Nattozimes

Sinopsis

Nattozimes®: A Comprehensive Encyclopedic Reference

1. Identity, Nomenclature, and Source

Nattozimes® is a proprietary, trademarked blend of fungal-derived proteolytic enzymes developed and manufactured by the National Enzyme Company (NEC), a U.S.-based enzyme technology company. Nattozimes are a proprietary blend of fungal-derived proteolytic enzymes — typically extracted from Aspergillus oryzae and Aspergillus melleus — designed to mimic the fibrinolytic activity of nattokinase, the clot-dissolving enzyme found in the Japanese fermented food natto.

Nattozimes® is a proteolytic system designed to provide activity equivalent to that expressed by nattokinase as an alternative for use in dietary supplements, and is a nutritional cardiovascular support alternative to nattokinase. The ingredient is not a single purified enzyme but rather an enzyme system (also referred to as a "protease system"), meaning it contains a combination of proteolytic activities working in concert.

National Enzyme Company developed Nattozimes® as a result of the need for a natto-like enzyme in the U.S. health supplement market. Specifically, the Food and Drug Administration (FDA) in the United States rejected nattokinase in 2003 for being misbranded. This regulatory action created a demand for a functionally equivalent, commercially acceptable alternative that could be lawfully marketed in the U.S. dietary supplement sector.

The two source organisms are filamentous fungi in the genus Aspergillus:

Aspergillus oryzae — also known as kōji mold, the organism central to Japanese, Chinese, and broader East Asian fermentation traditions.
Aspergillus melleus — a closely related fungal species also utilized for its robust protease-producing capacity.

While nattokinase is derived from Bacillus subtilis during soy fermentation, Nattozimes are non-soy, non-bacterial, and vegan-friendly, making them a suitable alternative for individuals with soy allergies or dietary restrictions.

The activity of Nattozimes® is quantified in Fibrin Units (FU), which measure the enzyme's ability to degrade the fibrin protein. Fibrin units (FU) measure the enzyme's ability to break down fibrin, a protein involved in blood clot formation. A secondary activity measurement used in some formulations is HUT (hemoglobin units on a tyrosine basis), which reflects broader proteolytic activity. Some formulations report activity as 3,000 FU (8,450 HUT) per dose, derived from Aspergillus oryzae and Aspergillus melleus.

2. Distinction from Nattokinase

To understand Nattozimes® fully, it is necessary to understand its conceptual parent, nattokinase. Nattokinase (NK) is an alkaline protease of 275 amino acid residues with a molecular weight of approximately 28 kDa; it is the most active ingredient of natto and is responsible for many favourable effects on cardiovascular health. Despite its name, nattokinase is not a kinase enzyme but a serine protease of the subtilisin family, exhibiting strong fibrinolytic activity, thrombolytic effects, and reduction of platelet aggregation and clotting.

Nattozimes® differs from nattokinase in several important ways:

Microbial origin: Nattokinase is produced by the bacterium Bacillus subtilis var. natto during soybean fermentation, whereas Nattozimes® are produced by the fungi Aspergillus oryzae and Aspergillus melleus.
Soy content: While nattokinase is famous for its potent fibrinolytic activity, its traditional sourcing presents challenges for patients with severe food sensitivities or those avoiding soy. Nattozimes® are a soy-free alternative.
Vitamin K2 content: Traditional natto and some nattokinase preparations contain significant amounts of vitamin K2 (menaquinone-7). The lack of vitamin K1 (or K2) in Nattozimes® makes it potentially safer than traditional natto food products in the context of patients on anticoagulant therapy where vitamin K intake must be carefully managed.
Regulatory status in the U.S.: The enzymes in Nattozimes® are the fermentation byproducts of the fungus species Aspergillus melleus and Aspergillus oryzae, which are already acceptable for use in dietary supplements in the United States.
Activity profile: Nattozimes® is a protease system with the same activity as nattokinase in the laboratory, known scientifically as its in vitro activity.

