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An Evidence-Based Systematic Review of
Green-Lipped Mussel (Perna canaliculus)by
the Natural Standard Research Collaboration
Catherine Ulbricht, PharmD
Wendy Chao, PhD
Dawn Costa, BA, BS
Yen Nguyen, PharmD
Erica Seamon, PharmD
Wendy Weissner, BA
ABSTRACT. This paper is an evidence-based systematic review in-
cluding written and statistical analysis of scientific literature, expert
opinion, folkloric precedent, history, pharmacology, kinetics/dynamics,
interactions, adverse effects, toxicology, and dosing. Search strategy.
To prepare each Natural Standard review, electronic searches are con-
ducted in nine databases, including AMED, CANCERLIT, CINAHL,
CISCOM, the Cochrane Library, EMBASE, HerbMed, International
Pharmaceutical Abstracts, Medline, and NAPRALERT. Search terms in-
clude the common name(s), scientific name(s), and all listed synonyms
for each topic. Hand searches are conducted of 20 additional journals (not
Catherine Ulbricht is affiliated with the Massachusetts General Hospital and the
Natural Standard Research Collaboration
Wendy Chao, Dawn Costa, and Wendy Weissner are affiliated with the Natural
Standard Research Collaboration
Yen Nguyen is affiliated with the Massachusetts College of Pharmacy and the
Natural Standard Research Collaboration
Erica Seamon is affiliated with the Nova Southeastern University and the Natural
Standard Research Collaboration
Address correspondence to: Catherine Ulbricht (jds@naturalstandard.com)
54
Journal of Dietary Supplements, Vol. 6(1), 2009
Available online at www.informaworld.com/WJDS
C
2009 by Informa Healthcare USA, Inc. All rights reserved.
doi: 10.1080/19390210802690191
Ulbricht et al. 55
indexed in common databases), and of bibliographies from 50 selected
secondary references. No restrictions are placed on language or quality
of publications. Researchers in the field of complementary and alterna-
tive medicine (CAM) are consulted for access to additional references or
ongoing research. Selection Criteria. All literature is collected pertaining
to efficacy in humans (regardless of study design, quality, or language),
dosing, precautions, adverse effects, use in pregnancy/lactation, interac-
tions, alteration of laboratory assays, and mechanism of action (in vitro,
animal research, human data). Standardized inclusion/exclusion criteria
are utilized for selection. Data Analysis. Data extraction and analysis are
performed by healthcare professionals conducting clinical work and/or
research at academic centers, using standardized instruments that pertain
to each review section (defining inclusion/exclusion criteria and analytic
techniques, including validated measures of study quality). Data are
verified by a second reviewer. Review Process. A blinded review is con-
ducted by multidisciplinary research-clinical faculty at major academic
centers with expertise in epidemiology and biostatistics, pharmacology,
toxicology, CAM research, and clinical practice. In cases of editorial
disagreement, a three-member panel of the Editorial Board addresses
conflicts, and consults experts when applicable. Authors of studies are
contacted when clarification is required.
KEYWORDS. Adverse effects, green-lipped mussel (Perna canalicu-
lus), dosing, evidence-based, interactions, pharmacodynamics, pharma-
cology, pharmacokinetics, systematic review
Synonyms/Common Names/Related Substances: Betain, brevetoxin
B analog B4 (BTXB4), chondroitin sulfate, eicosatetraenoic acids,
freeze-dried mussel powder, glycosaminoglycans, green lipped mussel,
Green Lips
R, green shell mussel, Greenback
R, Greenshell
R, Greenshell
R
Mussel, heparin, Lyprinol
R, marine oils, mollusk, Mytilidae (fam-
ily), New Zealand green-lipped mussel, okadaic acid, pectenotoxins,
Perna canaliculus, pernin, shellfish lipid extract, Seatone, sterol esters,
yessotoxins.
Combination product examples: Sanhelios Mussel Lyprinol
RLipid
Complex (green-lipped mussel extract and omega-3 fatty acids), PernaTM
Plus (green-lipped mussel extract, glucosamine sulfate, methylsulfonyl-
methane, manganese acid chelate).
56 JOURNAL OF DIETARY SUPPLEMENTS
CLINICAL BOTTOM LINE/EFFECTIVENESS
Brief Background
rThe green-lipped mussel (Perna canaliculus)isnativetotheNew
Zealand coast, and is a staple diet of the indigenous Maori culture
(particularly those who live in coastal regions).
rInterest in the health benefits of green-lipped mussel stemmed from the
observation that coastal Maoris had lower incidence of arthritis than
their European or inland Maori cohorts (Halpern & Georges, 2000).
Thus, the anti-inflammatory effects of green-lipped mussel have been
studied extensively in vitro, in vivo, and in clinical trials.
rGreen-lipped mussel products have been proposed as adjunct therapies
for a number of inflammatory conditions (Ferreira, 2005) including
asthma, osteoarthritis, and rheumatoid arthritis.
rThere is limited evidence for the use of green-lipped mussel for treating
asthma, but the preliminary evidence is encouraging. Its most popular
use, besides as food, is to help relieve joint pain and inflammatory
joint disorders; while there is some evidence supporting the use of
green-lipped mussel in treating osteoarthritis, the overall evidence for
rheumatoid arthritis suggests inefficacy.
Scientific Evidence for Common/Studied Uses
Indication Evidence Grade
Asthma C
Osteoarthritis C
Rheumatoid arthritis D
Natural Standard evidence-based validated grading rationaleTM
rGrades reflect the level of available scientific evidence in support of the
efficacy of a given therapy for a specific indication.
rExpert opinion and folkloric precedent are not included in this assess-
ment, and are reflected in a separate section of each review (“Strength
of Expert Opinion and Historic/Folkloric Precedent”).
rEvidence of harm is considered separately; the below grades apply only
to evidence of benefit.
Ulbricht et al. 57
Level of Evidence Grade Criteria
A (Strong Scientific Evidence) Statistically significant evidence of benefit from >2
properly randomized trials (RCTs), OR evidence from
one properly conducted RCT AND one properly
conducted meta-analysis, OR evidence from multiple
RCTs with a clear majority of the properly conducted
trials showing statistically significant evidence of benefit
AND with supporting evidence in basic science, animal
studies, or theory.
B (Good Scientific Evidence) Statistically significant evidence of benefit from 1–2
properly randomized trials, OR evidence of benefit from
>1 properly conducted meta-analysis OR evidence of
benefit from >1 cohort/case-control/nonrandomized
trials AND with supporting evidence in basic science,
animal studies, or theory.
C (Unclear or conflicting
scientific evidence)
Evidence of benefit from >1 small RCT(s) without
adequate size, power, statistical significance, or quality
of design by objective criteria, ∗OR conflicting evidence
from multiple RCTs without a clear majority of the
properly conducted trials showing evidence of benefit
or ineffectiveness, OR evidence of benefit from >1
cohort/case-control/nonrandomized trials AND without
supporting evidence in basic science, animal studies,
or theory, OR evidence of efficacy only from basic
science, animal studies, or theory.
D (Fair Negative Scientific
Evidence)
Statistically significant negative evidence (i.e., lack of
evidence of benefit) from
cohort/case-control/nonrandomized trials, AND
evidence in basic science, animal studies, or theory
suggesting a lack of benefit.
F (Strong Negative Scientific
Evidence)
Statistically significant negative evidence (i.e., lack of
evidence of benefit) from >1 properly randomized
adequately powered trial(s) of high-quality design by
objective criteria.*
Lack of Evidence†Unable to evaluate efficacy due to lack of adequate
available human data.
∗Objective criteria are derived from validated instruments for evaluating study quality, including the
5-point scale developed by Jadad et al., in which a score below 4 is considered to indicate lesser quality
methodologically (Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay
HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical
Trials 1996; 17[1]:1–12).
†Listed separately in reviews in the “Historical or Theoretical Uses which Lack Sufficient Evidence” section.
58 JOURNAL OF DIETARY SUPPLEMENTS
Historical or Theoretical Uses Which Lack Sufficient Evidence
rAbortifacient (uterine contraction stimulant) (Shiels & Whitehouse,
2000), ankylosing spondylitis, antihistamine, anti-inflammatory (But-
ters & Whitehouse, 2003; Halpern, 2000a; Halpern & Georges, 2000;
McPhee et al., 2007; Meletis, 2000; Miller, Dodd, Ormrod, & Geddes,
1993; Miller & Ormrod, 1980; Shiels & Whitehouse, 2000; White-
house et al., 1997; Whitehouse, 2004; Yuan, Wahlqvist, He, Yang, &
Li, 2006; ), atopic dermatitis, breast cancer (Anon, 1999 ), bursitis, car-
diovascular disease (Sinclair, Murphy, & Li, 2000), connective tissue
disorders, dysmenorrhea (Shiels & Whitehouse, 2000), eye disorders
(retinal disorders) (Sinclair et al., 2000), inflammatory bowel disease
(Tenikoff, Murphy, Le, Howe, & Howarth, 2005), inflammatory joint
disease (Couch, Ormrod, Miller, & Watkins, 1982; Whitehouse, 2004),
Lyme disease, mucositis (Torres et al., 2008), multiple sclerosis, nerve
disorders (Sinclair et al., 2000), prostate cancer ( Anon, 1999 ), psoria-
sis, sports injuries, systemic lupus erythematosus (prevention) (Mani &
Lawson, 2006), ulcers (NSAID-induced).
