Serrapeptase
Common Name(s): Serralysin, Serrapeptasa (Spanish), Serrapeptase (INN), Serrapeptasi (Italian), Serrapeptidase, Serratia peptidase, Serratiopeptidase
Medically reviewed by Drugs.com. Last updated on Jan 23, 2023.
Clinical Overview
Use
Serrapeptase is promoted as an anti-inflammatory and mucolytic agent, but efficacy for either use has not been well established. Two randomized controlled trials reported no reduction in swelling caused by sprained ankles, and results of studies evaluating use for pain and swelling after dental surgery are conflicting. Two clinical trials evaluating serrapeptase as a mucolytic agent also reported conflicting results. Serrapeptase has also been investigated for adjunctive use to antibiotics to enhance antibiotic activity; however, evidence is limited to 2 low-quality clinical studies.
Dosing
The usual adult dosage of serrapeptase is 10 mg 3 times daily (maximum dose, 60 mg/day) taken 2 hours after meals, with typical treatment durations of up to 1 week when used as an anti-inflammatory agent and up to 4 weeks when used as a mucolytic agent.
Contraindications
None known.
Pregnancy/Lactation
Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.
Interactions
None well documented.
Adverse Reactions
Serrapeptase was well tolerated in short-term clinical trials, but long-term safety has not been evaluated. Rare, serious adverse effects reported with serrapeptase include eosinophilic pneumonitis, bullous pemphigoid, hemorrhage in a patient with Behçet disease, and possibly Stevens-Johnson syndrome.
Toxicology
No data.
Source
Serratiopeptidase is an extracellular proteolytic enzyme produced by Serratia marcescens ATCC 27117 (formerly Serratia strain E-15).Bhagat 2013, Longhi 2008 In the 1960s, the bacterium was isolated from the intestines of the silkworm Bombyx mori.Bhagat 2013 This strain of Serratia performs an important function in the life cycle of the silkworm. The serrapeptase that it secretes dissolves the silkworm's cocoon, enabling it to emerge as a moth.
History
In 1968, serrapeptase was introduced to the Japanese pharmaceutical market for a broad range of indications, including use as an anti-inflammatory agent for swelling due to surgery or trauma; for the treatment of chronic sinusitis and breast engorgement; as a mucolytic agent in patients with bronchitis, asthma, and tuberculosis; and for the clearing of bronchial secretions after surgery.Takeda 2011 In 2011, the manufacturer voluntarily recalled its serrapeptase anti-inflammatory preparation from the Japanese market after postmarketing clinical trials found it ineffective for anti-inflammatory use.Takeda 2011 In India, serrapeptase is marketed alone or in combination with a nonsteroidal anti-inflammatory drug (NSAID), including diclofenac and aceclofenac.Joshi 2012 In 2014, serrapeptase was licensed as a natural health product in Canada.Health Canada 2018
Chemistry
Serrapeptase is an extracellular metalloendopeptidase composed of 470 amino acids, with a molecular weight of approximately 50,000 kDa.Maeda 1995 The active site of the enzyme, which contains a zinc atom, hydrolyzes nonterminal peptide linkages of polypeptides. Maximal proteolytic activity occurs at 40°C (104°F) and at a pH of approximately 8 (range, 6 to 10).Baumann 2013, Bhagat 2013 Maintaining the temperature at 55°C (131°F) for 15 minutes inactivates the enzyme.Selan 1993 Serrapeptase is manufactured by fermentation technology in which the enzyme is purified from bacterial culture. According to the Japanese Pharmacopoeia, 1 unit of serrapeptase produces 5 mcg of tyrosine per minute from 5 mL of substrate solution, with 2,000 to 2,600 units equivalent to 1 mg of serrapeptase.Yamaguchi 2009 A dose of 10,000 to 20,000 units is equivalent to 5 to 10 mg of serrapeptase.