3. Traditional and Historical Background

Nattozimes® itself is a modern, proprietary ingredient created in the early 2000s and has no traditional or historical use as such. However, it was explicitly designed as a functional analog to nattokinase, which is derived from natto — a food with a deep historical record in Japanese culture. The traditional context for Nattozimes® is therefore inseparable from the history of natto and its parent fungi.

3.1 Natto: The Historical Food Matrix

Natto is a traditional Japanese food that has been consumed for at least 1,000 years. 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.

Natto's origins trace to at least the Heian Period (10th century), when it was first recorded in Japanese texts, said to have been created by monks fermenting soybeans in rice straw. During the Edo Period, samurai and farmers consumed natto as a "strength booster," believing it could "improve blood flow and prevent strokes." Post-WWII Japan researchers observed that regions where natto was commonly eaten had significantly lower cardiovascular mortality rates, sparking scientific interest.

Natto, a soybean product fermented by the bacterium Bacillus subtilis (natto), has been consumed as a traditional food in Japan for over a thousand years. Reports have suggested that natto contributes significantly to the longevity of Japanese people.

3.2 Aspergillus oryzae (Kōji): Historical Use

Though the enzymes in Nattozimes are derived from fungal fermentation, the Aspergillus genus has a long history of use in Asian fermentation traditions, particularly in the production of soy sauce, miso, and sake. Aspergillus oryzae, in particular, is considered a "national fungus" in Japan due to its critical role in traditional food cultures. While it was not originally cultivated for medicinal enzymes, its use has evolved with modern biotechnology to produce a wide range of enzymes for industrial and health applications.

The long history of safe use of A. oryzae by the food fermentation industry and the lack of aflatoxin production has earned it GRAS (generally recognized as safe) status from the FDA.

3.3 Discovery of Nattokinase (The Scientific Catalyst)

Before the 1980s, very little was known about the mechanism by which natto consumption led to overall cardiovascular health. In 1987, Sumi et al. discovered that natto contained a potent fibrinolytic enzyme called nattokinase (NK).

Hiroyuki Sumi placed a sample of natto on an artificial blood clot in a petri dish and watched it dissolve the clot within 18 hours. That discovery launched decades of research into the enzyme as a natural fibrinolytic agent. The first commercial nattokinase product was marketed in Japan in 1998. It was the subsequent U.S. regulatory challenges that directly prompted NEC to develop Nattozimes® as a domestically acceptable alternative.

4. Source Organisms, Production, and Regulatory Status

4.1 Aspergillus oryzae

Regulatory authorities in the United States, Europe, Japan, and many other countries have classified Aspergillus oryzae and its enzymes as GRAS for food production and supplementation. A. oryzae has consistently been concluded safe as a production organism in food manufacturing, with no evidence of pathogenic or toxigenic concerns.

Aspergillus oryzae produces a broad spectrum of enzymes (including amylase, protease, and lipase) that enhance digestive health and food breakdown. It has been widely used for centuries in fermented foods and now in enzyme supplements for digestion and overall well-being.

However, some important nuances apply to the organism's safety characterization. To ensure the safety of food-grade enzymes, the Joint FAO/WHO Expert Committee on Food Additives requires that food enzymes derived from fungal sources do not contain detectable amounts of aflatoxin B1, ochratoxin, sterigmatocystin, T-2 toxin, or zearalenone. Although no strains of A. oryzae have been found to produce aflatoxins, some strains of A. oryzae can produce mycotoxins such as cyclopiazonic acid (CPA), a neurotoxin, and 3-nitropropionic acid. Quality-controlled manufacturing processes are therefore essential.

4.2 Aspergillus melleus

Aspergillus oryzae and Aspergillus melleus are used for cardiovascular, anti-inflammatory, respiratory, and immune support applications within the Nattozimes® system. In the Natto-Serrazime® formulation, Aspergillus melleus is the specific source organism for the Serrazimes® component (the serrapeptidase-analog), while Aspergillus oryzae is the primary source for Nattozimes®. Natto-Serrazime is a dietary supplement formulation that blends Nattozimes® (from Aspergillus oryzae) and Serrazimes® (from Aspergillus melleus).