Expert Opinion and Historic/Folkloric Precedent
rAs a food or as a dietary supplement, green-lipped mussel is not regu-
lated by the U.S. Food and Drug Administration (FDA). It is not listed in
the FDA GRAS (Generally Recognized as Safe) list as a food additive.
rThe anti-inflammatory effects of green-lipped mussel have been stud-
ied extensively. Green-lipped mussel products have been proposed as
adjunct therapies to a number of standard treatments for chronic inflam-
matory conditions (Ferreira, 2005).
rRigorous clinical trials that examine the purported 5-lipoxygenase
(5-LOX) inhibitory activity of Lyprinol
Rgreen-lipped mussel extract
(Whitehouse, 2002), as well as its purported ability to inhibit cyclooxy-
genase (COX) enzyme activity are warranted (Whitehouse, 2005).
rMost of the anti-inflammatory activity of green-lipped mussel is believed
to be in the lipid fraction. According to industry, the original freeze-dried
powder preparations are up to 125 times less potent than stabilized lipid
extracts (such as Lyprinol
R), and many currently available powders have
little or no anti-inflammatory activity. The delipidated byproducts of the
extraction process, which also have very little (if any) anti-inflammatory
activity, have also been packaged and sold in low cost green-lipped
mussel products (Halliday, 2008).
Ulbricht et al. 59
Brief Safety Summary
rLikely safe: When eaten in moderation, due to its long history of use in
the Maori diet (Halpern & Georges, 2000).
rPossibly safe: When handling green-lipped mussels, although there
have been occupational case reports of lung dysfunction and multiple
respiratory symptoms in New Zealand mussel openers (Glass et al.,
1998).
rPossibly unsafe: When used in immunosuppressed patients, or in pa-
tients not vaccinated against the polio virus (Greening, Dawson, &
Lewis, 2001). When used in patients with pulmonary disorders such as
asthma (Emelyanov et al., 2002; Glass et al., 1998; Halpern, 2000b).
rLikely unsafe: When used in patients with hepatitis or other hepatic dis-
orders (MacKenzie et al., 2002; Miles et al., 2004; Suzuki, MacKenzie,
Stirling, & Adamson, 2001); possible toxic hepatitis has been associated
with Seatone in several case reports (Ahern, Milazzo, & Dymock, 1980;
Croft, 1980; Fabrin, 1988). When used in patients with neurotoxicity
(Ishida et al., 2004; Morohashi et al., 1999). When used in allergic pa-
tients (Glass et al., 1998). When used in patients who are pregnant or
breastfeeding (Miller & Wu, 1984; Shiels & Whitehouse, 2000).
rNote: Green-lipped mussel appears to be generally well tolerated in
nonallergic people (Cho et al., 2003; Halpern & Georges, 2000), and
secondary sources suggest that heavy metal contamination is usually
not a concern (unlike oysters). However, the B4 analog of brevetoxin
B (BTXB4), has been associated with neurotoxic shellfish poisoning
(Ishida et al., 2004; Morohashi et al., 1999). Complete toxin profiles
of green-lipped mussel may also include yessotoxins (YTXs), pecteno-
toxins (PTXs), and low levels of okadaic acid (OA) (MacKenzie et al.,
2002; Miles et al., 2004; Suzuki et al., 2001). Possible toxic hepatitis
has been associated with Seatone in several case reports (Ahern et al.,
1980; Croft, 1980; Fabrin, 1988).
DOSING/TOXICOLOGY
General
rRecommended doses are based on those most commonly used in avail-
able trials or on historical practice. However, with natural products it
often is not clear what the optimal doses are to balance efficacy and
safety. Preparation of products may vary from manufacturer to manu-
60 JOURNAL OF DIETARY SUPPLEMENTS
facturer, and from batch to batch within one manufacturer. Because it
often is not clear what the active component(s) of a product is, standard-
ization may not be possible, and the clinical effects of different brands
may not be comparable.
Standardization
rThere is no well-known standardization for green-lipped mussel. Green-
lipped mussels provide omega-3 fatty acids, and each capsule of
Lyprinol
Ris standardized to contain 50 mg omega-3 fatty acids and
100 mg olive oil (Emelyanov et al., 2002).
Dosing:
Adult (age ≥18):
Oral:
rGeneral: According to Internet websites, oral green-lipped mussel sup-
plementation typically consists of about 200 mg daily of lipid extract,
or 1,000 mg daily of the powdered form.
rAsthma: Two capsules of Lyprinol
R(containing 50 mg of omega-
3 polyunsaturated fatty acids and 100 mg olive oil per capsule) has
been used twice daily for eight weeks for steroid-na¨
ıve atopic asthma
(Emelyanov et al., 2002).
rOsteoarthritis: Green-lipped mussel has been used in the following
doses to treat osteoarthritis: 1,050 mg mussel extract (three capsules)
daily for 3–6 months (Gibson, Gibson, Conway, & Chappell, 1980),
six capsules Seatone daily (no details given) for six months (Audeval
& Bouchacourt, 1986), 210 mg Lyprinol
R(or 1,150 mg mussel pow-
der) daily for 3–6 months (Gibson & Gibson, 1998), or four capsules
Lyprinol
Rdaily (dose not specified) for two months followed by four
months of two capsules daily (Lau et al., 2004). Lyprinol
Rwas used as
a 5-LOX inhibitor for osteoarthritis at a dosage of two capsules twice
daily for 4–8 weeks (Cho et al., 2003).
rRheumatoid arthritis: Mussel extract capsules have been used daily for
90 days (Gibson et al., 1980). A 210 mg Lyprinol
Rhas been used daily
for three to six months (Gibson & Gibson, 1998). For inflammatory
rheumatoid arthritis, an unclear dose of Sanhelios Mussel Lyprinol
R
Lipid Complex (a “special combination of Lyprinol and omega-3 fatty
Ulbricht et al. 61
acids”) has been used for 12 weeks (Gruenwald, Graubaum, Hansen, &
Grube, 2004).
Children (age <18)
rInsufficient available evidence.
Toxicology
rGreen-lipped mussel appears to be generally well tolerated, and sec-
ondary sources suggest that heavy metal contamination is usually not
a concern (unlike oysters). However, the B4 analog of brevetoxin B
(BTXB4), has been identified as the major toxin in green-lipped mussels
and has been associated with neurotoxic shellfish poisoning (Ishida et al.,
2004; Morohashi et al., 1999). Complete toxin profiles of green-lipped
mussel may also include yessotoxins (YTXs), pectenotoxins (PTXs),
and low levels of okadaic acid (OA) (MacKenzie et al., 2002; Miles
et al., 2004; Suzuki et al., 2001). Possible toxic hepatitis has been as-
sociated with Seatone in several case reports (Ahern et al., 1980; Croft,
1980; Fabrin, 1988).
PRECAUTIONS/CONTRAINDICATIONS
Allergy
rKnown allergy/hypersensitivity to green-lipped mussel or other shellfish
such as mollusks and crustaceans.
rIt has been reported that freeze-dried preparations of green-lipped mus-
sel contain more proteinaceous allergens than lipid preparations. Aller-
gic reactions to gelatin (used in capsule preparations) have also been
noted. Allergic reactions to green-lipped mussel may include rash (itch-
ing or hives), swelling of the face or hands, swelling or tingling in the
mouth or throat, chest tightness, and difficulty breathing. Allergic or
sensitive individuals may experience difficulty breathing after ingesting
or inhaling green-lipped mussel products. Lung dysfunction and mul-
tiple respiratory symptoms have been reported in New Zealand mussel
openers (Glass et al., 1998).