Serrapeptase is a member of the serralysin subfamily of proteases secreted by gram-negative bacteria with similar physiochemical properties.Azzopardi 2013, Baumann 2013, Maeda 1995 Serratia proteases are considered major virulence factors. Pathogenic effects in infected hosts include enhanced vascular permeability via activation of Hageman factor, inflammation via inactivation of human plasma protease inhibitors such as alpha-1-protease inhibitor and alpha-2-macroglobulin (which regulate the kallikrein-kinin cascade), and tissue degradation (via breakdown of fibronectin and collagen).Azzopardi 2013, Häse 1993, Maeda 1995
Uses and Pharmacology
A systematic review identified 17 published clinical studies evaluating serrapeptase for a broad range of indications.Bhagat 2013 Most of these studies had poor methodology according to grading by the Scottish Intercollegiate Guidelines Network checklist. Limitations included small sample size, poorly defined enrollment criteria and outcomes, unclear statistical methods, short duration, and failure of some studies to report the dose and duration of therapy. Two low-quality studies evaluated serrapeptase as an adjunct to increase the penetration of antimicrobial drugs into sites of infection. Other conditions evaluated in the low-quality studies included postoperative or traumatic swelling, carpal tunnel syndrome, secretory otitis media, and chronic airway disease, but the resulting evidence was insufficient to evaluate the efficacy of serrapeptase for these indications. Among the 17 clinical studies identified, 5 were randomized controlled trials published in English and with a low risk of bias and are summarized in the following sections.Al-Khateeb 2008, Chopra 2009, Kee 1989, Mazzone 1990, Tachibana 1984
Adjunct to antibiotics
Animal and in vitro data
Serrapeptase has the potential to enhance the activity of antibiotics by inhibiting the production of biofilms and adhesion to host cells by pathogenic bacteria. In an in vitro study involving strains of Pseudomonas aeruginosa and Staphylococcus epidermidis obtained from infected prosthetic joints, serrapeptase reduced biofilm formation and enhanced the activity of ofloxacin against these pathogens in sessile culture.Selan 1993 In another in vitro study, serrapeptase reduced the ability of Listeria monocytogenes to form biofilms, invade host cells, and lyse red blood cells.Longhi 2008 Mass spectrometry analysis found that serrapeptase inhibited the production of proteins necessary for L. monocytogenes to invade host cells. Additional studies reported a similar effect of serrapeptase on Staphylococcus aureus and S. epidermidis, with a reduction in biofilm formation and inhibition of specific cell surface proteins necessary for virulence.Artini 2013, Papa 2013 Inhibition of fibrinolysis by serrapeptase is proposed to enhance the penetration of antibiotics to sites of infection.Kakinuma 1982, Mecikoglu 2006
In a rat model of prosthetic joint infection with S. epidermidis, 1 group of animals was untreated, another received ofloxacin alone, and the third received ofloxacin and serrapeptase injected into the affected joint. Incidences of persistent infection were 63.2%, 37.5%, and 5.6%, respectively.Mecikoglu 2006
Clinical data
Two low-quality studies evaluated the ability of serrapeptase to increase absorption of antibiotics in bone and joint infections, as well as into pulmonary tissue in lung cancer patients undergoing thoracotomy.Bhagat 2013, Koyama 1986, Okumura 1977 An open-label trial in 8 patients with bone or joint infections found that serrapeptase tended to increase the penetration of sulbenicillin into exudates.Okumura 1977 In the study of thoracotomy patients, the ratio of cefotiam in pulmonary tissue to blood was 29% with cefotiam alone and 44% with cefotiam plus serrapeptase (P<0.05).Koyama 1986 These preliminary studies suggest that serrapeptase has the potential to enhance the absorption of antibiotics into infected tissues.
Antiatherosclerotic effects
Although serrapeptase has been promoted to prevent atherosclerosis, evidence to support use is only anecdotal.Bhagat 2013
Anti-inflammatory activity/Postoperative pain and swelling
Anti-inflammatory activity of serrapeptase has been attributed to hydrolysis of inflammatory mediators such as bradykinin, histamine, and serotonin.Bhagat 2013 However, experimental evidence to support this mechanism has not been published.