4.3 Manufacturing and Stability

The Aspergillus-derived enzymes have been tested using the TNO Intestinal Model (TIM), a highly advanced, computer-controlled system that simulates the exact pH, temperature, and peristaltic movements of the human gastrointestinal tract. The TIM studies demonstrated that both Nattozimes® and Serrazimes® exhibit remarkable stability. This gastrointestinal stability is a significant practical advantage, as some enzyme supplements are degraded before they can be absorbed.

Through advanced bio-engineering, this fungal extract perfectly mimics the in vitro fibrinolytic activity of bacterial nattokinase, allowing it to efficiently degrade the fibrin protein mesh that forms blood clots. Some preparations of Nattozimes® specify that the specimen is cultured in allergen-free media (glucose), which may reduce the risk of residual allergenic material in the finished enzyme preparation.

5. Key Constituents and Mechanisms of Action

5.1 Enzyme Composition

Nattozimes® is not a single isolated enzyme but a proteolytic enzyme system — a blend of multiple serine and other proteases produced during the controlled fermentation of Aspergillus oryzae and Aspergillus melleus. The enzymes in Nattozimes® hydrolyze peptide bonds in a manner that gives them a similar in vitro fibrinolytic activity as nattokinase.

The primary functional activities of Nattozimes® are:

Fibrinolytic activity — direct degradation of the fibrin protein matrix.
Thrombolytic activity — dissolution or prevention of blood clots (thrombi).
General proteolytic activity — broader protein-digesting capability.

Studies have shown that Nattozimes® and Serrazimes® have the same thrombolytic and fibrinolytic activities as the popular enzyme products nattokinase and serrapeptidase; therefore, they can be used as functional substitutions for these applications.

5.2 Mechanism of Fibrinolysis

The established mechanism by which nattokinase — and by extension its functional analog Nattozimes® — exerts its fibrinolytic effects is well characterized in the peer-reviewed literature. Nattokinase can break down blood clots by directly hydrolyzing fibrin and plasmin substrate, converts endogenous prourokinase to urokinase (uPA), degrades PAI-1 (plasminogen activator inhibitor-1), and increases tissue plasminogen activator (t-PA), which supports fibrinolytic activity.

These enzyme blends are formulated to have thrombolytic (clot-dissolving) and fibrinolytic (fibrin-degrading) properties. Fibrin is an insoluble protein involved in blood clot formation, and excessive fibrin buildup can contribute to cardiovascular disease, poor circulation, and inflammation.

The biological effects of nattokinase are similar to those of plasmin, which is a naturally-occurring enzyme that degrades fibrin. By acting on multiple nodes of the coagulation cascade simultaneously — directly on fibrin, through PAI-1 inhibition, and through upregulation of t-PA — these enzymes have a potentially multi-pronged antithrombotic effect compared to agents that act at only one site.

Regarding antihypertensive activity, the related compound nattokinase has documented ACE (angiotensin-converting enzyme) inhibitory action. Nattokinase has natural ACE inhibition activity. In a double-blind, randomized, placebo-controlled trial in subjects with pre-hypertension or stage 1 hypertension, nattokinase was shown to affect blood pressure.

5.3 Systemic Bioavailability

A key pharmacokinetic question for any orally administered enzyme supplement is whether it survives gastrointestinal conditions and reaches systemic circulation intact. For the reference compound nattokinase, orally supplemented nattokinase is detectable in serum, peaking at approximately 11–15 hours after ingestion (one 100 mg dose), indicating that oral supplementation is an effective way of delivering this enzyme to tissues and that it remains bioactive after digestion. A separate pharmacokinetic study found that peak serum concentrations were reached at 13.3 ± 2.5 hours after dosing.

