Nattokinase: Benefits, Forms, Dosing, and Side Effects

Table of Contents

• Current evidence position
• Key safety points
• Brad's videos on this topic
• Overview
• Forms and Bioavailability
• Evidence for Benefits
• Recommended Dosing
• Safety and Side Effects
• Drug Interactions
• Dietary Sources
• References

Current evidence position

Brad has not made a video on this topic; this is a summary of the evidence, not his view. Nattokinase is an enzyme from natto that breaks down fibrin, and in small human studies a single 2,000 FU dose, or two 2,000 FU capsules a day for 2 months, changed clotting and clot-breakdown markers ^{[19, 26]}. Blood pressure results are mixed: an 8-week trial of 2,000 FU a day lowered systolic pressure by 5.55 mmHg compared with placebo, but a 3-year trial of 2,000 FU a day found no effect on blood pressure or on thickening of the carotid artery wall ^{[31, 34]}. Randomized trials have not shown that nattokinase alone improves cholesterol or global cognition, and the authors of the 3-year trial noted that no large, long-term cardiovascular study had been done before theirs ^{[34, 38, 44]}. Its main risk is bleeding, including a fatal bleed into the abdomen and a brain bleed in a patient also taking aspirin, so people who take blood thinners or have a bleeding risk should talk to their doctor first ^{[52, 53]}.

Brad's videos on this topic

None yet.

1. Overview

Nattokinase is an enzyme found in natto, a Japanese food made by fermenting soybeans. Sumi and colleagues reported strong clot-dissolving (fibrinolytic) activity in natto in 1987 and named the enzyme nattokinase ^[57]. It is a subtilisin-like serine protease of 275 amino acids, with a molecular weight of 27,728 ^[7].

Nattokinase breaks down fibrin, the protein mesh that holds blood clots together. In lab work it also cut and inactivated plasminogen activator inhibitor 1 (PAI-1), one of the body's brakes on clot breakdown, and it dissolved fibrin directly ^[6]. In a rat model of carotid artery thrombosis, it restored more blood flow than plasmin on a molar basis (62.0% versus 15.8%) ^[25].

A 2018 review described possible effects of nattokinase on blood pressure, atherosclerosis, cholesterol, platelets and the nervous system ^[4]. In lab tests, natto and some other fermented foods blocked angiotensin-converting enzyme (ACE) ^[8], and nattokinase broke down amyloid fibrils, protein clumps linked to Alzheimer's disease ^[10].

Nattokinase strength is given in fibrinolytic units (FU), a measure of enzyme activity, because weight alone does not show how active a preparation is. In one study, a softgel holding about 100 mg of NSK-SD nattokinase supplied 2,000 FU ^[18].

In rats, nattokinase placed in the small intestine was absorbed and broke down fibrinogen in the blood ^[14]. In people, a single 2,000 FU softgel raised blood levels of nattokinase from 2 to 24 hours after the dose, with a peak at about 13.3 hours ^[18].

Most human studies of nattokinase are small and short. The authors of the 2021 Hodis trial noted that no large-scale, long-term cardiovascular study of nattokinase had been done before theirs ^[34].

2. Forms and Bioavailability

Supplement Forms

Nattokinase is sold as capsules, enteric-coated capsules, softgels and powders.

Standard capsules: Trials have used capsules of 2,000 FU each ^{[26, 31]}.

Enteric-coated capsules: These have a coating meant to resist stomach acid and dissolve in the intestine. Rat work shows that nattokinase can be absorbed from the intestine ^[14], but coated and uncoated capsules have not been compared in people.

Softgel capsules: The human blood-level study used NSK-SD softgels of about 100 mg ^[18].

Powdered/functional food forms: Powders for mixing into drinks are also sold. The trials described here used capsules or softgels.

NSK-SD — A Proprietary Form

NSK-SD is a branded nattokinase from Japan Bio Science Laboratory ^[19]. It is a fermented soy extract from which vitamin K2 has been removed ^[32]. It was used in the single-dose trials and in an 8-week blood pressure trial ^{[18, 19, 32]}, and safety studies of NSK-SD are described under Safety and Side Effects ^[22].

