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Nattokinase

Common Name(s): Cardiokinase, Fermented soybeans, Natto, Subtilisin NAT, Subtilisin natto

Medically reviewed by Drugs.com. Last updated on Jan 22, 2024.

Clinical Overview

Use

Although nattokinase is promoted for use as a fibrinolytic and thrombolytic agent, clinical trials are lacking to support such use. There is also no substantial evidence that nattokinase lowers blood pressure in hypertension.

Dosing

Clinical studies to guide safe and effective nattokinase dosing are lacking. Nattokinase 100 mg/day (equivalent to 2,000 fibrinolytic units [FU]), typically for a duration of 8 weeks, has been used in some studies evaluating thrombolytic/fibrinolytic and blood pressure effects.

Contraindications

Avoid use of nattokinase in individuals with ischemic stroke, peptic ulcer, and coagulation disorders, as well as before and after surgery.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

Nattokinase has pharmacologic effects that could increase the risk of bleeding when administered with anticoagulant and antiplatelet agents. High concentrations of vitamin K2 in natto (a traditional Japanese food) can reduce the international normalized ratio (INR) when coadministered with warfarin; this may also occur with nattokinase supplements if vitamin K2 is not removed during the production process.

Adverse Reactions

Small, short-term trials evaluating nattokinase reported no adverse reactions. There is a theoretical risk of bleeding, based on a case report of acute cerebellar hemorrhage in a patient with a history of ischemic stroke. Thrombosis was reported after substitution of nattokinase for warfarin in a patient with a mechanical aortic valve. Rare cases of late-onset anaphylaxis with natto have been attributed to poly-gamma-glutamic acid, a product of the fermentation process that may be present in nattokinase supplements.

Toxicology

No data.

Source

Nattokinase is a fibrinolytic enzyme found in natto, a traditional Japanese food. It is produced by Bacillus subtilis (also called Bacillus natto or Bacillus subtilis natto) during the fermentation process that turns boiled soybeans into natto. Similar fibrinolytic enzymes are found in other traditional fermented foods, including chungkook-jang in Korea, douchi in China, thua nao in Thailand, and tempeh in Indonesia.Dabbagh 2014, Inatsu 2006 Fermentation technology is used to manufacture nattokinase supplements that are then formulated into powders, pills, and capsules, alone or with other ingredients.Dabbagh 2014, Sumi 1987

History

The fermentation of soybeans is a common traditional Asian and African culinary practice. Natto is a traditional Japanese food that has been consumed for at least 1,000 years. It is usually served as breakfast with rice, on toast, or as sushi; it is also available as an ice cream flavor. Traditionally, it has been used for heart conditions, to relieve fatigue, and as an antiberiberi agent. In the 1980s, researchers investigating food substances for thrombolytic properties isolated the enzyme nattokinase from natto.Inatsu 2006, Sumi 1987, Tai 2006 The first commercial nattokinase product was marketed in Japan in 1998. Although nattokinase has been marketed as a dietary supplement in many parts of the world since that time, Health Canada determined in 2012 that safety concerns, including the potential for increased bleeding risk, had not been adequately addressed to allow the marketing of nattokinase.Health Canada 2012 An application was filed in the European Union for approval of nattokinase as a novel food.ACNFP 2012 Nattokinase currently does not have generally recognized as safe (GRAS) status with the US Food and Drug Administration.

Chemistry

Natto has a characteristic smell (possibly because of its pyrazine content), a viscous texture, and a strong, distinct flavor; it has been described as a "vegetable cheese" because of its consistency. Although the name implies that it is a kinase, nattokinase is actually an alkaline serine protease with an amino acid sequence similar to that of subtilisin, which is used in laundry detergents. It contains 275 amino acids and has a molecular weight of 27.7 kDa.Dabbagh 2014 The enzyme catalyzes the cleavage of proteins to polypeptides and has high substrate specificity for fibrin, with substantial fibrinolytic activity at a pH range of 6 to 12.Dabbagh 2014 The proteolytic activity of nattokinase is measured in fibrinolytic units (FU).Japan Bio 2014 A 50 g serving of natto provides 1,500 FU of nattokinase. The enzyme can withstand temperatures of up to 50°C (122°F) and repeated freezing and thawing, but it is inactive in acidic conditions. Microencapsulated and enteric-coated formulations have been developed to reduce degradation of nattokinase by gastric acid.Dabbagh 2014