Animal and in vitro data
The results of rat studies investigating the anti-inflammatory activity of oral serrapeptase are conflicting. In a rat model of acute inflammation due to scalding, Serratia protease inhibited activation of fibrinolysis; this activity was related to the enzyme's proteolytic activity.Kakinuma 1982 In a study evaluating carrageenan-induced paw edema for acute inflammation and cotton pellet–induced granuloma for subacute inflammation, serrapeptase demonstrated dose-dependent anti-inflammatory activity that was synergistic with aspirin.Viswanatha 2008 In a study evaluating formalin-induced paw edema, serrapeptase demonstrated dose-dependent inhibition of acute and chronic inflammation that was comparable with that of diclofenac.Jadav 2010 In a later study evaluating carrageenan-induced paw edema, a low dose of diclofenac reduced edema formation, but serrapeptase did not reduce edema and did not demonstrate a synergistic effect with diclofenac.Health Canada 2018
Following development of a wound healing formulation incorporating metronidazole and serratiopeptidase into alginate-based microspheres in vitro, wound healing performance of the experimental formulations was compared with marketed product in rabbits; experimental data suggest wound healing properties with serratiopeptidase and metronidazole in full thickness wounds.Rath 2011
Clinical data
Two Japanese postmarketing studies found serrapeptase to be ineffective for relief of sprained ankle swelling. Synopses provide limited information regarding these unpublished multicenter, double-blind, parallel-group trials in which patients were randomized to receive serrapeptase 10 mg 3 times daily after meals or placebo for 1 week. The first study, completed in 2002, enrolled 301 patients. The second study, completed in 2009, enrolled 252 patients. In both studies, there was no difference between serrapeptase and placebo for the primary end point (rate of change in the injured ankle joint sectional area on computed tomography scan).Takeda 2011, Takeda 2011
Three randomized, double-blind clinical trials evaluated serrapeptase for relief of pain and swelling after extraction of impacted third molars. Although 1 study suggested that adding serrapeptase to acetaminophen may have some benefit over acetaminophen alone, 2 studies suggested that serrapeptase is ineffective.Al-Khateeb 2008, Chopra 2009, Murugesan 2012 In a crossover study, 24 patients with symmetrically impacted mandibular third molars had their molars removed in 2 sessions. After each session, patients were randomized to receive either acetaminophen 1,000 mg plus serrapeptase 5 mg or acetaminophen 1,000 mg plus placebo, with both regimens taken 3 times daily for 7 days. The addition of serrapeptase to acetaminophen reduced pain intensity on postoperative days 1 to 3 and reduced cheek swelling on days 2, 3, and 7.Al-Khateeb 2008 In a second study, 150 patients were randomized to receive ibuprofen 600 mg, acetaminophen 1,000 mg, betamethasone 0.5 mg, serrapeptase 20 mg, or placebo 3 times daily for 7 days after third molar extraction. While ibuprofen and betamethasone reduced postoperative pain and swelling, results with serrapeptase did not differ from those with placebo for either outcome.Chopra 2009 A third study randomized 110 patients to receive dexamethasone 1 mg or serrapeptase 10 mg 3 times daily for 3 days after third molar extraction. Dexamethasone was more effective than serrapeptase in reducing pain and swelling.Murugesan 2012 In a 5-day study of patients undergoing surgical removal of mandibular third molars (N=100), serrapeptase (10 mg twice daily) outperformed methylprednisolone (4 mg 3 times daily) in improving swelling and trismus, but was less effective in controlling pain (moderate analgesic activity).Chappi 2015 A systematic review and meta-analysis of studies identified 5 studies (N=474) investigating the effect of serrapeptase after surgical removal of impacted molars. Pooled data from 2 studies reporting on facial swelling found serrapeptase to be less effective than corticosteroids. In contrast, serrapeptase was more effective for improving trismus (lock jaw). The quality of studies for both outcomes was graded as low. Data could not be pooled for pain, as each study utilized a different comparator.Sivaramakrishnan 2018