Vitamin K Content in Nattokinase

Natto contains much menaquinone-7 (MK-7), a form of vitamin K2 ^[23]. Vitamin K helps the liver make clotting factors. Natto-derived MK-7 at 50 mcg a day or more may interfere with warfarin-type anticoagulants ^[59], and in one study of healthy volunteers on a warfarin-type drug, doses as low as 10 mcg a day lowered INR in some of them ^[60]. A lower INR means the blood thinner is working less well.

Some nattokinase products, such as NSK-SD, have the vitamin K2 removed ^[32]. This is the supplement, not natto: natto food still contains its vitamin K2. If you take warfarin, choose a product labelled vitamin K-free, and check with your doctor or anticoagulation clinic before taking nattokinase or eating natto.

Absorption and Bioavailability

Nattokinase is a protein, so how much survives digestion is uncertain. Studies suggest that some of it reaches the blood:

• In 12 healthy young men, a single 2,000 FU dose of NSK-SD raised fibrin and fibrinogen breakdown products at 4 hours and D-dimer at 6 and 8 hours, compared with placebo ^[19].
• Nattokinase capsules or natto taken by mouth produced a mild and frequent increase in clot-breaking activity in plasma ^[3].
• In 11 healthy adults, nattokinase was detectable in blood from 2 to 24 hours after one 2,000 FU softgel ^[18].
• In rats, nattokinase given into the intestine was found in blood drawn 3 and 5 hours later ^[14].

Empty Stomach vs. With Food

Advice to take nattokinase on an empty stomach rests on theory, not on trials comparing it with and without food.

Standardization and Potency

Look for activity in FU on the label, because milligrams alone do not show enzyme activity. In one study, about 100 mg of NSK-SD supplied 2,000 FU ^[18]; other preparations may differ.

3. Evidence for Benefits

Blood Clots and Thrombosis

In animal studies, nattokinase broke down clots in dogs with induced thrombosis and in rats with blocked carotid arteries ^{[3, 25]}. The authors of the 3-year Hodis trial noted that no large-scale, long-term cardiovascular study had been done, so it is unknown whether nattokinase alone prevents clots, heart attacks or strokes ^[34].

Fibrinolytic activity in healthy subjects: In a placebo-controlled crossover trial in 12 healthy young men, a single 2,000 FU dose of NSK-SD raised fibrin breakdown products at 4 hours and D-dimer at 6 and 8 hours, lowered factor VIII at 4 and 6 hours, and lengthened the activated partial thromboplastin time at 2 and 4 hours ^[19]. All the changes stayed within the normal range ^[19].

Clotting factor reduction: In an open-label study with no placebo group, 45 people (healthy volunteers, people with cardiovascular risk factors and people on dialysis) took two 2,000 FU capsules a day for 2 months ^[26]. Across the groups, fibrinogen fell by 7% to 10%, factor VII by 7% to 14% and factor VIII by 17% to 19%, while blood lipids did not change ^[26].

Sustained fibrinolytic activity: Sumi and colleagues reported that nattokinase capsules or natto taken by mouth gave a mild and frequent increase in plasma clot-breaking activity and in tissue plasminogen activator ^[3].

Deep vein thrombosis prevention: The LONFLIT-FLITE trial randomized 204 high-risk travellers on 7- to 8-hour flights to Flite Tabs (150 mg pinokinase) or placebo ^[27]. No deep vein thrombosis occurred with treatment, while 5 of 92 controls had a deep vein thrombosis and 2 had a superficial thrombosis ^[27]. Flite Tabs are a branded product rather than plain nattokinase, so the result cannot be credited to nattokinase alone.

Epidemiological data from Japan: In the Takayama cohort of 13,355 men and 15,724 women followed for 16 years, the highest quarter of natto intake had lower ischemic stroke mortality than the lowest (HR 0.67, 95% CI 0.47 to 0.95) ^[29]. This is a study of natto food, which also contains vitamin K2 and soy, so it cannot show an effect of nattokinase supplements.

Limitations: Most trials are small and short, and the longest trial found no benefit on carotid artery thickening ^[34].

Blood Pressure

Results are mixed. Short trials found small falls in blood pressure, while a 3-year trial found none ^{[31, 33, 34]}.

Positive short-term studies:

In a trial of 86 adults with untreated systolic pressure of 130 to 159 mmHg, one 2,000 FU capsule a day for 8 weeks lowered systolic pressure by 5.55 mmHg (95% CI -10.5 to -0.57 mmHg) and diastolic pressure by 2.84 mmHg compared with placebo ^[31]. Renin activity fell by 1.17 ng/mL/h compared with placebo ^[31].