For Nattozimes® specifically, the TIM (TNO Intestinal Model) studies demonstrated that the enzymes exhibit remarkable gastrointestinal stability, providing evidence of survivability through the digestive process, although direct human pharmacokinetic studies of the Nattozimes® enzyme system in isolation have not been identified in the indexed literature.

6. Scientific Evidence by Area of Use

Critical caveat: Human clinical trials have been conducted on nattokinase (from Bacillus subtilis), not on Nattozimes® as a separate ingredient. The extrapolation of nattokinase clinical evidence to Nattozimes® is predicated on their claimed equivalence in vitro. Studies have shown that Nattozimes® and Serrazimes® have the same thrombolytic and fibrinolytic activities as the popular enzyme products nattokinase and serrapeptidase; therefore, they can be used as a 1:1 substitution for these applications. However, this equivalence has been demonstrated in vitro, and direct clinical trials specifically testing Nattozimes® in humans are not currently identified in the peer-reviewed literature. The following clinical evidence therefore pertains to the nattokinase reference compound, with the in vitro equivalence claim stated explicitly.

6.1 Cardiovascular Health — Fibrinolysis and Antithrombotic Effects

Evidence type: Multiple animal studies, several human clinical trials, one systematic review and meta-analysis.

Since the fibrinolytic activity of nattokinase was discovered in the 1980s, a variety of animal-based studies have been made to support its strong thrombolytic activity. Even a single dose of oral nattokinase was shown to enhance fibrinolysis and anticoagulation in humans.

Nattokinase positively affected various blood rheological parameters in a dose-dependent manner, including platelet aggregation, red blood cell aggregation, whole blood viscosity and vascular tension, which could be considered indicative of improved blood flow.

A study found that 4,000 FU of nattokinase (from two enteric-coated capsules) taken daily for two months decreased levels of blood-clotting factors — fibrinogen, factor VII, and factor VIII — by approximately 7% to 19% in healthy people as well as those with cardiovascular risk factors or those undergoing dialysis. Blood pressure remained stable except for a slight decline of −3.73 mmHg in systolic blood pressure.

A venous thrombosis prevention study used nattokinase in long-haul flight passengers. Some research indicates that supplements containing nattokinase may reduce the risk of a blood clot in the legs. The regimen in this study consisted of 300 mg of the supplement two hours before a flight followed by another 300 mg six hours after the flight.

Strength of evidence: Preliminary to moderate. Human evidence for fibrinolytic biomarker improvements is supported by several trials, but large randomized controlled trials with hard clinical endpoints (myocardial infarction, stroke, DVT) are not yet available.

6.2 Blood Pressure (Antihypertensive Effects)

Evidence type: Multiple randomized controlled trials (RCTs), one systematic review and meta-analysis (2023).

A randomized, double-blind, placebo-controlled, multicenter North American trial by Errichi et al. evaluated nattokinase in a hypertensive population. A randomized, double-blind, placebo-controlled, parallel-arm clinical study was performed to evaluate nattokinase (NSK-SD). Based on the results from previous studies on Asian populations, 79 subjects were enrolled upon screening for elevated blood pressure (BP; systolic BP ≥130 or diastolic BP ≥90 mmHg) who consumed placebo or 100 mg nattokinase/day for the 8-week study duration.

The most comprehensive synthesis of this evidence comes from a 2023 systematic review and meta-analysis published in Reviews in Cardiovascular Medicine: Six studies were eligible for quantitative analysis with 546 participants. The overall methodological quality of included studies was high. Nattokinase supplementation significantly reduced systolic blood pressure (MD = −3.45, 95% CI: −4.37 to −2.18, p < 0.00001) and diastolic blood pressure (MD = −2.32, 95% CI: −2.72 to −1.92, p < 0.00001) as compared to placebo.

This study further supports that nattokinase can be used as an effective adjunctive therapy for hypertension.

