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Spirulina

Scientific Name(s): Arthrospira maxima Setchell et Gardner, Arthrospira platensis (Nordstedt) Gomont
Common Name(s): Dihe, Spirulina, Tecuitlatl

Clinical Overview

Use

Spirulina is sold in the United States as a health food or supplement. Myriad claims exist for its immunostimulatory, hypolipidemic, antiviral, and anticancer effects; however, there is limited evidence to support these indications.

Dosing

Doses in clinical studies have ranged from 1 to 10 g/day.

Contraindications

Phenylketonuria; however, this has not been substantiated.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Because of possible presence of mercury and other heavy metal contaminants, spirulina should be avoided during pregnancy.

Interactions

None well documented.

Adverse Reactions

Few reports of adverse reactions are available. However, spirulina-associated hepatotoxicity and reactions from heavy metal contamination are possible.

Toxicology

Spirulina is considered nontoxic to humans at usual levels of consumption; however, information is limited.

Biology

Spirulina, a blue-green algae (cyanophytes/cyanobacteria), grows as microscopic, corkscrew-shaped multicellular filaments and is now classified as a distinct genus, Arthrospira. A. platensis is found in Africa and Asia, and A. maxima is found in Central America.1, 2 Free growing, spirulina exists only in high-salt alkaline water in subtropical and tropical areas, sometimes imparting a dark-green color to bodies of water.3 Spirulina is noted for its characteristic behavior in carbonated water and energetic growth in laboratory cultures.4 It is commercially grown in the United States and has been proposed as a primary foodstuff to be cultivated during long-term space missions because it withstands extreme conditions.5, 6 Due to its unique growth requirements, contamination of open pond cultures of spirulina by other microorganisms is usually slight, with the alga growing as a relatively pure culture.

For information on red, blue, or green algae, see the Seaweed monograph.

History

Spirulina has been described in literature since the 16th century. Spanish explorers observed the Aztecs harvesting a blue mud that probably consisted of spirulina.2 The mud, which was dried to form chips or flavored loaves, was obtained from Lake Texcoco near Mexico City. Spirulina was similarly harvested in the Sahara Desert from small lakes near Lake Chad, where it was called dihe. Thus, 2 cultures approximately 10,000 km apart, independently discovered and utilized the nutritional properties of spirulina.2 Currently, spirulina is actively marketed by numerous companies as a nutritional supplement.7

Chemistry

Spirulina is composed of approximately 65% crude protein, high levels of B-complex vitamins,8 vitamin E,9 beta-carotene,10 and zeaxanthin.4, 11 The protein content includes 22 essential amino acids2, 12 and the total protein is nutritionally superior to legume protein, but inferior to meat protein.2 The proteins C-phycocyanin and allophycocyanin in spirulina have been the focus of much research.13, 14 High levels of gamma linolenic acid, a polyunsaturated fatty acid, are present.15 An assay for spirulina lipids using high-pressure liquid chromatography-mass spectrometry has been developed.16 Spirulina preparations contain 300 to 400 ppm iron (dry weight), and unlike many forms of plant iron, has high bioavailability when ingested by humans. A dosage of 10 g/day can contain 1.5 to 2 mg of absorbable iron, similar to that of standard ferrous sulfate.17, 18 Trace elements present at high levels include manganese, selenium, and zinc. Calcium, potassium, and magnesium are also concentrated in the organism.19 Calcium spirulan, a sulfated polysaccharide, was characterized from A. platensis.20

Uses and Pharmacology

Clinical trials have investigated spirulina's potential but have been too small to support its purported effects.21

Allergic rhinitis and asthma

Experimental data have suggested that C-phycocyanin can selectively inhibit release of histamine from mast cells and prevent increases in immunoglobulin E. A small study in patients with mild to moderate asthma suggested that spirulina supplementation (1 g/day) produced improvement in lung function parameters.22 A study evaluating spirulina in allergic rhinitis suggested a positive effect on laboratory values, but no clinical outcomes were reported.23 A 6-month, double-blind, placebo-controlled study (n = 150) of allergic rhinitis found superior efficacy for spirulina 2 g/day versus placebo with regard to diary-based symptom scores of nasal discharge.24