In a North American trial in 79 people with raised blood pressure, NSK-SD 100 mg a day for 8 weeks lowered average diastolic pressure from 87 to 84 mmHg, while it stayed at 87 mmHg with placebo; in men it fell from 86 to 81 mmHg ^[32]. Among people with low renin activity at the start, renin rose in 66% with nattokinase and 8% with placebo, a trend that did not reach statistical significance (P<0.1) ^[32].

Meta-analysis: A 2023 meta-analysis of 6 randomized trials with 546 participants found that nattokinase lowered systolic pressure by 3.45 mmHg (95% CI -4.37 to -2.18) and diastolic pressure by 2.32 mmHg (95% CI -2.72 to -1.92) compared with placebo ^[33].

Negative long-term studies:

In the Hodis trial, 265 adults with a median age of 65.3 years and no cardiovascular disease took 2,000 FU a day or placebo for a median of 3 years, and nattokinase did not significantly change blood pressure ^[34].

Practical interpretation: Any fall in blood pressure from nattokinase appears small, a few mmHg, and the longest trial found none ^{[33, 34]}.

High Cholesterol and Lipid Metabolism

In cholesterol-fed rats, natto extracts lowered triglycerides and total cholesterol and reduced lipid oxidation ^[36]. These were natto fractions, not purified nattokinase. Randomized trials in people have not found that nattokinase alone improves cholesterol ^{[33, 38]}.

Negative controlled trials:

In a 6-month trial in 47 people with high blood lipids, nattokinase alone (two 50 mg capsules twice a day) did not differ from placebo on total cholesterol, LDL cholesterol or the cholesterol-to-HDL ratio after adjusting for baseline, while nattokinase with red yeast rice did ^[38].

In the 3-year Hodis trial, 2,000 FU a day did not significantly change any laboratory measure, which included metabolic factors ^[34].

Meta-analysis (unfavorable): The 2023 meta-analysis found that relatively low total doses of nattokinase raised total cholesterol (mean difference 5.27) and LDL cholesterol (6.49) and lowered HDL cholesterol (-2.76), and higher total doses also raised total cholesterol (3.18); triglycerides did not change ^[33].

One positive clinical study (with caveats): A clinical study of 1,062 participants reported that 10,800 FU a day for 12 months improved blood lipids, with improvement rates of 66.5% to 95.4%, and that 3,600 FU a day was ineffective ^[39]. A correction to the paper was later published, and the result has not been repeated in a randomized placebo-controlled trial.

Synthesis: Randomized trials have not shown that nattokinase alone lowers cholesterol ^{[33, 34, 38]}. It is not a dependable way to lower cholesterol.

Atherosclerosis and Arterial Plaque

Several studies have tested whether nattokinase slows plaque build-up in arteries (atherosclerosis).

Carotid intima-media thickness (CIMT): negative RCT: The Hodis trial randomized 265 healthy older adults to 2,000 FU a day or placebo. After a median of 3 years, the yearly change in carotid intima-media thickness (CIMT) and carotid artery stiffness did not differ between the groups ^[34].

CIMT and plaque, high-dose study: In the Chen study of 1,062 participants, 10,800 FU a day for 12 months was linked to thinner carotid artery walls and smaller carotid plaques, and people who also took vitamin K2 and aspirin did better ^[39].

Plaque comparison with simvastatin: In a Chinese trial, 82 patients with carotid atherosclerosis and high blood lipids took nattokinase 6,000 FU a day or simvastatin 20 mg a day for 26 weeks, and 76 completed it ^[40]. Plaque size fell by 36.6% with nattokinase and 11.5% with simvastatin, while simvastatin lowered cholesterol and triglycerides more ^[40].

Other markers: In the Jensen trial, von Willebrand factor, a clotting protein, fell in women taking nattokinase, a trend that did not reach statistical significance (P<0.1) ^[32].

Interpretation: In low-risk adults, the best evidence, a 3-year placebo-controlled trial, found no effect on artery thickening at 2,000 FU a day ^[34]. The higher-dose results ^{[39, 40]} need confirmation in larger randomized trials.

Alzheimer's Disease and Cognitive Function

Nattokinase has been studied for brain health because it can break down amyloid fibrils in the lab.