62 JOURNAL OF DIETARY SUPPLEMENTS
Adverse Effects/Post Market Surveillance
rGeneral: Green-lipped mussel products have been generally well toler-
ated in clinical trials. However, possible side effects of Seatone use have
been noted by the Australian Rheumatism Association (Brooks, 1980).
rCardiovascular: In a clinical trial, one patient in the Lyprinol
Rtreatment
group suffered heart failure (Lau et al., 2004). The relevance of this to
the treatment is unclear. Fluid retention has been reported as an adverse
effect of green-lipped mussel use (Gibson & Gibson, 1998).
rDermatologic: The Australian Rheumatism Association listed skin rash
as a possible adverse effect of using Seatone green-lipped mussel extract
(Brooks, 1980). In a randomized controlled trial, two patients (one taking
Lyprinol
Rand one taking placebo) complained of itch, and three patients
(one Lyprinol
R, two placebo) complained of metallic taste (Emelyanov
et al., 2002).
rGastrointestinal: The Australian Rheumatism Association reported
stomach upset as a possible adverse effect of using Seatone green-
lipped mussel extract (Brooks, 1980). Mild nausea occurred in clinical
studies (Gruenwald et al., 2004; Lau et al., 2004), and upset stomach
and flatulence were reported in a study of Seatone (Gibson & Gibson,
1981a).
rThe Australian Rheumatism Association reported hepatitis as a possible
adverse effect of using Seatone green-lipped mussel extracts (Brooks,
1980). Possible toxic hepatitis has been associated with Seatone in
several case reports (Ahern et al., 1980; Croft, 1980; Fabrin, 1988). In a
randomized controlled trial, two subjects taking Lyprinol
Rdropped out
due to nausea and abnormal liver function, although causality is unclear
(Lau et al., 2004).
rMusculoskeletal: The Australian Rheumatism Association listed gout
as a possible adverse effect of using Seatone green-lipped mussel ex-
tract (Brooks, 1980). Of rheumatoid arthritis patients taking Seatone
for 90 days, 10% reported a transient worsening of symptoms, al-
though no other adverse events were experienced (Gibson et al.,
1980).
rNeurologic/CNS: The B4 analog of brevetoxin B (BTXB4), has
been identified as the major toxin in green-lipped mussel, and has
been associated with neurotoxic shellfish poisoning (Morohashi et al.,
1999).
rPulmonary/respiratory: Although green-lipped mussel extract has
been suggested as an asthma treatment (Emelyanov et al., 2002), allergic
Ulbricht et al. 63
or sensitive individuals may experience difficulty breathing after in-
gesting or inhaling green-lipped mussel products. Lung dysfunction
and multiple respiratory symptoms have been reported in New Zealand
mussel openers (Glass et al., 1998).
rRenal: Fluid retention has been reported as an adverse effect of green-
lipped mussel use (Gibson & Gibson, 1998).
rOther: Polioviruses have been shown to survive in green-lipped mus-
sels, both in fresh mussels and in those frozen for up to 28 days at
−20 degrees Celsius; this may constitute a significant public health risk
(Greening et al., 2001).
Precautions/Warnings/Contraindications
rUse cautiously in patients taking anti-inflammatory medications. It has
been suggested that green-lipped mussel may enhance not only the
benefits of other anti-inflammatory drugs, but also their adverse effects
(particularly gastrointestinal upset).
rUse cautiously in patients with asthma; although green-lipped mus-
sel has been suggested to have anti-asthmatic effects (Emelyanov et al.,
2002; Halpern, 2000b), lung dysfunction and multiple respiratory symp-
toms have been reported in New Zealand mussel openers (Glass et al.,
1998).
rAvoid in patients with liver disease, due to potential toxic hepatitis
associated with green-lipped mussel (Ahern et al., 1980; Brooks, 1980;
Croft, 1980; Fabrin, 1988).
rAvoid in patients with known allergy/hypersensitivity to green-lipped
mussel or other shellfish (mollusks, crustaceans). Powdered green-
lipped mussel is reported to be more allergenic than lipid extracts;
allergic reactions to gelatin (used in capsule preparations) have also
been noted.
Pregnancy and Lactation
rNot recommended due to potential uterotrophic effects (Shiels & White-
house, 2000). Similar to prostaglandin synthetase inhibitors (such as
aspirin, indomethacin, and naproxen, which may interfere with ovula-
tion and prolong the gestation period), Seatone does appear to inhibit
prostaglandin biosynthesis (Miller & Wu, 1984).
64 JOURNAL OF DIETARY SUPPLEMENTS
INTERACTIONS
Green-Lipped Mussel/Drug Interactions
rAntiasthma agents: Based on in vitro study, green-lipped mussel may
have antiasthmatic effects (Halpern, 2000b).
rAntihistamines: Based on in vitro study, green-lipped mussel is pur-
ported to have antihistamine effects (Kosuge, Tsuji, Ishida, & Yam-
aguchi, 1986); however, in vivo acute irritation study of Lyprinol
R
showed little or no activity against histamine (Whitehouse et al., 1997).
rAnti-inflammatory agents: Green-lipped mussel has been demon-
strated to have anti-inflammatory effects, particularly lipoxygenase in-
hibiting action (Halpern, 2000b). It has been suggested that green-lipped
mussel may enhance not only the benefits of other anti-inflammatory
drugs, but also their adverse effects (particularly gastrointestinal upset).
rCorticosteroids: Lyprinol
Rhas been suggested to have anti-
inflammatory action similar to low-dose prednisone, and has been
used in combination with pentoxifylline (Pentoxil
R) in animal stud-
ies (Whitehouse, 2004).
rImmunomodulating agents: Based on in vitro study, green-lipped mus-
sel extract may have immunomodulating effects (Lawson, Belkowski,
Whitesides, Davis, & Lawson, 2007).
rLeukotriene receptor antagonists: Lyprinol
Rhas been suggested to
act as a leukotriene receptor antagonist, which may contribute to
uterotrophic effects (Shiels & Whitehouse, 2000).
rPentoxifylline (Pentoxil
R): Lyprinol
Rhas been suggested to have anti-
inflammatory action similar to low-dose prednisone, and has been used
in combination with pentoxifylline (Pentoxil
R) in animal studies to treat
chronic inflammation (Whitehouse, 2004).
rUterotrophic agents: Lyprinol
Rhas been suggested to act as a
leukotriene receptor antagonist, which may contribute to uterotrophic
effects (Shiels & Whitehouse, 2000).
Green-Lipped Mussel/Herb/Supplement Interactions
rAntiasthma herbs and supplements: Based on in vitro study, green-
lipped mussel may have antiasthmatic effects (Halpern, 2000b).
rAntihistamines: Based on in vitro study, green-lipped mussel is pur-
ported to have antihistamine effects (Kosuge et al., 1986); however,
Ulbricht et al. 65
in vivo acute irritation study of Lyprinol
Rshowed little or no activity
against histamine (Whitehouse et al., 1997).
rAnti-inflammatory herbs and supplements: Green-lipped mussel
has been demonstrated to have anti-inflammatory effects, particularly
lipoxygenase inhibiting action (Halpern, 2000b). It has been suggested
that green-lipped mussel may enhance not only the benefits of other
anti-inflammatory herbs and supplements, but also their adverse effects
(particularly gastrointestinal upset).
rImmunomodulating herbs and supplements: Based on in vitro study,
green-lipped mussel extract may have immunomodulating effects (Law-
son et al., 2007).
rOmega 3 fatty acids: In human study that combined Lyprinol
Rwith
omega-3 fatty acids, one adverse event of mild nausea was experienced
(Gruenwald et al., 2004); however, it was unclear whether this was due
to the Lyprinol
R, the omega-3 fatty acids, their combination, or none of
these agents.
rUterotrophic herbs and supplements: Lyprinol
Rhas been suggested
to act as a leukotriene receptor antagonist, which may contribute to
uterotrophic effects (Shiels & Whitehouse, 2000).
Green-Lipped Mussel/Food Interactions
rInsufficient available evidence.
Green-Lipped Mussel/Lab Interactions
rLiver function tests: In clinical study, altered liver function was ob-
served in both the Lyprinol
Rtreatment group and the placebo group (Lau
et al., 2004). Possible toxic hepatitis has been associated with Seatone
in several case reports (Ahern et al., 1980; Croft, 1980; Fabrin, 1988).
MECHANISM OF ACTION
Pharmacology
rConstituents: Green-lipped mussel has been reported to contain ap-
proximately 61% protein, 13% carbohydrates, 12% glycosaminoglycans
(GAGs), 5% lipids (including eicosatetraenoic acids, or ETAs), 5%
minerals, and 4% water. The protein fraction of green-lipped mussel
66 JOURNAL OF DIETARY SUPPLEMENTS
hemolymph consists mainly of pernin, a glycosylated protein with serine
protease inhibitor activity (Scotti, Dearing, Greenwood, & Newcomb,
2001). According to industry, green-lipped mussel contains betain, gly-
cosaminoglycans (including chondroitin sulphate and heparin), and 18
amino acids; these nutritional elements are retained in Lyprinol
Rlipid
extracts after processing (Halliday, 2008).
rLipid extracts of green-lipped mussel (such as Lyprinol
Rcontain mostly
sterol esters (cholesterol and desmosterol/brassicasterol), triglycerides,
free fatty acids, sterols, and phospholipids (Murphy, Mann, & Sinclair,
2003; Sinclair et al., 2000).
rLike many other bivalves, green-lipped mussels contain toxins; the B4
analog of brevetoxin B (BTXB4), has been identified as the major
toxin in green-lipped mussels, and has been associated with neurotoxic
shellfish poisoning (Morohashi et al., 1999). Green-lipped mussel may
also contain yessotoxins (YTXs), pectenotoxins (PTXs), and low levels
of okadaic acid (OA) (MacKenzie et al., 2002; Miles et al., 2004; Suzuki
et al., 2001).