Antimicrobial activity

In vitro data

A provocative suggestion has been made that human cultures in which large amounts of algae are consumed have lower levels of HIV infection.25 Spirulina and its extracts have been evaluated for antiviral activity. One in vitro study found that the sulfated polysaccharide calcium spirulan interfered with the replication of several enveloped viruses, including herpes simplex, cytomegalovirus, mumps, measles, influenza A, and HIV-1.20 Another study described a slightly different range of viruses susceptible to the extract.26 HIV-1 adsorption and penetration were inhibited by an aqueous extract of spirulina, and a crude hot water extract reduced HIV-1 replication.25 This type of in vitro activity is common to acidic polysaccharides from a variety of sources. Enterovirus is also susceptible to spirulina, and allophycocyanin was the active constituent.27 Spirulina demonstrated some in vitro activity against common human bacterial pathogens but less than that of the standard comparator.28 Immune stimulation by phycocyanin and polysaccharides of spirulina led to an antifungal and antibacterial effect in mice.29

Cinical data

An evidence-based review (14 studies; n = 1,725 adults, 271 children) evaluated the benefits of nutritional supplements including spirulina in HIV infected people. The reviewers found firm conclusions difficult to make due to the small study sizes and heterogeneity of studies. No mortality benefit was seen for nutritional supplement nor spirulina compared with control (placebo or no supplement) in malnourished, antiretroviral therapy naive adults in the 2 studies evaluating these treatments. The pediatric study that evaluated spirulina’s effect on anthropometric measures found no benefit from 10 g/day of spirulina after 8 weeks compared with control, with both groups consuming the same diet. In general, the available evidence did not support use of specific macronutrients, whey protein, or spirulina for improvements in anthropometric, immunologic, or clinical outcomes in HIV-infected adults and children.111

Antioxidant

Experimental and animal data

The spirulina protein phycocyanin in pure form was active in 4 different cell-free radical-scavenging assays; however, phycocyanin-containing selenium was more effective.81 In cellular assays of antioxidant activity, 4 commercial spirulina preparations were also active.82 Spirulina supplementation of rats did not increase plasma or liver alpha-tocopherol levels83; however, another study reported effective antioxidant activity using combinations of whey protein and spirulina.84 C-phycocyanin from spirulina reduced oxidative stress in hamsters fed an atherogenic diet.85 Similarly, rabbits fed a high-cholesterol diet were protected from oxidative stress by 4 to 8 weeks of spirulina in feed at 1% or 5%.86 An in vitro study determined that both the phycocyanin and non-phycocyanin bioactive compounds in a novel A. platensis–based aqueous cyanophyta extract contributed to antioxidant and anti-inflammatory effects without a negative impact on blood clotting. At doses between 125 and 500 mcg/mL, there were more events of clots, which showed to be statistically significant (P < 0.05) in the presence of phycocyanin, non-phycocyanin, and aqueous cyanophyta extract. However, lipoxygenase inhibition was associated specifically with the non-phycocyanin components.113

Clinical data

Other studies suggest spirulina as an antioxidant87, 115 but clinical importance has not been demonstrated88, 89 and 1 small clinical study showed spirulina to be without effect on plasma antioxidant status.90

Cancer

Experimental and animal data

C-phycocyanin showed a dose-dependent inhibition of HeLa and human chronic myeloid leukemia cell growth and proliferation in vitro.30, 31 Induction of apoptosis was considered to be one of the mechanisms involved.32 Doxorubicin-resistant HepG2 liver cancer cells were inhibited by spirulina C-phycocyanin through an apoptotic mechanism33 while water-soluble polysaccharides were implicated as the active agent against stomach cancer cells.34 A combination of selenium and spirulina inhibited MCF-7 breast cancer cells via growth arrest and apoptosis.35 Survival rates increased in mice with liver cancer treated with C-phycocyanin, and tumor regression has been reported in animals with oral cancer.36, 37, 38 Activation of antitumor natural killer cells by spirulina enhanced antitumor efficacy in a B16 mouse melanoma model, and the effect was abolished in MyD88 null/null mice, indicating that NK cell activation was a key pathway.39 In a hamster cheek pouch model of carcinogenesis, 10 mg/day of spirulina extract reduced dysplastic changes40 which was further confirmed by an immunohistochemical study.41 Spirulina was chemopreventative in a dibutyl nitrosamine carcinogenesis model.42 It also induced lesion regression in tobacco chewers with oral leukoplakia in a study conducted in India.43

Diabetes

Animal data

A study in alloxan-induced diabetic rats revealed that spirulina at 10 mg/kg orally for 30 days lowered glucose levels, while slightly elevating insulin.44

