What are the main nattokinase side effects?

Across six randomized controlled trials and 546 participants, researchers recorded no notable adverse events from nattokinase [1] — and yet the supplement carries a short list of warnings serious enough that Health Canada requires them on the label.

That gap is the whole story. Nattokinase is unusually well tolerated in trials, but its fibrinolytic activity creates real risks for specific people — and the documented harms come almost entirely from case reports, not trials.

Here's what the evidence shows, ranked by how much it should matter to you.

Table of Contents

1. What Clinical Trials Actually Report
2. The Side Effects People Actually Notice
3. Bleeding: The Risk That Matters Most
4. Interactions That Change Your Risk Profile
5. Who Should Not Take Nattokinase
6. Symptoms Often Blamed on Nattokinase
7. The Downside That Isn't a Side Effect: It May Not Do Anything
8. Soy, Natto Allergy and Delayed Reactions
9. How Formulation Affects What You Experience
10. Frequently Asked Questions
11. Conclusion
12. Research References

1. What Clinical Trials Actually Report

The single best summary of nattokinase safety is a 2023 systematic review in Reviews in Cardiovascular Medicine [1], which pooled six randomized controlled trials covering 546 participants at daily doses ranging from 1,200 to 8,000 FU. Its finding on safety was blunt: no notable adverse events were reported in any group, and average compliance exceeded 95% in three of the trials. People took it, and they kept taking it.

The longest trial reinforces that. The Nattokinase Atherothrombotic Prevention Study [2] randomized 265 adults with a median age of 65.3 years to 2,000 FU daily or placebo for three years. Beyond finding no benefit on artery wall thickness (0.013 mm per year on nattokinase versus 0.011 mm on placebo, p = 0.31), it found no detectable effect on prothrombin time, activated partial thromboplastin time, or von Willebrand factor antigen at 1 week or 1, 3, and 6 months.

Toxicology points the same direction. A 2016 assessment in Food and Chemical Toxicology [8] found 10 mg/kg daily for 28 days was well tolerated in human volunteers, and a 1,062-participant study using 10,800 FU per day for a year [9] recorded no noticeable adverse effects. That last dose is more than five times what most supplements provide.

So why the warnings? Because trials enroll people who are screened out if they have the conditions that make nattokinase risky. The harms show up in the population trials exclude.

2. The Side Effects People Actually Notice

The commonly reported effects are mild and gastrointestinal: nausea, loose stools, stomach upset. These typically settle within the first week or two, and they are the reason nattokinase is generally taken once daily on an empty stomach — at least 30 minutes before or 2 hours after food — as set out in the directions on the BioAbsorb Nattokinase Enzyme product page.

Digestive complaints are frequently confused between the food and the supplement. Natto — the whole fermented soybean — contains fibre and fermentation by-products that reliably produce gas in people unaccustomed to it, while a 100 mg isolated enzyme capsule does not carry that load. We covered that distinction separately in whether natto causes gas.

The second noticeable effect is blood pressure. Pooled across three trials with 223 participants, nattokinase reduced systolic pressure by 3.45 mmHg and diastolic by 2.32 mmHg [1] versus placebo. For someone with untreated hypertension, that's a modest benefit. For someone already on two antihypertensives, it can present as lightheadedness on standing.

• Mild GI upset: usually resolves within 1–2 weeks
• Blood pressure drop: about 3.45/2.32 mmHg on average [1]
• Blood glucose: a slight rise of 0.40 mmol/L across two trials with 341 participants [1]
• Sleep: no direct effect demonstrated in any trial — see whether nattokinase affects sleep

3. Bleeding: The Risk That Matters Most

Nattokinase breaks down fibrin, the protein scaffold that holds a clot together. That is the entire point of the supplement, and it is also the source of its only genuinely serious risk. The 2023 meta-analysis reports a 2019 trial of 76 participants [1] in which nattokinase significantly extended collagen–epinephrine closure time (p = 0.001) and activated partial thromboplastin time (p = 0.016) — measurable changes in how quickly blood stops flowing.