rAntihistamine effects: Green-lipped mussel is purported to have anti-
histamine effects (Kosuge et al., 1986); however, one in vivo acute irri-
tation study of Lyprinol
Rshowed little or no activity against histamine
(Whitehouse et al., 1997). A substance with antihistamine activity has
been isolated from green-lipped mussel (Kosuge et al., 1986), but has
not been thoroughly characterized.
rAnti-inflammatory effects: Natural antioxidants (such as carotenoids)
are suggested to contribute to anti-inflammatory effects; Lyprinol
Ris
suggested to contain more bioactive lipids than other plane or marine
oils (McPhee et al., 2007). The anti-inflammatory effects of green-
lipped mussel have previously been attributed to a proteinaceous macro-
molecule (Couch et al., 1982) or a polysaccharide/protein (glycogen)
component (Miller et al., 1993). However, the lipid fraction is currently
believed to hold the most therapeutic potential (Singh et al., 2008; Woly-
niak, Brenna, Murphy, & Sinclair, 2005). The anti-inflammatory activity
of green-lipped mussel extract is said to vary in potency depending on
the stability of the preparation. However, Lyprinol
Ris prepared using a
supercritical fluid extraction (SFE) process of the stabilized freeze-dried
mussel powder; the resulting extract represents about 5% w/v of freeze-
dried mussel powder, and purportedly demonstrates superior stability
and potency (Halpern & Georges, 2000).
rExtracts of green-lipped mussel have been shown to moderately inhibit
purified COX-1 and COX-2 enzymes in vitro, in vivo, and in clinical
Ulbricht et al. 67
studies (Halpern, 2000b; McPhee et al., 2007; Whitehouse et al., 1997).
Lyprinol
R, which is a green-lipped mussel extract hydrolyzed with
potassium hydroxide (KOH), demonstrated strong inhibition of COX
enzymes in vitro. Lyprinol
Rpolyunsaturated fatty acids act as compet-
itive inhibitors of arachidonic acid (AA) metabolism (McPhee et al.,
2007). A bioactive compound of green-lipped mussel has shown inhi-
bition of lipoxygenase products of the AA pathway (Treschow et al.,
2007). Green-lipped mussel extract has been demonstrated to affect the
5-lipoxygenase pathway on several levels and has been suggested to
modulate the 12–1ipoxygenase pathway (Halpern & Georges, 2000).
Lyprinol
Rsubfractions have also been shown to inhibit leukotriene B4
(LTB4) biosynthesis by polymorphonuclear cells (Halpern, 2000b) and
human monocytes (Dugas, 2000); it also may inhibit cytokine produc-
tion by activated macrophages (Halpern, 2000b). Lyprinol
Rhas also
been suggested to act as a leukotriene receptor antagonist, which may
contribute to uterotrophic effects (Shiels & Whitehouse, 2000).
rLyprinol
Rhas been suggested to mimic the anti-inflammatory effects
of corticosteroids (such as prednisone); it has been used in combi-
nation with pentoxifylline (an inhibitor of TNF-alpha production) to
treat chronic inflammation in rodents (Whitehouse, 2004). The anti-
inflammatory effects of Lyprinol
Rhave been shown to benefit ex-
perimentally induced inflammatory bowel disease (IBD) (Tenikoff et
al., 2005) and intestinal mucositis (Couch et al., 1982) in rodents.
Lyprinol
Rhas also been tested as an asthma treatment (Emelyanov et al.,
2002).
rEndocrine effects: Similar to prostaglandin synthetase inhibitors (such
as aspirin, indomethacin, and naproxen, which may interfere with ovu-
lation and prolong the gestation period), Seatone green-lipped mus-
sel extract may contain pharmacologically active material inhibiting
prostaglandin biosynthesis. (Miller & Wu, 1984).
rImmunomodulating effects: In monocytes stimulated in vitro with
lipopolysaccharide (LPS), green-lipped mussel extracts reduced cy-
tokine production and neutrophil superoxide burst (Lawson et al., 2007),
which may benefit inflammatory diseases with a proinflammatory cy-
tokine component (Lawson et al., 2007). Extracts prepared with deter-
gent (Tween-20) and hydrochloric acid (HCl) also demonstrated anticy-
tokine activity and inhibition of immunoglobulin G production (Mani &
Lawson, 2006). Lyprinol
Rhas been demonstrated to suppress the hyper-
activation of monocytes in allergic patients, which has been suggested
to contribute to its antiallergy effects (Dugas, 2000).
68 JOURNAL OF DIETARY SUPPLEMENTS
rOcular effects: Docosahexaenoic acid (DHA), the main marine omega-
3 fatty acid, is abundant in green-lipped mussel; DHA is localized in the
retina (Sinclair et al., 2000), and may play a role in retinal function.
rUterotrophic effects: Lyprinol
Rhas been suggested to act as a
leukotriene receptor antagonist, which may contribute to uterotrophic
effects (Shiels & Whitehouse, 2000).
Pharmacodynamics/Kinetics
rInsufficient available evidence.
HISTORY
rAccording to the Food and Agriculture Organization of the United Na-
tions, the New Zealand green-lipped mussel has been widely consumed
since the civilization of New Zealand. Commercial farming of green-
lipped mussel began in the early 1970s. At the present time, the United
States is a major importer of green-lipped mussels, which are mar-
keted under the trademarks Greenshell
R, Green Lips
R, and Greenback
R
owned by the New Zealand Mussel Industry Council (NZMIC) (Halli-
day, 2008).
rPotential anti-inflammatory effects of green-lipped mussel were rec-
ognized in the mid 1970s, and studies commenced that examined its
potential use for treating chronic inflammatory diseases. An early trial
found no clinical benefit (Highton & McArthur, 1975). Soon after, Gib-
son and colleagues of the Glasgow Homoeopathic Hospital in Scotland
published controversial evidence that Seatone (a powdered green-lipped
mussel extract) effectively treats osteoarthritis and rheumatoid arthritis
(Gibson et al., 1980).
Condition: Refers to the medical condition or disease targeted by a
therapy.
Study Design: Common types include:
rRandomized controlled trial (RCT): An experimental trial in which
participants are assigned randomly to receive either an intervention be-
ing tested or placebo. Note that Natural Standard defines RCTs as being
placebo controlled, while studies using active controls are classified as
equivalence trials (see later). In RCTs, participants and researchers are
often blinded (i.e., unaware of group assignments), although unblinded
EVIDENCE TABLE
Quality of
Study
0–2 =poor;
Study Author, Statistically 3–4 =good; Magnitude
Condition Design Year N Significant? 5 =excellent of Benefit ARR NNT Comments
Asthma Randomized
controlled trial,
double-blind
Emelyanov, 2002 46 Yes 5 Medium NA NA Strong methodological design.
Reviewed by Halpern and
Georges, 2000.
Osteoarthritis Systematic review Brien, Prescott,
Coghla, Bashir,
and Lewith, 2008
4 NA NA Medium NA NA Three randomized controlled trials
(Audeval & Bouchacourt, 1986;
Gibson et al., 1980; Lau et al.,
2004) and one randomized
equivalence trial (Gibson &
Gibson, 1998) were included in
the study; two were excluded
from analysis due to
inappropriate blinding and
statistical analysis.
Osteoarthritis Systematic review Cobb and Ernst, 2006 4 NA NA Small NA NA Review included two randomized
controlled trials (Audeval &
Bouchacourt, 1986; Gibson
et al., 1980) and two studies of
lesser design strength (Gibson &
Gibson, 1998; Kendall, Lawson,
& Hurley, 2000).
Osteoarthritis Randomized
controlled trial,
double-blind
Lau et al., 2004 80 Yes 3 Small NA NA Significant improvement in pain at
weeks 8 and 12; significant
improvements in patient global
assessment at weeks 12 and 18.
Assigned a Jadad score of 3 by
one systematic review (Brien
et al., 2008).
69
Osteoarthritis Randomized
controlled trial
Audeval, 1986 53 Yes 3 Small NA NA Of 10 outcome measures, four showed
improvement in Seatone group vs. placebo.
One outcome measure showed significant
placebo effect vs. Seatone. Two separate
systematic reviews gave different Jadad
scores: 4 (Cobb & Ernst, 2006) and 2
(Brien et al., 2008).
Osteoarthritis Randomized
controlled trial
Gibson, 1980 38 Yes 3 Large 32% 3 This controversial study was later refuted and
criticized for improper controls, blinding,
and statistical analysis (Larkin, Capell, &
Sturrock, 1985). Two separate systematic
reviews gave different Jadad scores: 4
(Cobb & Ernst, 2006) and 1.5 (Brien et al.,
2008). This study also examined in parallel
28 patients with rheumatoid arthritis.
