A new review examined rare allergic reactions some people have to folic acid and folinic acid, which are forms of vitamin B9 found in supplements and fortified foods. While these allergies are uncommon, they can happen with synthetic versions of these vitamins but not with natural folates from food. Researchers looked at reported cases, how these allergies might work in the body, and ways doctors can test for them. The study suggests that a newer blood test called the basophil activation test might help doctors diagnose these allergies more accurately in the future.

The Quick Take

  • What they studied: Rare allergic reactions that some people have to synthetic folic acid and folinic acid (forms of vitamin B9), including how these reactions happen in the body and how doctors can diagnose them
  • Who participated: This was a review of published medical cases and research, not a study with participants. Researchers examined documented cases of people who had allergic reactions to folic acid or folinic acid supplements
  • Key finding: Allergic reactions to synthetic folic acid and folinic acid are very rare and only happen with man-made versions, not with natural folates from food. A blood test called the basophil activation test appears promising for diagnosing these allergies
  • What it means for you: If you’ve had unexplained reactions after taking B9 supplements, talk to your doctor about testing. However, most people can safely take folic acid supplements without problems. Natural folates from foods like leafy greens are safe for everyone

The Research Details

This was a review article, meaning researchers looked at and summarized all the published medical cases and studies about folic acid allergies they could find. Instead of doing their own experiment with new participants, they gathered information from existing research and case reports to understand the bigger picture. This approach helps doctors and scientists see patterns across many different cases and understand what we know (and don’t know) about a rare problem.

The researchers examined clinical cases where people reported allergic reactions, looked at the possible ways these reactions happen in the body, checked for cross-reactions with similar compounds, and reviewed current testing methods. They focused on understanding why some people react to synthetic versions but not natural folates from food.

Review articles are important for rare conditions because individual cases are scattered across medical literature and hard to find. By gathering all known cases together, researchers can spot patterns, understand how common the problem really is, and identify the best ways to diagnose and treat it. This helps doctors recognize the condition when they see it and know what to do

This review summarizes published medical cases and existing research, so its reliability depends on the quality of those original sources. The authors note that there are no validated tests yet for diagnosing these allergies, which means doctors currently struggle to confirm this condition. The review is helpful for understanding what we know, but more research is needed to develop better diagnostic tools and understand exactly why these reactions happen

What the Results Show

The review found that allergic reactions to folic acid and folinic acid are very uncommon. These reactions only occur with synthetic (man-made) versions of these vitamins, not with natural folates found in foods like spinach, broccoli, and other leafy greens. This is an important distinction because it means people with these rare allergies can still get vitamin B9 from their diet.

The researchers identified that both types of immune reactions can happen: some involve the body’s IgE antibodies (the same ones involved in peanut allergies), while others work through different immune pathways. However, the exact mechanism—how and why the body reacts—is not yet fully understood. The review also found that people allergic to folic acid might have cross-reactions with similar compounds, including some cancer medications like methotrexate.

The review highlighted that diagnosing these allergies is currently very difficult. There are no standard blood tests or skin tests that doctors can reliably use to confirm folic acid allergies. However, a newer test called the basophil activation test (BAT) shows promise. This test looks at how certain immune cells respond to the suspected allergen in a blood sample. While not yet validated for routine use, it appears to be a better option than current methods for identifying people with these rare allergies.

This review brings together scattered case reports and research that previously existed in isolation. By organizing this information, it confirms that folic acid allergies are genuinely rare and distinct from other vitamin allergies. The finding that only synthetic versions cause reactions—not natural folates—is consistent across the cases reviewed and helps distinguish this condition from other food allergies

The main limitation is that this is a review of existing cases and research, not new research itself. The number and quality of published cases are limited, so we don’t have a complete picture of how common these allergies really are. Additionally, there are no validated diagnostic tests yet, which means some cases may be missed or misdiagnosed. The exact biological mechanism remains unclear, so doctors can’t yet explain why some people react while others don’t. More research with larger groups of affected people is needed to better understand and diagnose these allergies

The Bottom Line

If you suspect you have a folic acid allergy: Tell your doctor about your symptoms and when they occur. Ask about the basophil activation test if standard allergy testing is negative. Avoid synthetic folic acid supplements and fortified foods if confirmed allergic. Get vitamin B9 from natural food sources instead (leafy greens, legumes, asparagus). If you need folic acid for medical reasons, work with your doctor to find safe alternatives. Confidence level: Moderate—based on case reports rather than large studies

This information is most relevant for people who have had unexplained allergic reactions after taking folic acid supplements or eating fortified foods. Pregnant women and people with certain medical conditions who need folic acid should discuss any concerns with their doctor. Healthcare providers should be aware of this rare condition when patients report unusual reactions to supplements. Most people (the vast majority) can safely take folic acid supplements without any problems

If you have a true folic acid allergy, reactions typically occur within minutes to hours of exposure. Switching to natural food sources of B9 should eliminate symptoms immediately if folic acid was the cause. If you’re trying to get adequate B9 from food alone, it may take a few weeks of consistent eating of folate-rich foods to notice improvements in energy or other B9-deficiency symptoms

Want to Apply This Research?

  • If you suspect a folic acid sensitivity, track supplement intake and any symptoms (itching, swelling, rash, stomach upset) within 2 hours of taking supplements. Note the specific product name and whether it contains synthetic folic acid or folinic acid
  • Switch from synthetic folic acid supplements to getting B9 from whole foods: add one serving daily of leafy greens (spinach, kale), legumes (lentils, chickpeas), or asparagus. Track which foods you eat and how you feel to identify safe sources
  • Keep a 30-day symptom and food log if you suspect folic acid sensitivity. Record all supplements taken, all B9-containing foods eaten, and any physical symptoms. Share this log with your doctor to help identify patterns and confirm whether folic acid is truly the problem

This review discusses rare allergic reactions to folic acid and folinic acid supplements. If you experience symptoms after taking B9 supplements—such as rash, swelling, difficulty breathing, or severe stomach upset—stop taking the supplement and seek immediate medical attention. Do not stop taking prescribed folic acid or folinic acid without consulting your doctor, as these may be medically necessary. This information is educational and should not replace professional medical advice. Anyone concerned about folic acid allergies should consult with an allergist or their healthcare provider for proper evaluation and testing. Pregnant women and people with specific medical conditions should discuss any supplement concerns with their doctor before making changes.