During the natto fermentation process, B. subtilis also produces and secretes vitamin K2 (menaquinone-7), bacillopeptidase F (another fibrinolytic enzyme marketed as a dietary supplement), and other proteolytic enzymes.Hitosugi 2014, Kaneki 2001 Vitamin K2 may be removed from nattokinase supplements in the manufacturing process. Methods have been described to optimize the production of the enzyme, remove vitamin K2, and eliminate the characteristic natto odor from nattokinase products.Fujita 1993, Ku 2009, Sumi 1987, Tai 2006, Wang 2009, Wei 2012, Weng 2009

Uses and Pharmacology

A single-dose study evaluated the pharmacokinetics of oral nattokinase (capsules containing approximately 100 mg of nattokinase [2,000 FU]) in 11 healthy volunteers. Peak serum concentrations were reached at 13.3±2.5 hours after dosing. Because nattokinase was detected in the serum with an enzyme-linked immunosorbent assay using a polyclonal antibody that reacts with both nattokinase and metabolites, it is unclear whether the nattokinase detected in this study was biologically active.Ero 2013

Amyloid plaque

Animal and in vitro data

In an in vitro study, nattokinase degraded amyloid fibrils, suggesting a potential role in the treatment of amyloid-related diseases such as Alzheimer disease.Hsu 2009 In an Alzheimer disease rat model, nattokinase increased expression levels of A disintegrin and metalloproteinase domain 9 and 10 (ADAM9 and ADAM10) genes, particularly at higher doses.Fadl 2013 In theory, increasing ADAM10 activity could play a role in managing Alzheimer disease.

Antiplatelet activity

Ex vivo, in vivo, and in vitro data

Ex vivo studies suggest that nattokinase may have antiplatelet activity. Nattokinase inhibited collagen- and thrombin-induced platelet aggregation in a study using rabbit platelets. Nattokinase appeared to inhibit thromboxane A2 production by activated platelets.Jang 2013 In rat platelets, nattokinase increased cyclic adenosine monophosphate, which inhibits platelet aggregation. In human platelets, nattokinase appeared to inhibit mobilization of calcium stores within platelets in response to platelet activation by thrombin.Ji 2014

Dyslipidemia

Clinical data

In a double-blind, placebo-controlled, randomized clinical trial evaluating the effects of nattokinase 50 mg capsules (either alone or in combination with red yeast rice) in 47 patients with hyperlipidemia, significant decreases in total cholesterol, low-density lipoprotein cholesterol, and total cholesterol/high-density lipoprotein cholesterol ratio were observed in the combination group compared to baseline and to placebo (P<0.0001); however, no differences were demonstrated between the nattokinase alone group and the placebo group.Yang 2009 In a study evaluating the fibrinolytic effects of nattokinase (2 capsules [2,000 FU per capsule] daily for 8 weeks) in 45 subjects (healthy, with cardiovascular risk factors, or undergoing dialysis), no effects on lipid profile were observed.Hsia 2009 In a crossover comparison study evaluating fermented soya (natto) extract and NKCP (the main components of which are subtilisin NAT and bacillopeptidase F, respectively), no significant effects on lipid profile were observed.Hitosugi 2014

Fibrinolytic and thrombolytic effects

Animal and in vitro data

The fibrinolytic action of nattokinase has been studied extensively in vitro. Unlike streptokinase, nattokinase does not act directly on plasminogen. The enzyme appears to cleave plasminogen activator inhibitor type 1, thereby increasing the activity of tissue plasminogen activator and promoting the conversion of plasminogen to plasmin, with a resultant increase in clot lysis. Nattokinase also acts directly on thrombi by lysing crosslinked fibrin with the preceding fibrinogenolytic activity dependent on serine protease. The fibrinolytic action of nattokinase is reportedly 4 times that of plasmin. Using human whole blood exposed to nattokinase, dose-dependent decreases in red blood cell aggregation and low-shear viscosity have also been demonstrated.Pais 2006, Peng 2005, Sumi 1987, Tai 2006, Urano 2001, Wu 2019