Osteoarthritis Before and after
comparison
Cho et al., 2003 60 NA NA Large NA NA Prospective multicenter trial lacked
randomization, placebo control, and
blinding.
Osteoarthritis Equivalence trial,
double-blind,
crossover design
Gibson, 1998 30 Yes NA Large NA NA Comparison of stabilized mussel powder and
lipid extract. Criticized for inappropriate
randomization, controls, blinding, and
statistical analysis (Huskisson, Scott, &
Bryans, 1981). Systematically reviewed by
Brien et al. (who gave a Jadad score of
2.5) (Brien et al., 2008) and Cobb and
Ernst (Cobb & Ernst, 2006). The study also
examined in parallel 30 patients with
rheumatoid arthritis.
Rheumatoid arthritis Systematic review Cobb and Ernst, 2006 6 NA NA Small NA NA Included five randomized controlled trials
(Caughey, et al., 1983; Gibson et al., 1980;
Highton & McArthur, 1975; Huskisson
et al., 1981; Larkin et al., 1985) and one
non-RCT (Gibson & Gibson, 1998). Found
little evidence to support the efficacy of
freeze-dried green-lipped mussel extract.
(Continued on next page)
70
Quality of
Study
0–2 =poor;
Study Author, Statistically 3–4 =good; Magnitude
Condition Design Year N Significant? 5 =excellent of Benefit ARR NNT Comments
Rheumatoid arthritis Randomized
controlled trial
Larkin et al., 1985 35 No 4 NA NA NA Randomization method not
stated, but study was
otherwise of strong
methodological design. Study
was given a Jadad score of
only 3 in a systematic review
(Cobb & Ernst, 2006), but
rationale was unclear.
Rheumatoid arthritis Randomized
controlled trial,
crossover design
Highton and
McArthur, 1975
6 No 4 NA NA NA Small pilot study included in a
systematic review (Cobb &
Ernst, 2006), which assigned a
Jadad score of 4. All five
subjects completing the study
increased acetaminophen use,
and showed no preference for
treatment (Seatone) or
placebo.
Rheumatoid arthritis Randomized
controlled trial,
double-blind
Caughey, 1983 47 No 3 NA NA NA Jadad score based on a
systematic review (Cobb &
Ernst, 2006); treatment
unclear, but suggested to be
Seatone (Cobb & Ernst, 2006;
Larkin et al., 1985).
71
EVIDENCE TABLE
(Continued)
Rheumatoid arthritis Randomized
controlled trial,
crossover design
Huskisson et al.,
1981
30 No 3 NA NA NA Methods of randomization not stated;
placebo appropriate (dried fish),
but blinding was not stated. Strong
placebo response. Included in a
systematic review (Cobb & Ernst,
2006).
Rheumatoid arthritis Randomized
controlled trial
Gibson, 1980 28 Yes 3 Medium 32% 3 This controversial study was later
refuted and criticized for improper
controls, blinding, and statistical
analysis (Larkin et al., 1985). Two
separate systematic reviews gave
different Jadad scores: 4 (Cobb &
Ernst, 2006) and 1.5 (Brien et al.,
2008). This study also examined in
parallel 38 patients with
osteoarthritis.
Rheumatoid arthritis Equivalence trial,
double-blind,
crossover design
Gibson, 1998 30 Yes NA Large NA NA Compar ison of stabilized mussel
powder and lipid extract;
systematically reviewed (Cobb &
Ernst, 2006); criticized for
inappropriate randomization,
controls, blinding, and statistical
analysis (Halpern & Georges,
2000; Author, 1981; Huskisson et
al., 1981). The study also
examined in parallel 30 patients
with osteoarthritis, systematically
reviewed by Brien et al. (2008).
Rheumatoid arthritis Clinical trial, before
and after
comparison
Gruenwald et al.,
2004
50 Yes 1 Medium NA NA Treatment used was Lyprinol
RLipid
Complex (a special combination of
Lyprinol and omega-3 fatty acids).
Significant effects were reported;
however, study design was weak.
72
Ulbricht et al. 73
and quasi-blinded RCTs are also often performed. True random allo-
cation to trial arms, proper blinding, and sufficient sample size are the
basis for an adequate RCT.
rEquivalence trial: An RCT which compares two active agents. Equiv-
alence trials often compare new treatments to usual (standard) care, and
may not include a placebo arm.
rBefore and after comparison: A study that reports only the change in
outcome in each group of a study, and does not report between-group
comparisons. This is a common error in studies that claim to be RCTs.
rCase series: A description of a group of patients with a condition, treat-
ment, or outcome (e.g., 20 patients with migraine headache underwent
acupuncture and 17 reported feeling better afterwards). Case series are
considered weak evidence of efficacy.
rCase-control study: A study in which patients with a certain outcome
are selected and compared to similar patients (without the outcome) to
see if certain risk factors/predictors are more common in patients with
that outcome. This study design is not common in the complementary
and alternative medicine literature.
rCohort study: A study which assembles a group of patients with certain
baseline characteristics (for example, use of a drug), and follows them
forward in time for outcomes. This study design is not common in the
complementary and alternative medicine literature.
rMeta-analysis: A pooling of multiple trials to increase statistical power
(often used to pool data from a number of RCTs with small sample
sizes, none of which demonstrates significance alone but in aggregate
can achieve significance). Multiple difficulties are encountered when
designing/reviewing these analyses; in particular, outcomes measures or
therapies may differ from study to study, hindering direct comparison.
rReview: An author’s description of his or her opinion based on personal,
nonsystematic review of the evidence.
rSystematic review: A review conducted according to pre-specified cri-
teria in an attempt to limit bias from the investigators. Systematic reviews
often include a meta-analysis of data from the included studies.
rP: Pending verification.
Author, Year: Identifies the study being described in a row of the table.
N: The total number of subjects included in a study (treatment group plus
placebo group). Some studies recruit a larger number of subjects initially,
but do not use them all because they do not meet the study’s entry criteria.
In this case, it is the second, smaller number that qualifies as N. N includes
all subjects that are part of a study at the start date, even if they drop out,
74 JOURNAL OF DIETARY SUPPLEMENTS
Jadad Score Calculation
Item Score
Was the study described as randomized (this includes words such as randomly,
random, and randomization)?
0/1
Was the method used to generate the sequence of randomization described and
appropriate (table of random numbers, computer-generated, etc)?
0/1
Was the study described as double blind? 0/1
Was the method of double blinding described and appropriate (identical placebo,
active placebo, dummy, etc)?
0/1
Was there a description of withdrawals and dropouts? 0/1
Deduct one point if the method used to generate the sequence of randomization
was described and it was inappropriate (patients were allocated alternately, or
according to date of birth, hospital number, etc).
0/−1
Deduct one point if the study was described as double blind but the method of
blinding was inappropriate (e.g., comparison of tablet vs. injection with no
double dummy).
0/−1
are lost to follow up, or are deemed unsuitable for analysis by the authors.
Trials with a large number of dropouts that are not included in the analysis
are considered to be weaker evidence for efficacy. (For systematic reviews
the number of studies included is reported. For meta-analyses, the number
of total subjects included in the analysis or the number of studies may be
reported.) P =pending verification.
Statistically Significant?: Results are noted as being statistically signif-
icant if a study’s authors report statistical significance, or if quantitative
evidence of significance is present (such as pvalues). P =pending verifi-
cation.
Quality of Study: A numerical score between 0 and 5 is assigned as a
rough measure of study design/reporting quality (0 being weakest and 5
being strongest). This number is based on a well established, validated
scale developed by Jadad et al. (Jadad AR, Moore RA, Carroll D, et al.
Assessing the quality of reports of randomized clinical trials: is blinding
necessary? Controlled Clinical Trials 1996;17[1]:1–12). This calculation
does not account for all study elements that may be used to assess quality
(other aspects of study design/reporting are addressed in the “Evidence
Discussion” sections of reviews).
rA Jadad score is calculated using the seven items in the table below.
The first five items are indications of good quality, and each counts as
one point towards an overall quality score. The final two items indicate
Ulbricht et al. 75
poor quality, and a point is subtracted for each if its criteria are met. The
range of possible scores is 0 to 5.
Magnitude of Benefit
This summarizes how strong a benefit is: small, medium, large, or
none. If results are not statistically significant “NA” for “not applicable”
is entered. In order to be consistent in defining small, medium, and large
benefits across different studies and reviews, Natural Standard defines the
magnitude of benefit in terms of the standard deviation (SD) of the outcome
measure. Specifically, the benefit is considered:
rLarge: if >1SD
rMedium: if 0.5 to 0.9 SD
rSmall: if 0.2 to 0.4 SD
P=Pending Verification: In many cases, studies do not report the SD
of change of the outcome measure. However, the change in the SD of
the outcome measure (also known as effect size) can be calculated, and is
derived by subtracting the mean (or mean difference) in the placebo/control
group from the mean (or mean difference) in the treatment group, and
dividing that quantity by the pooled SD (Effect size =[Mean Treatment –
Mean Placebo]/SDp).