Amyloid degradation (in vitro): Hsu and colleagues found in 2009 that nattokinase can break down amyloid fibrils, an ability shared by some other proteases but not by trypsin or plasmin ^[10].

Human clinical evidence (negative): The ICC-PACS trial randomized 120 adults (average age 58.3 years) with narrowed carotid or intracranial arteries but no symptoms to nattokinase 8,000 FU a day or placebo for 6 months ^[44]. Global cognition (MoCA score) did not differ between the groups, though an exploratory analysis found better visuospatial scores with nattokinase ^[44].

Synthesis: Lab findings on amyloid have not yet translated into better thinking in people ^[44].

Metabolism and Insulin Sensitivity

The 2023 meta-analysis found a slight rise in blood glucose with nattokinase compared with placebo (mean difference 0.40, 95% CI 0.20 to 0.60) ^[33].

Combination with Red Yeast Rice

Red yeast rice contains monacolin K, which lowers cholesterol in a statin-like way. Nattokinase acts on clots instead, and the two are sometimes combined.

In the Yang trial, nattokinase with red yeast rice lowered triglycerides by 15%, total cholesterol by 25% and LDL cholesterol by 41%, and raised HDL cholesterol by 7.5%, while nattokinase alone did not differ from placebo ^[38].

In the Liu trial, 178 patients whose coronary artery disease was stable took nattokinase with red yeast rice, nattokinase alone, red yeast rice alone or placebo for 90 days ^[35]. The combination lowered triglycerides, total cholesterol and diastolic pressure (by 7.39 mmHg) more than either supplement alone or placebo, and lowered thromboxane B2 and raised antithrombin III compared with placebo; no adverse effects were reported ^[35]. Because nattokinase alone has not lowered lipids in trials, the lipid effect likely comes mostly from red yeast rice.

SARS-CoV-2 Spike Protein

In cell experiments, nattokinase broke down the SARS-CoV-2 spike protein in a dose- and time-dependent way ^[48]. This is lab work only and is not evidence that nattokinase treats or prevents COVID-19.

Gastrointestinal Health

Any gut benefit of natto food has not been shown for nattokinase supplements.

4. Recommended Dosing

Clinical Study Doses

Trials have used 2,000 FU a day, two 2,000 FU capsules a day, 6,000 FU a day, 8,000 FU a day and 100 mg a day ^{[26, 31, 32, 34, 40, 44]}. The best dose for any purpose is unknown.

Dosing Recommendations by Source

The Chen study authors reported that 10,800 FU a day was safe and well tolerated, and argued that their results challenge the recommended dose of 2,000 FU a day ^[39]. Most randomized trials used 2,000 to 8,000 FU a day ^{[31, 34, 44]}.

Timing

Trials gave nattokinase once or twice a day ^{[26, 31, 38]}. The best time of day is unknown.

Practical Dosing Summary

• Doses studied: 2,000 to 8,000 FU a day in most randomized trials ^{[31, 34, 44]}
• Look for FU on the label: milligram amounts alone do not show enzyme activity
• Blood thinners: if you take warfarin, aspirin or another blood thinner, talk to your doctor before starting ^{[53, 60]}

5. Safety and Side Effects

General Tolerability

Trials reported no notable adverse events with nattokinase ^{[26, 33, 35]}.

Safety study: In safety studies of NSK-SD, 10 mg/kg a day for 4 weeks was well tolerated in healthy volunteers, and rats showed no adverse effects at doses up to 1000 mg/kg a day for 90 days ^[22].

Large-scale safety data: The Chen study reported no noticeable adverse effects at 10,800 FU a day for 12 months ^[39].

The longest randomized trial lasted a median of 3 years ^[34].

Risk of Bleeding

Bleeding is the main safety concern. Nattokinase breaks down fibrin, and a single dose lengthened a clotting time (the activated partial thromboplastin time) in healthy men ^[19]. It may add to the effect of blood thinners.

Fatal hemoperitoneum: An elderly woman taking nattokinase developed bleeding into the abdominal cavity (hemoperitoneum) and died, and the authors warned against taking nattokinase ^[52].