Nattokinase is a heparin-binding protein.Zhang 2015 The thrombolytic efficacy of nattokinase alone and in combination with heparin was explored in an "aged clot" in vitro experiment aimed to support clinical use of lower doses of heparin. Nattokinase alone reduced clot mass in a dose-dependent manner in rabbit blood, in contrast to low and moderate doses of heparin alone. A mild but important increase in thrombolysis occurred with the combination of nattokinase and high-dose heparin (12,500 units or 90 units/kg). The most prominent effects occurred at early time points (within 2 to 4 hours) and decayed over time, possibly because of the reversible and relatively low binding affinity between these 2 agents in modifying nattokinase lytic efficacy. Similar synergistic anticoagulant effects on clotting time were observed for the combination, with increases from a basal rate of 41 seconds to approximately 175, 207, and 510 seconds for nattokinase alone, heparin alone, and the combination, respectively. This effect was duplicated in mice in vivo.Wu 2019

Nattokinase was absorbed across rat intestine. The fibrinolytic and thrombolytic activity of nattokinase has been evaluated in animal experiments that induced thrombi and endothelial injury in the femoral arteries and common carotid artery in rats. Dietary supplementation with nattokinase suppressed intimal thickening, modulated the lysis of mural thrombi, and improved arterial blood flow more effectively than plasmin and elastase. In dogs, oral administration of nattokinase completely dissolved induced clots from major leg veins within 5 hours of administration, whereas the clots in dogs receiving placebo showed no thrombolysis for up to 18 hours.Chang 2010, Fujita 1995, Peng 2005, Suzuki 2003, Suzuki 2003 Two studies evaluated nattokinase in a rat model of carrageenan-induced thrombosis. In the first study, injection of nattokinase into rat tails before thrombosis shortened the length of tail thrombosis by approximately 15%.Kamiya 2010 In the second study, the area of thrombosis was reduced by the administration of nattokinase after thrombosis.Xu 2014 These studies suggest that nattokinase may affect clot formation and resolution.

Because excessive fibrin has been observed in nasal polyp tissue and in the mucus of patients with chronic rhinosinusitis and/or asthma, in vitro and in vivo experiments with nattokinase were conducted on samples collected from 14 chronic rhinosinusitis patients with nasal polyps to determine any fibrinolytic effect. Compared with control (saline solution), nattokinase significantly reduced nasal polyp tissue in a time- and dose-dependent manner (P<0.001) through fibrinolytic activity, not anticoagulant or proteolytic activity. The viscosity and gross appearance of mucus samples from these patients, including those with asthma, also improved significantly with nattokinase but not with control (P<0.01).Takabayashi 2017

Clinical data

Limited clinical trials have not produced definitive results regarding the efficacy of nattokinase as a fibrinolytic.Lee 2006, Tai 2006 In a study of 12 healthy Japanese adults taking natto 200 g daily, blood plasma tests showed enhanced fibrinolytic activity that lasted 2 to 8 hours after administration. Increases in euglobulin fibrinolytic activity, fibrin degradation products, and tissue plasminogen activator were recorded. However, data for all subjects were not published.Peng 2005, Tai 2006 In another study conducted in healthy Japanese males, a single oral dose of nattokinase (2,000 FU) in a softgel capsule form prolonged activated partial thromboplastin time, reduced factor VIII, and increased antithrombin within 8 hours after administration compared with placebo; increased levels remained safely within normal range.Kurosawa 2015 In an 8-week double-blind, randomized, placebo-controlled, multicenter study (N=79) investigating the effects of oral nattokinase (encapsulated in veggie caps with 100 mg per capsule and standardized to at least 2,000 FU per each 100 mg daily dose) on blood pressure in healthy adults, a slight but not statistically significant reduction was observed for von Willebrand factor. No change in platelet factor 4 levels was observed.Jensen 2016

An open-label trial evaluated the effect of nattokinase oral capsules administered over 2 months in healthy subjects or in patients with cardiovascular risk factors or on dialysis. Decreases in plasma fibrinogen and coagulation factors VII and VIII were observed over time in each group; however, no group effect was established. The sample size (N=45) was too small to draw firm conclusions.Hsia 2009