A double-blind, placebo-controlled trial evaluated use of serrapeptase in 174 patients undergoing Caldwell-Luc antrostomy for chronic sinusitis. Patients were randomized to receive placebo or serrapeptase 10 mg 3 times daily from the day before until 5 days after surgery. Swelling was evaluated by measuring the distance from ear to nose and from eye to mouth. Serrapeptase significantly reduced buccal swelling compared with placebo, as measured by the distance from ear to nose (P<0.05). Maximal swelling measured from ear to nose, which occurred 24 hours after surgery, was approximately 2 mm less with serrapeptase than placebo (P<0.01). There was no significant difference between serrapeptase and placebo for swelling, as measured by the distance from eye to mouth.Tachibana 1984
A randomized, open-label, comparator phase 4 trial conducted in 75 adults undergoing orthopedic surgery for reduction of fracture observed a reduction in symptoms of inflammation (erythema, local irritation, wound discharge, edema, tenderness, and pain) with administration of serrapeptase (5 mg for 10 days) but less than that with trypsin/chymotrypsin.Chandanwale 2016
Alzheimer disease
Animal data
In an Alzheimer rat model, both low and high doses of serrapeptase significantly improved brain cholinesterase activity, brain-derived neurotropic factor, transforming growth factor beta, insulinlike growth factor 1, and Fas apoptotic antigen compared with untreated Alzheimer controls (P<0.05). High-dose, but not low-dose, serrapeptase significantly improved brain interleukin 6 levels as well as gene expression of A disintegrin and metalloproteinase domains 9 and 10 (ADAM9 and ADAM10), which decrease amyloidogenesis.Fadl 2013
Breast engorgement
Clinical data
A 1989 randomized, placebo-controlled clinical trial evaluated serrapeptase 30 mg/day for 3 days in women with postpartum breast engorgement. On a composite score that considered swelling, induration, and impaired breastfeeding, the incidence of marked or moderate improvement was 85.7% with serrapeptase and 60% with placebo (P<0.05).Kee 1989 A 2016 updated Cochrane review of best treatments for breast engorgement during lactation identified only the above study from 1989 that investigated the use of serrapeptase.Mangesi 2016
Mucolytic activity
Clinical data
Serrapeptase appears to reduce the viscosity of both sputum and nasal mucus. An open-label study in 29 patients with chronic bronchitis and bronchiectasis reported that 4 weeks of treatment with serrapeptase reduced sputum volume, percent solid component, elasticity, viscosity, and neutrophil concentration.Nakamura 2003 A similar study in patients with chronic sinusitis found that 4 weeks of treatment with serrapeptase reduced nasal viscosity but not elasticity.Majima 1990
In a double-blind, randomized trial, 193 patients with acute or chronic ear, nose, and throat (ENT) disorders received 7 or 8 days of therapy with placebo or serrapeptase 10 mg 3 times daily after meals. Outcomes, evaluated in only 140 patients completing the study, included pain, quantity of secretions, purulence of secretions, difficulty swallowing, nasal obstruction, nasal dysphonia, anosmia, and temperature. An ENT specialist, blind to treatment allocation, rated outcomes on a 4-point scale. Scores for pain and quantity of secretions each significantly improved by approximately 1 point (P<0.001 for both) with serrapeptase. Purulence of secretions and difficulty swallowing each significantly improved by approximately 0.5 points (P<0.001 for both) with serrapeptase. Additional outcomes that improved significantly with serrapeptase over placebo included nasal dysphonia (P<0.001), nasal obstruction (P<0.001), anosmia (P<0.001), and temperature (P<0.01).Mazzone 1990
Takeda Pharmaceuticals conducted a postmarketing study evaluating serrapeptase as a mucolytic agent in chronic bronchitis. A synopsis provides limited information regarding this unpublished multicenter, double-blind, parallel-group trial in which 311 patients with difficulty expectorating were randomized to receive serrapeptase 10 mg 3 times daily after meals or placebo for 2 weeks. There was no difference between serrapeptase and placebo for the primary end point (difficulty expectorating).