The best-known case is a 2008 report in Internal Medicine: a patient on aspirin for secondary stroke prevention developed acute cerebellar hemorrhage after seven consecutive days of nattokinase at 400 mg daily [3]. Brain imaging showed multiple pre-existing microbleeds. Two risk factors stacked on the supplement: an antiplatelet drug and already-fragile cerebral vessels.

The second case is more serious still. A 2021 report in Cureus described nattokinase-associated hemoperitoneum in a 92-year-old woman [4] with chronic kidney disease and atrial fibrillation — spontaneous bleeding into the abdominal cavity. She was taking nattokinase for her atrial fibrillation and was not on aspirin or any anticoagulant. She did not survive. The authors' conclusion was explicit: they warned against consumption of nattokinase specifically.

Two published cases across decades of widespread use is not a pattern, but it is not nothing either, and supplement-related events are under-reported by design. Both patients had something stacked against them — one an antiplatelet drug and fragile cerebral vessels, the other advanced age and impaired kidney function — which is precisely the profile trials screen out. For a fuller treatment of the risk-versus-benefit question, see our review of the downsides of taking nattokinase.

Context still matters. Nattokinase is a mild fibrinolytic, not a pharmaceutical one — the longest and largest trial found no measurable effect on standard coagulation markers at supplement doses [2]. The risk is real, and it is concentrated in people who are already bleeding-prone.

4. Interactions That Change Your Risk Profile

Warfarin is the interaction to understand, and it runs in two opposite directions. Nattokinase's fibrinolytic activity can add to warfarin's anticoagulant effect. But Memorial Sloan Kettering notes that natto is rich in vitamin K2 [12], and Bacillus subtilis continues synthesizing vitamin K in the intestine after consumption — which works against warfarin by lowering INR. Whether a given product pushes INR up or down depends on how much K2 survives manufacturing.

This is why K2 content is a specification worth checking rather than a marketing detail. Products that remove vitamin K2 during processing — including the 2000 FU K2-free formulation from BioAbsorb Nutraceuticals — eliminate one of those two competing effects. They do not eliminate the bleeding-side interaction, and no formulation makes nattokinase safe to combine with warfarin without physician oversight.

Antiplatelet drugs carry the risk demonstrated in the 2008 case above. The same additive logic applies to direct oral anticoagulants such as apixaban and rivaroxaban, though no systematic data exist for those combinations. Supplements with mild blood-thinning activity compound in the same way — we looked at one common pairing in taking turmeric and nattokinase together.

5. Who Should Not Take Nattokinase

Canadian product licensing is unusually specific here. The Health Canada licensed natural health product listing [13] requires these statements on every compliant nattokinase label: do not use if you are pregnant or breastfeeding, if you take health products affecting blood coagulation, or if you have a bleeding disorder. It also mandates stopping 7 days before any scheduled surgery — or immediately in the case of unscheduled surgery or an injury causing bruising or bleeding — and consulting a practitioner before use if you have a cardiovascular, kidney, or liver disorder, or take any medication.

Mechanical heart valves are an absolute exclusion, and the reason is documented. A 2018 review in Biomarker Insights [10] describes a patient who substituted nattokinase for warfarin after aortic valve replacement; after roughly a year, a thrombus formed on the prosthesis and the valve had to be replaced again. Nattokinase is not equivalent to prescription anticoagulation and cannot replace it.

Soy allergy is the other hard stop, and it is more complicated than it looks. Beyond soy protein, natto contains poly-γ-glutamic acid, which causes late-onset anaphylaxis appearing 3 or more hours after ingestion [6]. A survey of 140 food-allergy outpatients identified 13 with natto allergy [7], with surfing a significant risk factor — jellyfish tentacles produce the same compound, and dermal exposure appears to sensitize people to it. And a 2022 report in Allergology International [5] documented anaphylaxis triggered by the nattokinase enzyme itself.