In another study, moderately hypercholesterolemic patients (N=76) not taking antihyperlipidemic therapies, anti-inflammatories, or medications affecting platelet function received nattokinase 100 mg/day (2,000 FU) or placebo for 8 weeks. The nattokinase group demonstrated significant increases in activated partial thromboplastin time, prothrombin time, and collagen-epinephrine closure time.Yoo 2019

Hypertension

Animal and in vitro data

Angiotensin-converting enzyme (ACE) was inhibited by nattokinase in an in vitro study. ACE inhibition appeared to be mediated by nattokinase peptide fragments and was not related to the proteolytic activity of intact nattokinase.Murakami 2012

A study in spontaneously hypertensive rats evaluated the antihypertensive mechanism of action of intact nattokinase and nattokinase peptide fragments.Fujita 2011 Although both the intact enzyme and the fragments reduced blood pressure, only the intact nattokinase reduced plasma fibrinogen levels. The intact nattokinase had no effect on the renin-angiotensin system. The nattokinase peptide fragments reduced plasma angiotensin II but had no effect on renin or ACE activity. The authors proposed that the fibrinolytic activity of the intact nattokinase reduced blood pressure by reducing blood viscosity; the mechanism of the nattokinase peptide fragments was unclear. In a second study, natto powder that contained gamma-aminobutyric acid and nattokinase reduced blood pressure in spontaneously hypertensive rats but not in rats with normal blood pressure.Suwanmanon 2014 Captopril reduced blood pressure more than natto powder.

Clinical data

In a double-blind, randomized clinical trial designed to evaluate the hypotensive effect of daily nattokinase administration (one capsule daily [2,000 FU per capsule] for 8 weeks) in subjects with prehypertension or stage 1 hypertension with a mean blood pressure of approximately 145/95 mm Hg at baseline (N=86), decreases in systolic and diastolic blood pressure were observed at 8 weeks, but not at 4 weeks. Conflicting results were obtained for plasma renin values.Kim 2008 A double-blind crossover study compared the effects of natto extract and bacillopeptidase F on blood pressure in 20 patients with "lifestyle" diseases, including hypertension, hyperlipidemia, and type 2 diabetes. The study reported that blood pressure decreased after treatment with bacillopeptidase F but not after nattokinase treatment. The clinical importance of these results is unclear because patients were not hypertensive at baseline.Hitosugi 2014 No hypotensive effect was found in a study evaluating the fibrinolytic effect of nattokinase oral capsules in healthy subjects or in patients with cardiovascular risk factors or on dialysis,Hsia 2009 or in another study evaluating effects on lipid profile in patients with hyperlipidemia.Yang 2009

In another double-blind, randomized, placebo-controlled, multicenter study (N=79), diastolic but not systolic blood pressure was significantly lowered in healthy adults after 8 weeks of nattokinase 100 mg/day (2,000 FU/day) in oral capsule form, compared with placebo (P<0.04). Although levels of von Willebrand factor decreased slightly, no statistically significant difference was observed for von Willebrand factor or platelet factor 4.Jensen 2016 A subgroup analysis of patients with "high-normal" blood pressure noted similar results, with greater reductions for diastolic pressure than for systolic pressure in males, and less reduction overall in females.Watanabe 2019

Vitreolysis

Animal data

In an experiment conducted in rabbits, intravitreal nattokinase induced posterior vitreous detachment via hydrolysis of collagen fibers, suggesting nattokinase may be a useful enzyme for pharmacologic vitreolysis.Takano 2006

Dosing

Clinical studies to guide safe and effective nattokinase dosing are lacking. Nattokinase 100 mg/day (equivalent to 2,000 FU), typically for a duration of 8 weeks, has been used in some studies evaluating thrombolytic/fibrinolytic and blood pressure effects.Jensen 2016, Kim 2008, Yoo 2019

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

The antithrombotic, fibrinolytic, and antiplatelet activities observed with nattokinase in vitro and in animal studies raise concerns that nattokinase may increase the risk of bleeding when administered with anticoagulant and antiplatelet agents.Ji 2014, Suzuki 2003, Xu 2014 In one unpublished study, 12 patients hospitalized for ischemic stroke who were receiving heparin and low-dose aspirin or clopidogrel also received nattokinase 6,000 FU/day for 7 days.ACNFP 2012, Japan Bio 2014 Coadministration of nattokinase reportedly increased bleeding time and clotting time and decreased prothrombin time, thromboplastin time, and D-dimer levels. Three unspecified temporary adverse reactions were reported. In another unpublished study, nattokinase 1,700 FU daily was given to 30 patients treated with warfarin for 26 weeks.ACNFP 2012, Japan Bio 2014 Coadministration of nattokinase reportedly stabilized INRs, but details were insufficient for evaluation.