Strength of evidence: Moderate. Multiple RCTs consistently show modest but statistically significant reductions in both systolic and diastolic blood pressure, supporting use as an adjunctive intervention. Effect sizes are modest (approximately 3–4 mmHg systolic reduction).

6.3 Atherosclerosis and Lipid Profile

Evidence type: Large retrospective clinical study (1,062 participants), early-phase RCTs, one meta-analysis.

A significant clinical study examined nattokinase at 10,800 FU/day in a large population. In this clinical study involving 1,062 participants, the objective was to examine the efficacy of NK in atherosclerosis and hyperlipidemia and safety at the dose of 10,800 FU/day after 12 months of oral administration. Various factors, including lower doses that influence NK pharmacological actions, were also investigated. NK at a dose of 10,800 FU/day effectively managed the progression of atherosclerosis and hyperlipidemia with a significant improvement in the lipid profile.

These findings provide clinical evidence on the effective dose of NK in the management of cardiovascular disease and challenge the recommended dose of 2,000 FU per day.

However, the 2023 meta-analysis of lower-dose RCTs found a more complex picture. Overall, the study involving 607 participants found that nattokinase might have a beneficial influence on blood pressure, but no significant improvements were observed in blood lipids and blood glucose. Despite the high methodological quality of eligible studies in this meta-analysis, the total number of studies examining any cardiovascular risk factor was small, so these findings should be interpreted cautiously.

The apparent discrepancy between large-dose and low-dose studies is notable. Meta-analyses conclude NK can be an adjunct for hypertension but that low-dose trials generally fail to show consistent lipid lowering or clear clinical antithrombotic benefit, while individual trials report favorable biomarker changes.

Strength of evidence: Mixed and dose-dependent. High-dose (10,800 FU/day) administration over 12 months showed significant improvements in lipid profiles and atherosclerosis markers in a large observational study, but lower-dose RCTs have not consistently replicated lipid-lowering effects. The meta-analytic evidence does not support lipid-lowering at standard doses.

6.4 Digestive and Systemic Protein Metabolism

As a proteolytic enzyme system, Nattozimes® is also positioned for digestive support. This product works in the digestive system to support protein digestion to systemically support joints, muscles, circulation, heart, and immunity.

The concept of using proteolytic enzymes for health dates back to traditional papaya (papain) and pineapple (bromelain) enzyme use in folk medicine for inflammation and digestion. However, direct human clinical evidence specifically for Nattozimes® in digestive applications has not been identified in the peer-reviewed literature.

Strength of evidence: Theoretical and indirect. The general principle of fungal protease activity on ingested proteins is mechanistically plausible, but specific clinical evidence for Nattozimes® in this context is absent from the indexed literature.

6.5 Potential Neuroprotective Effects

In both animal and human studies, nattokinase has demonstrated antihypertensive, anti-atherosclerotic, lipid-lowering, antiplatelet/anticoagulant, and neuroprotective actions, all of which have relevance to the prevention and treatment of CVD. The neuroprotective aspects are attributed primarily to improved cerebrovascular circulation rather than direct neuronal effects, but this area remains less studied in humans than the cardiovascular applications.

Strength of evidence: Preliminary; primarily animal and in vitro data. Human evidence specifically addressing neuroprotection is limited.

7. Body Systems and Health Areas

Based on the documented mechanisms and available clinical research, Nattozimes® is associated with the following body systems:

Cardiovascular system: Nattozimes® is a proteolytic system designed to provide activity equivalent to nattokinase, with high potency fibrinolytic activity comparable to nattokinase, providing nutritional systemic support for the cardiovascular system.
Circulatory system / Blood coagulation: These enzyme blends are formulated to have thrombolytic and fibrinolytic properties. Fibrin is an insoluble protein involved in blood clot formation, and excessive fibrin buildup can contribute to cardiovascular disease, poor circulation, and inflammation.
Musculoskeletal system: This product works in the digestive system to support protein digestion to systemically support joints, muscles, circulation, heart, and immunity.
Immune system: Included as a targeted area in the manufacturer's stated applications for the enzyme system.
Digestive system: The proteolytic activity of the enzymes can support general protein digestion in the gastrointestinal tract.