Clinical data

Two small clinical studies investigated the effects of spirulina supplementation in type 2 diabetes, with improvement noted in fasting blood sugar and lipid profiles. Suggested mechanisms of action include hypoglycemia caused by fiber content or possible insulin-stimulating action of peptides and polypeptides of spirulina proteins. The actions on lipids have been attributed to gamma linolenic acid content.45, 46 Insulin sensitivity and LDL cholesterol was reported to be significantly improved with administration of spirulina supplementation compared to placebo in obese patients with stable treated hypertension (P<0.001) in a randomized, controlled, double-blind trial (n=50).115

Dietary supplement

Animal data

Spirulina, considered a food item for centuries in many countries, is now popularly thought of as a dietary supplement.5 Spirulina consumption was purported to aid in weight loss because of its high phenylalanine content, but a US Food and Drug Administration review found no evidence to support this claim.47, 48 Suggestions that spirulina is a valuable source of vitamin B12 have been similarly disputed.5 Skeletal muscle protein (myosin) was increased in young rats fed spirulina as the sole dietary protein source compared with casein.49

Clinical data

A study of spirulina supplementation for 8 weeks demonstrated clinical improvement in weight gain and increased hemoglobin levels in malnourished children in the West African nation of Burkina Faso.50 Similar results have been demonstrated among children who are HIV-positive.51 In elderly Koreans, spirulina 8 g/day for 16 weeks had a variety of positive effects (cholesterol, antioxidant status, interleukin [IL]-2 and IL-6 levels) observed in a randomized, double-blind, placebo-controlled study.52 In a study of athletic training, spirulina increased time to fatigue, decreased carbohydrate oxidation rate, and increased fat oxidation rate, leading to an increase in exercise performance.53

Hyperlipidemia

Animal data

Experiments in rats suggest that C-phycocyanin exhibits hypocholesterolemic action.54 In rabbits fed a high-cholesterol diet, spirulina (1% or 5% in diet) lowered serum triglycerides, total cholesterol, and low-density lipoprotein (LDL) at 8 weeks. High-density lipoprotein (HDL) was markedly increased.55

Clinical data

Two small clinical studies examined the role of spirulina in hyperlipidemia secondary to nephrotic syndrome. Both populations showed an improved lipid profile with spirulina supplementation; however, the control group in 1 experiment also showed improvement. The gamma linolenic acid content of spirulina may have played a role in the mechanism of action.56, 57 A study in type 2 diabetes patients reported a reduction in triglycerides with 8 g/day of spirulina.58 In normal volunteers, 4.5 g/day of spirulina for 6 weeks lowered blood pressure, total cholesterol, LDL, and increased HDL.59, 60 A 15-day study in healthy volunteers found that 5 g/day of spirulina produced a significant reduction (−20%, P = 0.04) in postprandial triglyceride levels compared with baseline. Subgroup analysis found that triglyceride reduction was greatest in 10 to 12 year old study participants.112

Pooled results reported in a systematic review and meta-analysis of 7 randomized controlled trials (N=522) evaluating spirulina effects on lipid parameters supported efficacy in improving total cholesterol (weighed mean difference [WMD], −46.76 mg/dL; P<0.001), LDL (WMD, −41.32 mg/dL; P<0.001), triglycerides (WMD, −44.23 mg/dL; P<0.001), and HDL (WMD, +6.06 mg/dL; P=0.001); an effect that was found to be independent of dose. Diagnoses of participants included in trials were type 2 diabetes, ischemic heart disease, overweight, nephrotic syndrome, and HIV with one trial enrolling volunteers. No adverse events were reported for any of the dosages that ranged from 1 to 10 g/day and for a duration of 2 and 12 months.114

Immune system effects

Experimental and animal data

Most in vitro and animal experiments have suggested immunostimulatory effects; however, 1 study found a spirulina extract to be immunosuppressive.61 Activation of monocytes and macrophages62, 63 as well as augmentation of interleukin and interferon production, have been demonstrated.64 Intestinal epithelial lymphocytes of aged mice treated with spirulina were increased compared with the control aged group.65 An ex vivo study of NK cells from spirulina-treated healthy patients showed increased NK activity, which was confirmed by a second study in which NK cell and T-cell markers were increased by spirulina.66