An in vitro nattokinase experiment, aimed to support clinical use of lower doses of heparin, evaluated combining the 2 agents. The combination of nattokinase and high-dose heparin (12,500 units or 90 units/kg), but not low- or moderate-dose heparin, resulted in a mild but important increase in thrombolysis. The most prominent effects occurred early (within 2 to 4 hours) after administration. Similar synergistic anticoagulant effects on clotting time were observed for the combination, with increases from a basal rate of 41 seconds to approximately 175, 207, and 510 seconds for nattokinase alone, heparin alone, and the combination, respectively. This effect was duplicated in mice in vivo.Wu 2019

Patients treated with warfarin should avoid consuming natto because it can decrease INR. Substantial and sustained increases in serum vitamin K2 are attributed to high concentrations of vitamin K2 in natto and the long half-life of vitamin K2. In addition, natto contains living B. subtilis, which continues to synthesize vitamin K2 in the intestine for several days after natto consumption.Homma 2006, Kaneki 2001 Washing and boiling natto before eating may prevent sustained increases in vitamin K2 serum concentrations and reduce B. subtilis recovery from feces.Hitosugi 2015 Vitamin K2 is removed from some nattokinase supplements to eliminate this concern.

Adverse Reactions

Clinical trials evaluating nattokinase and enrolling small numbers of patients for up to 7 months have reported no adverse reactions.Health Canada 2012, Hitosugi 2014, Homma 2006, Hsia 2009, Kim 2008, Peng 2005 In a 4-week trial, nattokinase had no substantial effect on laboratory tests for hematologic, renal, or hepatic function. Small increases in hematocrit, platelet count, and serum cholinesterase remained within the normal range.Hitosugi 2014

The potential for increased bleeding risk with nattokinase has not been clearly substantiated. A case report described acute cerebellar hemorrhage in a 52-year-old woman with a history of ischemic stroke who was taking daily aspirin and had commenced nattokinase at 400 mg daily. Causality cannot be established because of her history.Chang 2008 However, given the theoretical risk of bleeding, nattokinase should not be taken by individuals with ischemic stroke, peptic ulcer, or coagulation disorders; by those undergoing concomitant anticoagulant therapy; or before or after surgery. Given that the vitamin K2 content of natto may offset potential bleeding risk, Health Canada has raised concern that removal of vitamin K2 from nattokinase supplements could theoretically increase bleeding risk.Health Canada 2012 Current safety data for nattokinase supplements do not address this concern.

A case report illustrates the potential harm of replacing an anticoagulant with nattokinase. A patient with a mechanical aortic valve developed thrombosis requiring valve replacement approximately a year after he substituted nattokinase 100 mg/day for warfarin.Elahi 2015

Natto can rarely cause late-onset anaphylaxis, with symptom onset occurring 4 to 15 hours after ingestion.Ikezawa 2015, Inomata 2011 Skin testing has implicated poly-gamma-glutamic acid, a product of the fermentation process, as the cause. Although the poly-gamma-glutamic acid content can be reduced in the manufacturing process, patients with a history of hypersensitivity reactions to natto should avoid nattokinase supplements.Wei 2012

Toxicology

A formulation of nattokinase was reported by the manufacturer to be nonmutagenic in the Ames test using 5 strains of bacteria, as well as in a cell-based chromosomal aberration study conducted in CHL/IU cells. Nattokinase was nontoxic in rodent studies that administered doses up to 1,000 mg/kg/day for up to 90 days. The median lethal dose in a rodent study was determined to be more than 20,000 FU/kg (more than 1,000 mg/kg).Japan Bio 2014

Index Terms

References

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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