Age alone is not a contraindication, though it changes the calculus — the 3-year trial in adults averaging 65 found no benefit on its primary endpoint [2], and the one fatal case report involved a 92-year-old with kidney disease [4]. We examined that trade-off in nattokinase for seniors, and duration of use in how long you can stay on nattokinase.

6. Symptoms Often Blamed on Nattokinase

Some reported effects don't survive contact with the evidence, and separating them matters — abandoning a supplement over an unrelated symptom is its own cost. Joint pain is the clearest example: across clinical trials there is no meaningful excess of joint-related complaints at standard doses, which we detail in whether nattokinase causes joint pain.

Heart palpitations are similar. No trial has identified palpitations as a nattokinase adverse effect, though the roughly 3.45 mmHg drop in systolic pressure [1] could plausibly produce a compensatory heart-rate response in someone already on blood pressure medication — an indirect route, not a direct one. We work through it in nattokinase and heart palpitations.

Liver stress is the third. A 120-day randomized trial in 113 people [11] testing a combination supplement — nattokinase together with red yeast rice — found no significant differences in coagulation, liver function, or renal function versus placebo, and no intervention-related adverse events. That trial cannot isolate nattokinase's own contribution, since red yeast rice supplies a statin. But the 3-year NAPS trial monitored the same parameters with nattokinase alone and found no signal either [2]. Note that Canadian labelling still directs anyone with a liver disorder to consult a practitioner before use [13]. Our full analysis is in whether nattokinase is hard on your liver.

7. The Downside That Isn't a Side Effect: It May Not Do Anything

The most common disappointment with nattokinase is not an adverse reaction. It is the absence of any noticeable effect at all.

The trial evidence is genuinely mixed, effects on the measures that have been studied are modest, and several of the outcomes people take nattokinase hoping to change — arterial plaque in particular — are not reliably moved by it at the doses in a standard capsule. Someone taking it for six months and feeling exactly as they did at the start has had the most statistically likely experience, not an unusual one.

That belongs on a page about downsides. The cost of a supplement that does nothing is not zero: it is the money, and it is the attention not given to the interventions that do have outcome data.

8. Soy, Natto Allergy and Delayed Reactions

The allergy question is more subtle than "avoid if allergic to soy."

Natto allergy and soy allergy are not the same thing. Reactions to natto have been documented in people who tolerate other soy foods without difficulty, and the suspected trigger is polyglutamic acid produced during fermentation rather than soy protein. So tolerating soy sauce and tofu is not a clearance for natto.

The pattern also differs from a typical food allergy. Reactions to natto are characteristically late-onset, appearing several hours after ingestion rather than within minutes — which makes them easy to attribute to something else entirely, and means the usual "if you were going to react, you'd know by now" reasoning does not hold.

A purified enzyme supplement carries less of the fermentation-derived material than the whole food, but anyone with a known natto reaction should treat both with the same caution.

9. How Formulation Affects What You Experience

Two formulation choices influence the side effect profile more than most people realise. The first is delivery. Nattokinase is a protein, and stomach acid degrades proteins — so manufacturers protect it. Traditional enteric coatings do this using phthalates and plasticizers; delayed-release vegetarian capsules achieve the same protection without them. BioAbsorb's Nattokinase Enzyme uses DRcaps delayed-release capsules delivering 100 mg (2000 FU) intact to the small intestine, taken once daily on an empty stomach.

The second is what else is in the capsule. Vitamin K2 is the variable that determines whether a product pulls against warfarin; the BioAbsorb formulation is intentionally K2-free, which matters both for anyone on anticoagulants and for anyone already supplementing K2 separately. The allergen profile is equally relevant given the anaphylaxis literature — the full ingredient and allergen disclosure lists it as free of gluten, nuts, eggs, dairy, fish, shellfish and all animal products, and 100% vegetarian. It remains derived from soy, so the soy-allergy exclusion applies regardless of formulation.