8. Dosage Forms and Reported Dosages

8.1 Commercially Available Forms

Nattozimes® is available as an ingredient in:

Vegetarian capsules — the most common delivery format for standalone Nattozimes® products.
Blended formulas — combined with other ingredients such as hawthorn berries, capsicum, dandelion leaf, and resveratrol (e.g., Nature's Sunshine Nattozimes Plus®).
Combination enzyme formulas — paired with Serrazimes® (e.g., Designs for Health Natto-Serrazime™).

8.2 Dosages Reported in Product Literature and Studies

The following dosages are drawn from product labeling and published sources:

Each capsule (Nature's Sunshine Nattozimes Plus) contains 165 mg of nattozimes material, providing 2,500 fibrin units (FU).
Swanson Triple-Strength Nattozimes® provides 195 mg per capsule as a proprietary blend.
One capsule of Natto-Serrazime™ (Designs for Health) provides 129 mg of Nattozimes® (4,516 FU) and 33 mg of Serrazimes® (20,000 units of enzymatic activity).
Some formulations provide 3,000 FU (8,450 HUT) per dose from Aspergillus oryzae and Aspergillus melleus.

8.3 Dosages Used in Nattokinase Clinical Studies (Reference Compound)

Since nattokinase and Nattozimes® are claimed to be 1:1 equivalent in vitro, the clinical dosages studied for nattokinase provide relevant reference points:

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. Clinical studies to guide safe and effective nattokinase dosing are lacking.
Most commonly, 100 mg (2,000 fibrinolytic units [FU]) of nattokinase are taken by mouth daily. This dose is reported to not cause adverse effects by the European Food Safety Authority (EFSA). Limited research using higher doses also reported no adverse effects. People living in China have taken 540 mg (10,800 FU) of nattokinase daily for a year, and adults living in the United States have taken 552 mg of nattokinase daily for four weeks without any reported adverse effects.
In a clinical study involving 1,062 participants, a dose of 10,800 FU/day administered for 12 months effectively managed the progression of atherosclerosis and hyperlipidemia.
The reported suggested use for Nattozimes Plus is 1 capsule between meals twice daily on an empty stomach.

9. Safety Considerations and Drug Interactions

9.1 General Safety Profile

No notable adverse events were reported in all studies due to intake of nattokinase in the 2023 meta-analysis of six RCTs. Although no adverse side effects have been observed from the consumption of nattokinase in various human trials, including clinical trials, the safety profile for NK, including the effect of repeat doses, acute toxicity, and genotoxicity, still needs to be thoroughly addressed.

The EFSA has evaluated multiple enzymes derived from Aspergillus oryzae in food applications. Genotoxicity tests did not raise a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level (NOAEL) of 1,000 mg TOS/kg body weight per day, the highest dose tested.

9.2 Bleeding Risk

The most clinically significant safety consideration for Nattozimes® is its fibrinolytic activity — the same mechanism that confers its proposed benefits also creates a potential bleeding risk:

Nattokinase use should be avoided in individuals with ischemic stroke, peptic ulcer, and coagulation disorders, as well as before and after surgery.

Because Natto-Serrazime™ (which contains Nattozimes®) exerts potent fibrinolytic and blood-thinning effects, it must be used with caution. This supplement is strongly contraindicated for individuals with active bleeding disorders (such as hemophilia), active stomach ulcers, or those scheduled for surgery within the next two weeks.

9.3 Drug Interactions

Anticoagulants and antiplatelet drugs: Nattokinase has pharmacologic effects that could increase the risk of bleeding when administered with anticoagulant and antiplatelet agents. 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). 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.