Intracerebral hemorrhage: A patient taking aspirin to prevent another stroke had a bleed in the cerebellum after taking nattokinase 400 mg a day for 7 days ^[53]. Brain scans also showed multiple small old bleeds (microbleeds), and the authors suggested nattokinase may raise the risk of brain bleeding in people with fragile small brain vessels who also take another antithrombotic drug ^[53]. For signs of a stroke or bleeding in the brain (face drooping, arm or leg weakness or numbness, trouble speaking, vision loss, even if it passes, or a sudden severe headache), call your local emergency number (111 in NZ, 000 in Australia, 911 in the US, 999 in the UK). Call it too for bleeding that will not stop or a suspected bleed inside the abdomen.

Theoretical risk of clot embolization: In theory, breaking up an existing clot could let a piece travel to the lungs or heart.

Blood Pressure Lowering

Nattokinase may lower blood pressure by a few mmHg; the 2023 meta-analysis found a fall in systolic pressure of 3.45 mmHg ^[33]. If you have low blood pressure or take blood pressure medicines, talk to your doctor first.

Allergic Reactions

Soy allergy: NSK-SD, the form used in several trials, is a fermented soy extract ^[32].

Natto allergy: A case report described anaphylaxis from nattokinase in a patient with natto allergy ^[55]. For trouble breathing, swelling of the face or throat, or fainting, call your local emergency number (111 in NZ, 000 in Australia, 911 in the US, 999 in the UK) or go to the emergency department.

Thyroid Considerations

Soy foods may mean that people with hypothyroidism need more thyroid hormone medicine, because soy can reduce its absorption, although hypothyroid adults need not avoid soy foods ^[56]. Whether soy-based nattokinase supplements have this effect is unknown.

Perioperative Risk

If you are having surgery or a procedure, tell your doctor you take nattokinase.

Contraindications

Talk to your doctor before taking nattokinase, or avoid it, if any of these apply:

• Bleeding disorders or a high risk of bleeding
• Anticoagulants (such as warfarin or heparin) or antiplatelet drugs (such as aspirin or clopidogrel) ^[53]
• Upcoming surgery or a procedure
• Stomach ulcers or other gut conditions prone to bleeding
• Pregnancy or breastfeeding, because safety data are lacking
• Allergy to natto or nattokinase ^[55], or soy allergy for products made from soy

6. Drug Interactions

Anticoagulants and Antiplatelet Agents

Nattokinase may add to the effects of these medicines and raise bleeding risk ^{[19, 53]}:

If you take warfarin, your doctor may want to check your INR more often if you start nattokinase.

Antihypertensive Medications

Trials found small falls in blood pressure with nattokinase ^{[31, 33]}, so it may add to blood pressure medicines. If you take them, check your blood pressure and talk to your doctor before starting.

Blood-Thinning Supplements

Other supplements that affect clotting may add to nattokinase's effects. These include:

• Fish oil / omega-3 fatty acids
• Vitamin E (high dose)
• Garlic supplements
• Ginkgo biloba
• Turmeric / curcumin

Combining several supplements that affect clotting may add to bleeding risk.

Vitamin K Interactions

Natto contains a lot of MK-7, a form of vitamin K2 ^[23], and MK-7 at doses as low as 10 mcg a day lowered INR in some healthy volunteers on a warfarin-type drug ^[60]. NSK-SD has its vitamin K2 removed ^[32], but other products may not state their vitamin K content. Nattokinase itself lengthened a clotting time in healthy men ^[19], so it may also add to the effect of warfarin. If you take warfarin, check with your doctor or anticoagulation clinic before taking nattokinase or eating natto.

No Known Interactions with Antibiotics

Interactions between nattokinase and antibiotics have not been studied. If you take prescription medicines, check with your doctor or pharmacist before starting.

7. Dietary Sources

Natto

Natto is the main food source of nattokinase. It is made by fermenting soybeans with Bacillus subtilis natto ^{[6, 57]}.

Nattokinase content: Sumi measured an average clot-dissolving activity of about 40 plasmin units per gram of natto, a different unit from FU ^[57].

Nutritional profile of natto: Natto is also high in MK-7, a form of vitamin K2 ^[23].

Characteristics: Natto is sticky and strong-smelling, and is often eaten with rice in Japan.

Other Fermented Soybean Products

Other fermented soybean foods made with Bacillus species, such as Korean cheonggukjang, may contain related enzymes, but nattokinase itself comes from natto.

Recombinant and Non-Soy Production

Nattokinase is produced by the bacterium Bacillus subtilis var. natto, which also ferments soybeans into natto ^[22].