Verification is the third piece. Every batch is third-party tested for nattokinase activity of at least 2000 FU per capsule, alongside heavy metals, gluten, and microbial contaminants, and manufactured in a GMP-certified Canadian facility — current specifications and pricing are listed on the product page. None of this makes nattokinase appropriate for someone with a bleeding disorder — formulation changes tolerability, not contraindications.

Frequently Asked Questions

How long do nattokinase side effects last?

Mild digestive effects generally settle within the first 1–2 weeks as your system adjusts. Blood pressure effects are ongoing rather than transient, since the roughly 3.45 mmHg systolic reduction persists for as long as you take it [1].

Can nattokinase cause internal bleeding?

Two published case reports describe serious bleeding events, and one was fatal. A patient taking aspirin with pre-existing cerebral microbleeds developed cerebellar hemorrhage [3], and a 92-year-old woman with chronic kidney disease developed spontaneous bleeding into the abdominal cavity and died [4]. Both had significant risk factors that clinical trials screen out. Across six controlled trials and 546 participants [1], no bleeding events were reported.

Do I need to stop nattokinase before surgery?

Yes. Canadian labelling requires stopping 7 days before any scheduled procedure, and immediately in the case of unscheduled surgery or any injury causing bruising or bleeding [13]. Tell your surgical team you have been taking it even if you stopped on schedule.

Is nattokinase safe if I take blood pressure medication?

It requires monitoring rather than avoidance. The additive effect is modest — around 3.45/2.32 mmHg [1] — but enough to matter if your pressure already runs low on treatment. Check readings for the first two weeks and involve your prescriber.

Can I take nattokinase if I'm allergic to soy?

No. Nattokinase is derived from fermented soybeans, and Canadian labels state plainly that it should not be used by anyone with a soy allergy [13]. The 2022 anaphylaxis case [5] showed the enzyme itself can act as an allergen, independent of residual soy protein.

Does nattokinase affect blood sugar?

Slightly. Two trials totalling 341 participants found a small increase in blood glucose of 0.40 mmol/L versus placebo [1]. This is not clinically meaningful for most people, but worth flagging to your doctor if you manage diabetes.

Is nattokinase safe to take every day long-term?

The longest trial ran three years at 2,000 FU daily without a safety signal, which is reassuring as far as it goes. It remains a single study, and long-term use alongside anticoagulants or antiplatelet drugs has not been studied to the same depth. For a healthy adult taking nothing else that thins the blood, daily long-term use is well supported by what exists.

Is nattokinase approved by the FDA?

No, and it would not be — nattokinase is sold as a dietary supplement, and the FDA does not approve supplements for safety or efficacy before sale. That is a regulatory category, not a verdict. It does mean quality control sits with the manufacturer rather than a regulator, which is why enzyme-activity labelling and third-party testing matter more here than they would for a drug.

Conclusion

The honest summary is that nattokinase produces very few side effects in the general population — no notable adverse events across 546 trial participants [1] — but carries a narrow set of contraindications that are serious and, in one documented case, fatal for the people they apply to. If you take an anticoagulant, have a bleeding disorder, are pregnant, have a mechanical heart valve, or are allergic to soy, this is not your supplement.

For everyone else, the practical step is a conversation with your doctor before you start, and a 7-day stop before any procedure. If you decide it fits, you can review the specifications on the BioAbsorb Nattokinase Enzyme product page.