Absolute Risk Reduction
This describes the difference between the percentage of people in the
control/placebo group experiencing a specific outcome (control event rate),
and the percentage of people in the experimental/therapy group experienc-
ing that same outcome (experimental event rate). Mathematically, Absolute
risk reduction (ARR) equals experimental event rate minus control event
rate. ARR is better able to discriminate between large and small treatment
effects than relative risk reduction (RRR), a calculation thatis often cited in
studies ([control event rate—experimental event rate]/control event rate).
Many studies do not include adequate data to calculate the ARR, in which
cases “NA” is entered into this column. P =pending verification.
76 JOURNAL OF DIETARY SUPPLEMENTS
Number Needed to Treat
This is the number of patients who would need to use the therapy under
investigation, for the period of time described in the study, in order for one
person to experience the specified benefit. It is calculated by dividing the
ARR into 1 (1/ARR). P =pending verification.
Comments
When appropriate, this brief section may comment on design flaws
(inadequately described subjects, lack of blinding, brief follow up, not
intention-to treat, etc.), notable study design elements (crossover, etc.),
dosing, and/or specifics of study group/sub-groups (age, gender, etc). More
detailed description of studies is found in the “Evidence Discussion” sec-
tion that follows the “Evidence Table” in Natural Standard reviews.
EVIDENCE DISCUSSION
Asthma
rSummary: Limited evidence suggests that green-lipped mussel supple-
mentation may be of benefit in allergic diseases, such as atopic asthma.
Additional research is needed before a recommendation can be made.
rRandomized trials: Emelyanov et al. (2002) conducted a randomized
controlled trial to assess the effects of green-lipped mussel lipid extract
(Lyprinol
R) on airway inflammation in patients with steroid-na¨
ıve atopic
asthma (Emelyanov et al., 2002). The study analyzed 46 patients, aged
between 18 and 56, with diagnoses of atopic asthma classified to the
National Institutes of Health/World Health Organization (NIH/WHO)
guidelines. Treatment consisted of two capsules of green-lipped mussel
lipid extract, each containing 50 mg of omega-3 polyunsaturated fatty
acids (eicosapentaenoic and docosahexaenoic acid) and 100 mg olive oil
(Mac Lab, Melbourne, Australia); placebo capsules contained 150 mg
of olive oil only. Treatment or placebo capsules were taken twice daily
orally for eight weeks. All patients completed the study; treatment ap-
peared to be well tolerated, with only two patients (one in each group)
complaining of itch and three patients (one treatment, two placebo)
complaining of metallic taste. Asthma symptoms were recorded by the
patients in a journal; peak expiratory flow (PEF) and hydrogen peroxide
Ulbricht et al. 77
(H2O2) in expired breath condensate were assessed as measures of air-
way inflammation. Compared to the placebo group, treatment was asso-
ciated with significantly decreased daytime wheeze and concentration
of exhaled H2O2and increased morning PEF. This study was of strong
methodological design, and suggested that green-lipped mussel supple-
mentation may positively benefit patients with atopic asthma. This study
was reviewed by Halpern and Georges (2000).
Osteoarthritis
rSummary: There is conflicting evidence supporting the efficacy of
green-lipped mussel supplementation for treating osteoarthritis, and
there has been a good deal of controversy surrounding this topic (Gibson
& Gibson, 1981b; Gibson & Gibson, 1981c; Gibson & Gibson, 1985;
Author, 1981 ). Reliable evidence is needed to resolve the controversial
efficacy of green-lipped mussel for this indication.
rPreclinical evidence: In veterinary studies, green-lipped mussel prepa-
rations have been well tolerated, and shown to improve symptoms in
arthritic dogs (Bierer & Bui, 2002; Bui & Bierer, 2003; Pollard, Guil-
ford, Ankenbauer-Perkins, & Hedderley, 2006).
rSystematic reviews: Brien et al. performed a systematic review of
published literature regarding green-lipped mussel supplementation
as a complementary treatment for osteoarthritis (Brien et al., 2008).
Cochrane Library, Medline, Embase, Amed, Cinahl, Scopus, and NeLH
databases were searched for clinical trials of adult patients with os-
teoarthritis of any joint. Studies considered included those that were
randomized, quasi-randomized, comparative, placebo controlled, and/or
crossover design. No studies were found that compared green-lipped
mussel to standard treatment in osteoarthritis. However, four random-
ized controlled trials were identified. Three were placebo controlled
(Audeval & Bouchacourt, 1986; Gibson et al., 1980; Lau et al., 2004),
and one compared lipid extract of green-lipped mussel with stabilized
mussel powder and was essentially an equivalence trial rather than a true
randomized controlled trial (Gibson & Gibson, 1998). Altogether, these
studies evaluated 201 subjects in total (male and female) with mean
age of 68.8 (total group) (Gibson et al., 1980), 65 (extract group) or
66 (placebo group) (Audeval & Bouchacourt, 1986), 57.3 (green-lipped
mussel extract group) or 52.8 (mussel powder group) (Gibson & Gib-
son, 1998), and 62.1 (Lyprinol
Rgroup) or 62.9 (placebo group) (Lau
et al., 2004). Each of these studies used green-lipped mussel extract as
78 JOURNAL OF DIETARY SUPPLEMENTS
an adjunct to conventional treatments of mild to moderate osteoarthri-
tis. Doses used were as follows: 1,050 mg mussel extract taken orally
daily for three to six months (Gibson et al., 1980), six capsules Seatone
taken orally daily (no details given) for six months (Audeval & Boucha-
court, 1986), 210 mg Lyprinol
R(or 1,150 mg mussel powder) taken
orally daily for 3–6 months (Gibson & Gibson, 1998), and four cap-
sules Lyprinol
Rdaily taken orally (dose not specified) for two months
followed by four months of two capsules daily (Lau et al., 2004). Three
of the studies reported adverse effect information: eight (12%) treatment
group vs. one (2%) placebo group (Gibson et al., 1980), one (7%) in
each treatment group (Gibson & Gibson, 1998), and three (7.5%) treat-
ment group vs. one (2.5%) placebo group (Lau et al., 2004). Various
outcome measures were used, including degree and duration of morn-
ing stiffness, visual analog scale (VAS) pain, joint mobility, and night
pain. Each study reported overall benefits achieved with supplemen-
tation. Two studies were excluded from analysis due to inappropriate
blinding and statistical analysis (Gibson et al., 1980; Gibson & Gibson,
1998). The remaining two studies (Audeval & Bouchacourt, 1986; Lau
et al., 2004), which were of higher methodological quality, suggested
that green-lipped mussel may offer greater clinical benefits than placebo
for treating mild to moderate osteoarthritis. Citing credible evidence of
anti-inflammatory activity of the omega-3 fatty acids in green-lipped
mussel, which may underlie this purported benefit, the authors called
for further research to determine the efficacy and optimal dosage of
green-lipped mussel for osteoarthritis treatment.
rCobb and Ernst conducted a systematic review of clinical trials that
tested the efficacy of green-lipped mussel supplementation in treating
osteoarthritis (Cobb & Ernst, 2006). Systematic literature searches were
performed to identify all published articles that examined green-lipped
mussel supplementation in Medline, PubMed, Cochrane Library, and
EMBASE (through February 2005). Two randomized controlled trials
were identified that used green-lipped mussel for treating osteoarthritis
(Audeval & Bouchacourt, 1986; Gibson et al., 1980). Two additional
studies of lesser design strength were also evaluated: an equivalence trial
comparing Seatone powdered mussel extract with Lyprinol
Rlipid extract
(Gibson & Gibson, 1998), and an open-label trial of either PernaTM
(500 mg green-lipped mussel extract and 100 mg alfalfa) or PernaTM
Plus (500 mg green-lipped mussel extract, 300 mg glucosamine sulfate,
200 mg methylsulfonylmethane, and 5 mg manganese acid chelate)
(Kendall et al., 2000). Data were systematically extracted by author
Ulbricht et al. 79
and validated by a second author. Though the results largely supported
the use of green-lipped mussel in osteoarthritis, methodological flaws,
and inconsistent results preclude the recommendation of green-lipped
mussel extract as a treatment for osteoarthritis.
rRandomized trials: Lau et al. (2004) conducted a randomized, placebo
controlled, double-blind study to assess the efficacy of Lyprinol
Ras
an adjunct treatment for standard osteoarthritis therapy. Chinese pa-
tients (N=80) with six-month diagnoses of knee osteoarthritis (without
rheumatoid arthritis), and not taking omega-3 fatty acid supplements,
were randomized to receive either Lyprinol
Rcapsules (dose unclear) or
placebo (olive oil capsules). Four capsules were taken daily orally for
two months, followed by two capsules daily until the end of the study
(week 24). Subjects ceased osteoarthritis medication one week before
the trial, and continued to take 2 g acetaminophen daily taken orally
throughout the trial. Additional acetaminophen was allowed as rescue
medication. Randomization methods were not reported. This study was
included in a systematic review by Brien et al. (2008). Five subjects
dropped out of the Lyprinol
Rgroup: one cited lack of efficacy, one was
later diagnosed with rheumatoid arthritis, and three developed adverse
effects (nausea, abnormal liver function test, or heart failure). Eight
subjects dropped out of the placebo: two refused to continue, three
cited lack of efficacy, one required joint steroid injection, one developed
abnormal liver function, and one did not comply. Outcome measures
of osteoarthritis did not differ significantly between the two treatment
groups, except for patient global assessment (score reduced in Lyprinol
R
group, but increased in placebo group). Although the data were inad-
equate, the authors concluded that Lyprinol
Rwas well tolerated and
associated with decreased pain perception. However, the clinical signif-
icance of this association remains unclear.
rAudeval and Bouchacourt conducted a randomized controlled trial that
examined Seatone as a treatment for knee osteoarthritis (Audeval &
Bouchacourt, 1986). Parisian patients (53 total) were selected based
on radiographic confirmation of osteoarthritis and clinically significant
pain. Patients were excluded if debilitating symptoms were present or
if intervening surgery was performed. Subjects took six capsules of
Seatone or placebo (details unclear) taken orally daily for six months.