High concentrations of vitamin K2 in natto (a traditional Japanese food) can reduce the international normalized ratio (INR) when co-administered with warfarin; this may also occur with nattokinase supplements if vitamin K2 is not removed during the production process. Because Nattozimes® is derived from Aspergillus fungi and not from soy fermentation, it does not inherently contain vitamin K2, distinguishing it from nattokinase preparations that may still carry residual K2.

Anticoagulants such as warfarin or heparin, when used with nattozimes, create a pronounced synergistic effect. Fibrinolysis activity is greatly increased, clotting time is prolonged, and the risk of internal and peripheral bleeding becomes noticeable.

Antihypertensive drugs: Interaction with antihypertensive drugs may trigger dizziness or hypotension, given the documented blood pressure-lowering effects of nattokinase-class enzymes.

9.4 Allergy Risk

Products containing Nattozimes® should not be used by individuals who are allergic to Aspergillus.

The EFSA has noted a general consideration for Aspergillus oryzae-derived enzymes: similarity of the amino acid sequence to those of known allergens was searched, and one match to a respiratory allergen was found (an amylase from another strain of A. oryzae). The Panel considered that, under the intended conditions of use, the risk of allergic sensitization and elicitation reactions by dietary exposure cannot be excluded, but the likelihood is considered to be low.

9.5 Special Populations

Consultation with a healthcare practitioner is advised prior to use if pregnant or breastfeeding, or if taking drugs affecting platelet aggregation, or in cases of genetic or acquired bleeding tendencies. Information regarding safety and efficacy in pregnancy and lactation is lacking.

9.6 Dosage Instability and Standardization Concerns

Unlike prescription anticoagulants, nattokinase supplements have inconsistent potency, lack standardized dosing, and are not monitored through reputable lab tests. These factors could make their blood-thinning effects unpredictable, increasing the risk of either too much or too little clot breakdown. This concern applies equally to Nattozimes®-containing products, where potency may vary across manufacturers and formulations.

10. Combination Products and Formulations

Nattozimes® is found in two main types of supplement products:

Nature's Sunshine Nattozimes Plus®: This product is an alternative to nattokinase, a protease compound formed during the soybean fermentation process. While natto has been consumed in Japan for thousands of years, only recently have scientists realized the health benefits of nattokinase. Because nattokinase is often expensive, unavailable or unstable, NSP designed Nattozimes Plus. In addition to protease enzyme complexes, it contains other heart-supporting herbs, including hawthorn berries, capsicum fruit, dandelion leaf and the nutrient resveratrol.

Designs for Health Natto-Serrazime™: Nattozimes® (derived from the fungi Aspergillus oryzae and Aspergillus melleus) and Serrazimes®, which are used for cardiovascular, anti-inflammatory, respiratory, and immune support. This product pairs the nattokinase-analog with a serrapeptidase-analog enzyme complex, aiming for combined anti-fibrinolytic and anti-inflammatory effects.

11. Evidence Gaps and Research Limitations

Several important evidence gaps limit definitive conclusions about Nattozimes®:

No direct human clinical trials of Nattozimes® itself: All clinical data are from nattokinase studies. The in vitro equivalence of Nattozimes® and nattokinase does not guarantee equivalent in vivo bioactivity, bioavailability, or clinical outcomes.
Limited number of high-quality RCTs even for nattokinase: Despite the high methodological quality of eligible studies in the 2023 meta-analysis, the total number of studies examining any cardiovascular risk factor was small, so these findings should be interpreted cautiously.
Dose-response uncertainty: Randomized evidence supports modest blood-pressure lowering with nattokinase and some favorable shifts in clotting biomarkers, but high-quality randomized proof that NK lowers LDL cholesterol or prevents clinical clotting events is lacking or inconsistent and appears sensitive to dose and co-interventions. Larger, well-controlled trials with standardized dosing and clinical endpoints are needed.
Long-term safety data: The safety profile for nattokinase, including the effect of repeat doses, acute toxicity, and genotoxicity, still needs to be thoroughly addressed in the formal literature, and this limitation extends to Nattozimes® as well.