Research References

1. Nattokinase Supplementation and Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Reviews in Cardiovascular Medicine, Vol. 24, Issue 8 (2023). Pooled six randomized trials covering 546 participants; found no notable adverse events, a systolic reduction of 3.45 mmHg, a diastolic reduction of 2.32 mmHg, and a slight blood glucose increase of 0.40 mmol/L.
2. Nattokinase atherothrombotic prevention study: A randomized controlled trial. Clinical Hemorheology and Microcirculation, Vol. 78, Issue 4 (2021), 339–353. Three-year trial in 265 adults at 2,000 FU daily; found no significant effect on carotid intima-media thickness progression and no detectable changes in coagulation or fibrinolysis markers.
3. Cerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds. Internal Medicine, Vol. 47, Issue 5 (2008), 467–469. Case report of acute cerebellar hemorrhage after seven days of nattokinase at 400 mg daily in a patient on aspirin with pre-existing cerebral microbleeds.
4. Nattokinase-Associated Hemoperitoneum in an Elderly Woman. Cureus, Vol. 13, Issue 12 (2021), e20074. Case report of a 92-year-old woman with chronic kidney disease and paroxysmal atrial fibrillation, taking nattokinase and no anticoagulant or antiplatelet drug, who developed spontaneous bleeding into the abdominal cavity and subsequently died. The authors warn explicitly against nattokinase consumption.
5. Anaphylaxis from nattokinase in a patient with fermented soybean (natto) allergy. Allergology International, Vol. 71, Issue 1 (2022), 153–154. Documented anaphylaxis attributable to the nattokinase enzyme itself rather than residual soy protein.
6. Late-onset anaphylaxis due to poly (γ-glutamic acid) in the soup of commercial cold Chinese noodles in a patient with allergy to fermented soybeans (natto). Allergology International, Vol. 60, Issue 3 (2011), 393–396. Identified poly-γ-glutamic acid as the allergen behind late-onset anaphylactic reactions occurring hours after natto ingestion.
7. Surfing as a risk factor for sensitization to poly(γ-glutamic acid) in fermented soybeans, natto, allergy. Allergology International, Vol. 67, Issue 3 (2018), 341–346. Survey of 140 food-allergy outpatients identifying 13 with natto allergy and establishing marine sports as a sensitization route.
8. Toxicological assessment of nattokinase derived from Bacillus subtilis var. natto. Food and Chemical Toxicology, Vol. 88 (2016), 87–99. Found daily consumption of 10 mg/kg for 4 weeks was well tolerated in healthy human volunteers.
9. Effective management of atherosclerosis progress and hyperlipidemia with nattokinase: A clinical study with 1,062 participants. Frontiers in Cardiovascular Medicine, Vol. 9 (2022), 964977. Retrospective analysis recording no noticeable adverse effects at 10,800 FU per day over one year. A corrigendum was published in Frontiers in Cardiovascular Medicine, Vol. 9 (2022), 1076420.
10. Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomarker Insights, Vol. 13 (2018). Review describing the mechanical valve thrombosis case following patient substitution of nattokinase for warfarin.
11. The Effect of Nattokinase-Monascus Supplements on Dyslipidemia: A Four-Month Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Nutrients, Vol. 15, Issue 19 (2023), 4239. Trial in 113 participants of a combination supplement containing nattokinase 2,500 FU and lovastatin 7 mg derived from red yeast rice; found no significant differences in coagulation, liver function, or renal function versus placebo.
12. Nattokinase. Memorial Sloan Kettering Cancer Center — About Herbs database. Summary of the bidirectional warfarin interaction, including vitamin K2 synthesis by Bacillus subtilis in the intestine.
13. Licensed Natural Health Products Database — Nattokinase product listing (Licence 80089299). Health Canada. Source of the mandated label cautions, including pregnancy and breastfeeding, bleeding disorders, concurrent anticoagulant use, soy allergy, and the 7-day pre-surgical discontinuation statement.

About the Author

David Kimbell is a health writer, digital entrepreneur and former aerospace engineer, based in Ottawa, Canada. He loves translating complex science into clear, actionable guidance for consumers seeking evidence-based solutions.

---

Important Disclaimers

Medical Disclaimer: This article provides educational information only and is not intended as medical advice. Always consult with a qualified healthcare provider before starting any new supplement, especially if you have existing health conditions, take medications, or are pregnant or nursing.

FDA/Health Canada Statement: These statements have not been evaluated by the Food and Drug Administration or Health Canada. This product is not intended to diagnose, treat, cure, or prevent any disease.