A systematic review by Brien et al. (2008) cited inappropriate statistical
analysis and assigned a Jadad score of 2; a separate systematic review
by Cobb and Ernst (Cobb & Ernst, 2006) assigned a Jadad score of 4.
Significant improvements in some outcome measures (pain, functional
80 JOURNAL OF DIETARY SUPPLEMENTS
state, patient/physician global assessment) were observed in the treat-
ment group, but not the placebo group. This study supported the use of
Seatone in treating osteoarthritis; however, due to inappropriate statisti-
cal analysis and flaws in study design, the results should be interpreted
with caution.
rGibson and Gibson conducted a randomized controlled trial of 38 pa-
tients with osteoarthritis (Gibson et al., 1980), which was included in
two systematic reviews (Brien et al., 2008; Cobb & Ernst, 2006). Patients
(who failed to respond to conventional treatment) were randomized to
receive either capsules containing mussel extract (Seatone) or placebo
(dried fish meal powder). Treatment or placebo was taken orally daily for
90 days, and outcome measures were assessed (joint stiffness, limbering
up time, grip strength, joint tenderness, pain, functional efficiency, and
walking speed. In the treatment group, six of the 16 patients showed
improvement, as did three of the 22 patients in the placebo group. Re-
analysis of the data by Brien et al. suggests a lack of benefit (Brien
et al., 2008). In a second three-month phase of the study, all patients
who responded well to the treatments (i.e., those who did not dropout)
were given Seatone for an additional three months. This second phase
was criticized for having lack of proper controls, as the subjects served
as their own controls (Author, 1981 ); thus, the study was essentially a
before-and-after comparison, rather than a true randomized controlled
trial. Furthermore, the active treatment group was further divided into
responders and nonresponders to Seatone, an unorthodox practice that
potentially complicates the interpretation of the data (Author, 1981 );
this criticism was later acknowledged by the study authors (Gibson &
Gibson, 1981a). The study was criticized by a later paper for improper
blinding and statistical analysis (Huskisson et al., 1981).
rStudies of lesser design strength: Cho et al. conducted a multicenter
clinical trial to evaluate the safety and clinical efficacy of Lyprinol
R
green mussel extract as a 5-LOX inhibitor (Cho et al., 2003). In this
study, 60 subjects with osteoarthritis of the knee and hip were adminis-
tered two capsules of Lyprinol
Rtwice daily for four to eight weeks. No
adverse events occurred during the trial. Outcome measures of efficacy
were visual analog scale (VAS), Lequesne functional index, global as-
sessment by patients, and global assessment by physician. After week
four, 53% of patients experienced pain relief and improved joint func-
tion; this number increased to 80% after week eight. This prospective
trial lacks several features of strong study design, such as randomization,
placebo, and blinding.
Ulbricht et al. 81
rGibson and Gibson compared the effectiveness of green-lipped mussel
powdered extract (Seatone) and lipid extract (Lyprinol
R) in treating
osteoarthritis and rheumatoid arthritis (Gibson & Gibson, 1998). In this
study, 30 patients with osteoarthritis were randomized to receive either
five capsules (1,150 mg) of Seatone daily, or three capsules (210 mg)
Lyprinol
Rdaily for three months. Thereafter, all subjects took lipid ex-
tract for an additional three months. There was no placebo group. Four
subjects (two in each group) dropped out due to transportation diffi-
culties. Outcome measures (patient and physician assessment) showed
that 76% of rheumatoid and 70% of osteoarthritis patients experienced
improved symptoms after three months. Three patients with rheuma-
toid arthritis, who responded particularly well to lipid treatment, were
later described in a case series (Gibson, 2000). Because the number
of capsules differed between the treatments (five vs. three capsules),
the double-blind aspect of this study was questionable. The lack of a
placebo arm further questions the validity of these results. This study
was evaluated in two systematic reviews (Brien et al., 2008; Cobb &
Ernst, 2006).
rKendall et al. (2000) conducted an uncontrolled evaluation (before and
after comparison) of PernaTM (500 mg green-lipped mussel extract and
100 mg alfalfa) or PernaTM Plus (500 mg green-lipped mussel extract,
300 mg glucosamine sulfate, 200 mg methylsulfonylmethane, and 5 mg
manganese acid chelate). This study followed 120 subjects with radio-
logically confirmed osteoarthritis over a one-year course of treatment.
In 111 of 120 patients, NSAID intake was reported to be reduced by
up to 50%; 83% of patients showed clinical improvement (assessed by
physicians). This study was included in a systematic reviewed by Cobb
and Ernst (Cobb & Ernst, 2006). Because the treatment was a combina-
tion product, it was excluded from the evidence table. Further analysis
is needed to distinguish the effects of the individual constituents.
Rheumatoid arthritis
rSummary: There is conflicting evidence supporting the efficacy of
green-lipped mussel supplementation for treating rheumatoid arthritis,
which has generated significant controversy (Gibson & Gibson, 1981b;
Gibson & Gibson, 1981c; Gibson & Gibson, 1985; Author, 1981 ).
Overall, the clinical evidence does not support the use of green-lipped
mussel for treating rheumatoid arthritis. Other reviews of complemen-
tary rheumatic disease treatment found lack of evidence supporting the
82 JOURNAL OF DIETARY SUPPLEMENTS
efficacy of green-lipped mussel (Jacobs, Rasker, Van Riel, Gribnau, &
van de Putte, 1991; Darlington & Ramsey, 1994).
rPreclinical evidence: In veterinary studies, green-lipped mussel prepa-
rations have been well tolerated, and shown to improve symptoms in
arthritic dogs (Bierer & Bui, 2002; Bui & Bierer, 2003; Pollard et al.,
2006).
rSystematic reviews: Cobb and Ernst conducted a systematic review
of the literature to examine green-lipped mussel supplementation in
the treatment of osteoarthritis and rheumatoid arthritis (Cobb & Ernst,
2006). Systematic literature searches were performed to identify all
published articles that examined green-lipped mussel supplementation
in Medline, PubMed, Cochrane Library, and EMBASE (through Febru-
ary 2005). Five randomized controlled trials were identified that used
green-lipped mussel for treating osteoarthritis (Audeval & Bouchacourt,
1986; Gibson et al., 1980). One additional equivalence trial compared
Seatone powdered mussel extract with Lyprinol
Rlipid extract (Gibson
& Gibson, 1998). Dosage information was unclear for these studies.
Data were systematically extracted by author and validated by a sec-
ond author. Four studies (Caughey, et al., 1983; Highton & McArthur,
1975; Huskisson et al., 1981; Larkin et al., 1985) found no significant
difference between green-lipped mussel and placebo. The overall lack
of effect precludes the recommendation for using green-lipped mussel
extract as a treatment for rheumatoid arthritis.
rRandomized trials: Larkin et al. (1985) conducted a randomized con-
trolled trial to examine the purported effectiveness of Seatone green-
lipped mussel extract in treating rheumatoid arthritis. Subjects (N=
35), who were refractory to standard treatment, were randomized to
receive either Seatone (20 patients) or placebo (15 patients). The active
treatment consisted of one 230 mg Seatone capsule, taken four times
daily orally for six months. The placebo was prepared to be indistin-
guishable from the active treatment. After six months of treatment, there
were no statistically significant improvements in laboratory or clinical
parameters of rheumatoid arthritis. There was a strong placebo effect;
in fact, none of the patients in the placebo group reported worsening
symptoms, yet six of the original 20 patients in the Seatone group felt
worse after treatment. Though the randomization method was unclear,
this study is otherwise of strong methodological design, and did not sup-
port the efficacy of green-lipped mussel in the treatment of rheumatoid
arthritis.
rHighton and McArthur (1975) published the first clinical study exam-
ining the effect of green-lipped mussel extract on rheumatoid arthritis.