Clinical data

A clinical study in healthy men found that oral administration of spirulina for 3 months resulted in enhanced interferon production and natural killer (NK) cell capacity.25 A clinical trial in elderly patients showed positive effects on anemia and immunosenescence after 6 and 12 weeks of supplementation.67 The immunostimulatory effects appear to be largely mediated by spirulina polysaccharides.62, 63

Prevention of toxicity due to metals or organic compounds

Animal data

A 5% spirulina-supplemented diet prevented carbon tetrachloride-induced fatty liver in rats.68 Cadmium toxicity in rats was reduced by spirulina, as measured by liver histopathology.70 Mercuric chloride-induced oxidative stress in mice was blocked by spirulina at 800 mg/kg orally for 40 days.71 Lead acetate damage to rats was minimized by spirulina via normalizing plasma and liver lipid levels, as well as via its antioxidant effect.72 A protein extract and purified phycocyanin protected neuroblastoma cells from iron-induced toxicity.73 Spirulina pretreatment protected mice against acetaminophen and galactosamine-induced liver damage.74 Liver and kidney enzyme markers of toxicity were reduced by spirulina following 4-nitroquinoline 1-oxide insult to rats.75 Spirulina decreased cisplatin-induced nephrotoxicity in rats, an effect attributed to an antioxidant action.76 Gentamicin-induced kidney damage in rats was reversed by intraperitoneal spirulina 1 g/kg daily.77 In pregnant mice, teratogenicity due to cadmium was reduced by 125 to 500 mg/kg of spirulina by intragastric administration for 17 days of gestation.78 Mutagenicity of cyclophosphamide in mice pretreated with spirulina was reduced.79

Clinical data

In a case series of 3 patients with nonalcoholic fatty liver disease, 4.5 g/day of spirulina for 3 months improved ALT values and lipid profiles.69 In a small, randomized, placebo-controlled trial, spirulina plus zinc increased urinary excretion of arsenic and decreased arsenic hair-content in people with long-term exposure to arsenic.80

Other uses

Animal data

C-phycocyanin inhibited platelet aggregation in ex vivo experiments.91 In mice with zymosan-induced arthritis, phycocyanin exerted a scavenging action against reactive oxygen species and anti-inflammatory activity.92 Similar experiments with complete Freund's adjuvant-induced arthritis found 800 mg/kg of oral spirulina effective in reducing inflammation.93 In rats, collagen-induced arthritis was inhibited by 400 mg/kg of spirulina.94 Osteoporosis was inhibited in rosiglitazone-treated rats by 500 mg/kg/day of oral spirulina.95 A rat study showed evidence that spirulina could protect neural stem cells and promote their growth96; however, an amyotrophic lateral sclerosis (ALS) support network did not find the evidence compelling for use in ALS.97 Pretreatment with spirulina 180 mg/kg orally in a rat cerebral ischemia-reperfusion injury model reduced neurologic deficits and histological changes.99 A polysaccharide extract of spirulina was antiangiogenic in a mouse corneal model.100 Spirulina also has been reported to protect mouse and human bone marrow cells against gamma radiation.23, 76, 87, 101, 102, 103

Clinical data

Spirulina supplementation (3 g/day) was ineffective against idiopathic chronic fatigue in a small study.98

Dosing

There is insufficient clinical data to guide dosing of spirulina for therapeutic effect. Spirulina has typically been studied in daily dosage of 1 to 10 g for 2 to 12 months.22, 50, 111, 112, 114

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Spirulina may contain more than 180 mcg of mercury per 20 g19 and should be avoided.

Interactions

None well documented. An antiplatelet effect has been demonstrated in vitro but was not clinically evaluated.91

Adverse Reactions

Few reports of adverse reactions are available. Case reports of immunoblistering104 and rhabdomyolysis105 linked to spirulina have been published. Cyanobacteria (blue-green algae) may contain the amino acid phenylalanine; therefore, people with phenylketonuria should avoid spirulina.5 A case of spirulina-associated hepatotoxicity has been reported.106 Hepatotoxic microcystins and neurotoxic anatoxin-a are produced by a number of cyanobacteria and have been reported as spirulina contaminants.107, 108 Other contaminants include the heavy metals mercury, cadmium, arsenic, and lead, as well as microbes cultivated on fermented animal waste.19, 109 There may be a potential for adverse reactions in people with autoimmune disorders who consume immunostimulatory herbal preparations.110

Toxicology

Information is limited. Spirulina is considered nontoxic to humans at usually consumed amounts.

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