointestinal (GI) side effects, including diarrhea, are possible [1.3.2, 1.4.1]. However, it's often not a direct result of the methylfolate itself but related to several contributing factors.

Potential Causes of Digestive Upset

Overdose Symptoms: Taking too much methylfolate can lead to symptoms of overdose, which may include stomach pain, nausea, and diarrhea [1.2.3, 1.11.2]. High doses can overwhelm the system, a state sometimes referred to as "over-methylation," which can also cause anxiety, insomnia, and irritability [1.3.1, 1.9.3].
Underlying Gut Health: Some experts suggest that digestive pain or discomfort after taking B vitamins might point to pre-existing issues in the digestive tract, such as Small Intestinal Bacterial Overgrowth (SIBO) or fungal overgrowth [1.3.1, 1.11.4]. Pathogenic bacteria can consume B vitamins, triggering symptoms like pain and diarrhea [1.3.1].
Other Ingredients in Supplements: Many methylfolate supplements are combined with other ingredients. For instance, some prenatal vitamins containing L-methylfolate also include iron, which is a known cause of constipation, belly pain, and diarrhea [1.2.1, 1.2.2, 1.11.1].
Detoxification Reactions: Methylfolate plays a role in the body's detoxification pathways. Introducing it, especially for those with MTHFR mutations, can enhance methylation activity suddenly. This can lead to temporary, flu-like "detox reactions," which may include headaches, fatigue, and digestive upset as the body processes and eliminates toxins [1.5.2, 1.10.2].

Folic Acid vs. Methylfolate: A Comparison of Side Effects

Choosing between folic acid and methylfolate often depends on an individual's ability to process them. Their side effect profiles also differ.


Feature	Folic Acid	L-Methylfolate
Form	Synthetic, oxidized form of folate [1.7.4]. Requires enzymatic conversion.	Active, bioavailable form of folate [1.6.3]. Ready for direct use.
Bioavailability	Lower, especially in those with MTHFR mutations [1.6.1].	High; bypasses the MTHFR conversion step, making it more effective for those with genetic variants [1.6.3].
Common GI Side Effects	Doses over 1mg daily may cause stomach upset, nausea, and diarrhea [1.2.4, 1.11.3].	Generally well-tolerated, but can cause nausea, abdominal distention, and gas [1.3.4, 1.9.4]. Diarrhea is a symptom of overdose [1.2.3].
Other Common Side Effects	Irritability, confusion, skin reactions, seizures at high doses [1.2.4].	Can include altered sleep, irritability, anxiety, headaches, and muscle aches, often linked to dose size [1.4.1, 1.4.2].
Risk of Masking B12 Deficiency	High intake can mask the hematological signs of a vitamin B12 deficiency, potentially allowing neurological damage to progress [1.7.4].	Less likely to mask a B12 deficiency because its metabolic pathway is dependent on vitamin B12 [1.7.4].

How to Manage and Minimize Side Effects

If you experience diarrhea or other side effects from methylfolate, there are several strategies you can employ in consultation with your healthcare provider:

Start Low and Go Slow: Begin with a lower dose (e.g., 400-800 mcg) and increase it gradually over weeks [1.10.1, 1.10.3]. This allows your body to adjust.
Take with Food: Taking the supplement with a meal can help prevent mild stomach discomfort or nausea [1.5.1, 1.10.4].
Time Your Dose: Since methylfolate can be energizing, taking it in the morning or early afternoon can prevent sleep disturbances like insomnia [1.10.4].
Support Cofactors: Methylation requires other nutrients to function optimally, particularly active forms of vitamin B12 (cobalamin) and B6 (P-5-P) [1.5.2, 1.10.2]. Ensuring adequate levels of these cofactors can improve tolerance.
Stay Hydrated and Eat Clean: Drinking plenty of water and eating a diet low in processed foods can support your body's natural detoxification processes, potentially easing side effects [1.5.2].
Reduce Folic Acid Intake: For those with MTHFR mutations, minimizing intake of fortified foods containing synthetic folic acid can be beneficial, as it competes with methylfolate [1.5.2, 1.10.2].

Conclusion: A Balanced Approach

So, can methylfolate cause diarrhea? Yes, it is a potential side effect, although it is less common than other effects like anxiety or insomnia. It is more likely to occur at high doses, as part of an initial adjustment period, or due to underlying gut issues rather than a direct reaction to the substance at a proper dose. By starting with a low dose, taking it with food, ensuring adequate intake of cofactors like B12 and B6, and consulting a healthcare provider, most users can minimize or avoid digestive upset and harness the significant benefits of this active form of folate.

For more information on the MTHFR gene, visit the National Institutes of Health's Genetic and Rare Diseases Information Center.

Frequently Asked Questions

The most commonly reported side effects are not gastrointestinal but neurological, including anxiety, irritability, insomnia, headaches, achy joints, and sore muscles [1.4.1, 1.4.2].

Side effects can appear shortly after starting, especially with a high dose. Some people feel great for a week before side effects like anxiety or muscle aches appear, while others react negatively even to a small amount right away [1.4.2, 1.4.3].

Yes, diarrhea, along with stomach pain, nausea, and vomiting, can be a symptom of overdose [1.2.3, 1.11.2].

The best time is usually in the morning or early afternoon. Because it can have an energizing effect, taking it later in the day might interfere with sleep [1.10.4].

Yes, taking methylfolate with food is recommended to help manage and prevent gastrointestinal disturbances like nausea or stomach upset [1.5.1, 1.10.4].

L-methylfolate is the body's most active, natural form of folate (vitamin B9). Folic acid is a synthetic version that must be converted by the MTHFR enzyme to become active, a process that is inefficient in many people [1.6.1, 1.6.3].

If you experience diarrhea, you should consult your doctor. They may recommend pausing or reducing your dosage, taking it with food, or investigating other potential causes before you stop completely [1.5.1, 1.5.2].