Ulbricht et al. 83
In this double-blind crossover trial, six subjects were randomized to re-
ceive either Seatone capsules (containing green-lipped mussel powder)
or placebo (identical placebo). There were no significant between-group
differences in any of the outcome measures tested (pain, grip strength,
articular index, limbering-up time, or walking time). All five subjects
completing the study increased acetaminophen use, and showed no
preference for treatment (Seatone) or placebo. This early study did not
support the efficacy of Seatone in treating rheumatic disease.
rCaughey et al. conducted a randomized controlled trial to test freeze-
dried extracts of green-lipped mussel as a treatment for rheumatoid
arthritis (Caughey et al., 1983). The study recruited 47 patients with
rheumatoid arthritis, who were to discontinue other therapies before
the experimental treatment. All subjects then started a naproxen regi-
men (750 mg daily for weeks 1–6, followed by placebo naproxen for
weeks 7–23). The subjects were additionally randomized to receive ei-
ther green-lipped mussel capsules 1,050 mg daily or identical placebo
for 12 weeks. No significant difference was observed in any of the out-
come measures between treatment arms (pain, grip strength, articular
index, and morning stiffness). After withdrawal of naproxen, there was
a high dropout rate due to joint pain (15 of 22 patients from the Seatone
group and 15 of 19 patients from the placebo group). This study was
included in a systematic review by Cobb and Ernst (2006) and suggests
a lack of effect of Seatone in rheumatoid arthritis.
rHuskisson et al. (1981) conducted a randomized, placebo controlled,
crossover trial to test whether Seatone green-lipped mussel extract was
superior to placebo for treating rheumatoid arthritis. Subjects (N=30)
were randomized to receive either Seatone (300 mg capsule, three times
daily) or an identical foul-smelling placebo. Treatment (or placebo) was
given for four weeks, followed by crossover to the alternate arm. Three
patients in the treatment group dropped out due to side effects; one
had headaches; another had diarrhea and headaches; the third suffered
constipation. One patient dropped out of the placebo group for reasons
unrelated to the study. All subjects responded to an advertisement for
a Seatone clinical trial and thought they were taking Seatone; this was
reflected in the strong placebo effect. Outcome measurements (pain,
morning stiffness, articular index, proximal interphalangeal joint size,
and analgesic consumption) were similar between active and placebo
treatments. The method of randomization and blinding status were not
stated in this brief report. A strong placebo effect was observed; it
was noted that one patient on placebo was “so enthusiastic” about her
treatment that she discontinued physiotherapy for rheumatoid arthritis.
84 JOURNAL OF DIETARY SUPPLEMENTS
rGibson and Gibson conducted a randomized controlled trial of 28 pa-
tients with rheumatoid arthritis (Gibson et al., 1980), which was included
in a systematic review by Cobb and Ernst (2006). Patients (who failed
to respond to conventional treatment) were randomized to receive ei-
ther capsules containing mussel extract (Seatone) or placebo (dried fish
meal powder). Treatment or placebo was taken orally daily for 90 days,
and outcome measures were assessed (joint stiffness, limbering up time,
grip strength, joint tenderness, pain, functional efficiency, and walking
speed). In the treatment group, 10% reported a transient worsening of
symptoms; no other adverse events were experienced. However, 68%
of rheumatoid arthritis patients experienced overall improvements. In
a second three-month phase of the study, all patients who responded
well to the treatments (i.e., those who did not drop out) were given
Seatone for an additional three months. This second phase was criti-
cized for having lack of proper controls, as the subjects served as their
own controls (Author, 1981 ). Furthermore, the active treatment group
was further divided into responders and nonresponders to Seatone, an
unorthodox practice that potentially complicates the interpretation of
the data (Author, 1981 ); this criticism was later acknowledged by the
study authors (Gibson & Gibson, 1981a). The study was criticized by
a later paper for improper blinding and statistical analysis (Huskisson
et al., 1981). A parallel study evaluated 38 osteoarthritis patients, which
was re-analyzed by Brien et al. and found to suggest lack of benefit
(Brien et al., 2008).
rStudies of lesser design strength: Gibson and Gibson conducted a
double-blind equivalence study which examined Lyprinol
Rgreen-lipped
mussel extract in the treatment of rheumatoid arthritis (38); this study
was systematically reviewed by Cobb and Ernst (Cobb & Ernst, 2006).
Thirty patients were randomized to receive either 210 mg Lyprinol
R
(three capsules, N=15) or 1,150 mg of stabilized mussel powder (five
capsules, N=15). Treatment (or placebo) was taken orally daily for
three months, followed by three months of Lyprinol
Rtreatment for all
subjects. Adverse events were mild and rare (one case each of fluid
retention and transient nausea). Outcome measures included articular
index of joint tenderness (AI), morning stiffness or limbering-up-time
(LUT), grip strength, VAS of pain, and functional index (FI). After the
three-month treatment, 76% of rheumatoid arthritis patients reported
benefits in AI, LUT, and FI. This study also examined 30 patients with
osteoarthritis, reviewed by Brien et al. (2008). Because the number of
capsules differed between the treatments (five vs. three capsules), the
Ulbricht et al. 85
double-blind aspect of this study was questionable. The lack of a placebo
arm further questions the validity of these results.
rGruenwald et al. (2004) conducted a clinical trial to evaluate the effi-
cacy of a mussel-lipid preparation on inflammatory rheumatoid arthritis.
Subjects in the trial had diagnoses of rheumatoid joint disorders with
at least moderate pain and morning stiffness. Potential subjects were
excluded if they were pregnant, breastfeeding, or had severe symptoms
of rheumatism requiring immediate treatment. Adult men and women
(50 total) took one Sanhelios Mussel Lyprinol Lipid Complex capsule,
containing 458 mg of fish oil concentrate (50% EPA and 50% DHA)
and 35 mg Lyprinol, twice daily (morning and evening) for two days;
thereafter, the dosage was increased to two capsules twice daily. Treat-
ment lasted for 12 weeks. Seven mild adverse events were noted. One
case of mild nausea and vomiting was attributed to the treatment, and
suggested to be due to fish oil aversion; this nausea improved by the end
of the trial. The majority of patients and physicians (98%) assessed the
tolerability of the study medication as “very good” or “good.” Of the 50
subjects, 34 required drug therapy before the study; by the end of the
study, 21 were able to reduce medication, and 13 terminated drug ther-
apy completely. One patient withdrew from the study at day 70; reasons
for withdrawal were not specified. At the conclusion of the study, 38%
of the patients were reported to be symptom-free. At six weeks, morning
stiffness was reduced significantly in the treatment group from baseline
measures of 13.7 ±5.9 min by 1.3 ±5.2 min (9.5%, p=.005). At
the end of the trial (12 weeks), morning stiffness was reduced by 2.1
±3.8 min (15.3%, p≤.001). Number of painful joints was reduced
significantly from 4.18 ±2.80 at baseline by 0.30 ±0.81 joints (7.2%,
p=.012) after 6 weeks and 0.60 ±1.18 joints (14.4%, P=.001) after
12 weeks. The number of swollen joints was reduced significantly from
2.62 ±2.29 at baseline by 0.36 ±0.78 joints (13.7%, p=0.002) after
six weeks and 0.68 ±1.00 joints (26.0%, p=.001) after 12 weeks. The
number of painful small joints was significantly reduced after 6 weeks
(9.3%; p=.022) and after 12 weeks (18.6%; p=.002). Pain intensity,
evaluated using a five-point scale (0 =no pain; 4 =very severe pain)
was reduced successively during the course of the trial. According to
physician assessments, the pain intensity decreased from moderate or
severe to mild in 44% (n=22) of treated patients by the completion of
the study; 38% (n=19) of patients reported this level of pain reduc-
tion. Patients with severe pain decreased from 60% at baseline to 25%
at the end of the study. Limitations of the study include lack of a control
group (and thus lack of randomization or blinding); thus, it is difficult to
86 JOURNAL OF DIETARY SUPPLEMENTS
attribute any of the observed effects to Lyprinol or the other constituents
of the treatment capsules.
PRODUCTS STUDIED
Brands Used in Statistically Significant Clinical Trials
rLyprinol
R(Cho et al., 2003; Emelyanov et al., 2002; Lau et al., 2004;
McPhee et al., 2007); PernaTM and PernaTM Plus (DaVinci Laboratories,
USA) (Kendall et al., 2000), Sanhelios Mussel Lyprinol
RLipid Complex
(Gruenwald et al., 2004); Seatone (Audeval & Bouchacourt, 1986; Gib-
son et al., 1980; Gibson & Gibson, 1998). Four studies (Caughey, et al.,
1983; Highton & McArthur, 1975; Huskisson et al., 1981; Larkin et al.,
1985) found no significant difference between Seatone and placebo.
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doi: 10.1080/19390210802690191