Serrapeptase also did not outperform placebo on secondary end points, including frequency of sputum, frequency of coughing, and global improvement.Takeda 2011
Periodontal gel delivery systems
Preliminary studies describe the development of topical products that pair serrapeptase with either ciprofloxacin or tetracycline for the management of periodontal disease.Maheshwari 2006, Singh 2014
Dosing
GI absorption of large proteins such as serrapeptase may be impeded by a number of factors, including hydrophilicity, large molecular weight, chemical instability, nonspecific binding to biologic surfaces, and metabolism by intestinal enzymes.Kv 2008 Some oral formulations of serrapeptase have an enteric coating intended to protect it from degradation in the stomach and enable dissolution in the more alkaline environment of the small intestines.Bhagat 2013 Although a study in rats reported GI absorption of serrapeptase into the systemic circulation in an active form, studies evaluating GI absorption in humans are lacking.Moriya 1994 A Canadian natural health product monograph notes that enteric-coated products are the only acceptable formulation of serrapeptase.Health Canada 2018
A dose of serrapeptase 5 to 10 mg is equivalent to 10,000 to 20,000 serrapeptase units.Yamaguchi 2009 For use as a natural health product in Canada, the maximum dose of serrapeptase is 60 mg/day (120,000 serrapeptase units/day).Health Canada 2018
Serrapeptase dosing recommendations are based on published clinical trials as well as postmarketing trials conducted by Takeda Pharmaceuticals. To reduce swelling and pain, a typical serrapeptase dosage has been 10 mg 3 times daily for up to 1 weekTachibana 1984, Takeda 2011, Takeda 2011; in studies of patients with pain and swelling following surgical removal of third molars, dosages of serrapeptase ranged from 20 to 60 mg daily, for durations of 3 to 7 days.Chappi 2015, Chopra 2009, Murugesan 2012 To reduce symptoms of ENT disorders or chronic bronchitis as a mucolytic enzyme, serrapeptase 10 mg 3 times daily for 1 to 2 weeks has been studied.Mazzone 1990, Takeda 2011 Durations of 4 weeks have been reported when used as a mucolytic agent.Majima 1990, Nakamura 2003
For serratiopeptidase products providing more than 60,000 units/day, a health professional should be consulted for use longer than 1 week; for serratiopeptidase products providing 60,000 units or less per day, a health professional should be consulted for use longer than 4 weeks.Health Canada 2018 Serratiopeptidase should be taken 2 hours after a meal.Bhagat 2013, Health Canada 2018
In 1968, serrapeptase was approved in Japan for use as a mucolytic and anti-inflammatory agent at a dosage of 10 mg 3 times daily after meals for 1 to 2 weeks. In 2011, the manufacturer voluntarily recalled its serrapeptase anti-inflammatory preparation from the Japanese market after postmarketing clinical trials found it ineffective for anti-inflammatory use.Takeda 2011, Takeda 2011, Takeda 2011, Takeda 2011
Pregnancy / Lactation
Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.
Interactions
None documented. Serrapeptase may increase the risk of bleeding if coadministered with anticoagulants or antiplatelet drugs.Bhagat 2013
Adverse Reactions
Serrapeptase was well tolerated in short-term clinical trials enrolling more than 1,400 patients, with an incidence of adverse effects similar to that with placebo.Al-Khateeb 2008, Chopra 2009, Mazzone 1990, Tachibana 1984, Takeda 2011, Takeda 2011, Takeda 2011 Hypersensitivity reactions and gastric pain have been reported.Health Canada 2018, Mazzone 1990 With treatment lasting only 1 to 2 weeks, these studies do not provide long-term safety data for serrapeptase.Bhagat 2013 In Japan, at least 4 cases of eosinophilic pneumonia have been reported with serrapeptase.Hirahara 1989, Kai 2009, Sasaki 2000, Yokota 1992 Single case reports of serious adverse effects associated with serrapeptase include bullous pemphigoid, hemorrhage in a patient with Behçet disease, and Stevens-Johnson syndrome.Celik 2013, Moitra 2014, Shimizu 1999 The case of Stevens-Johnson syndrome occurred with a combination product containing serrapeptase and diclofenac, an NSAID reported to cause Stevens-Johnson syndrome.Mockenhaupt 2008
In a case study, serrapeptase was identified as a possible catalyst in the formation of a periapical abscess based on its fibrinolytic activity. However, the study cited to support this fibrinolytic claim actually documented the "suppression of fibrinolysis" by serrapeptase.Kakinuma 1982, Rajaram 2016
Toxicology
No information regarding toxicity is available.
References
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