Journal of Dietary Supplements, 9(1):57–77, 2012

C 2012 by Informa Healthcare USA, Inc.
Available online at www.informahealthcare.com/jds
DOI: 10.3109/19390211.2012.653530

An Evidence-Based Systematic Review of Annatto

(Bixa orellana L.) by the Natural Standard
Research Collaboration

Catherine Ulbricht8 , Regina C. Windsor2 , Ashley Brigham1 , J.

Katherine Bryan2 , Julie Conquer3 , Dawn Costa2 , Nicole Giese2 ,
Jacquelyn Guilford2 , Elizabeth R.B. Higdon2 , Kyla Holmes4 , Richard Isaac2 ,
Sara Jingst1 , Juila Kats1 , Laurie Peery4 , Erica Rusie2 , Anneli Savinainen5 ,
Todd Schoen6 , Tera Stock7 , Shaina Tanguay-Colucci2 , & Wendy Weissner2
1
Northeastern University, Boston, Massachusetts, USA, 2 Natural Standard Research
Collaboration, Somerville, Massachusetts, USA, 3 RGB Consulting, London, Ontario,
USA, 4 Appalachian College of Pharmacy, Oakwood, Virginia, USA, 5 Millennium
Pharmaceuticals, Inc. (MPI), Cambridge, Massachusetts, USA, 6 St. John Fisher
College, Rochester, New York, USA, 7 Massachusetts College of Pharmacy and Health
Sciences, Boston, Massachusetts, USA , 8 Massachusetts General Hospital, Boston,
Massachusetts, USA

SYNONYMS/COMMON NAMES/RELATED SUBSTANCES

• Acetate, acetone, achiot (Spanish-–Colombia), achiote (Spanish–-Peru), achiote
seeds, achiotillo, achiotin, annotta, annatto extract, annatto tree, aploppas,
apocarotenoids, arnotta, arnotto (Native American), azo dyes, biche, bija, Bixa
acuminata, Bixa acuminata Bojer, Bixa americana, Bixa americana Poiret, Bixa
katangensis Delpierre, Bixa odorata, Bixa odorata Ruiz & Pav. ex G. Don., Bixa
orellana, Bixa platycarpa, Bixa platycarpa Ruiz & Pav. ex G. Don., Bixa pur-
purea, Bixa purpurea Hort., Bixa tinctoria, Bixa tinctoria Salixb., Bixa upatensis,
Bixa upatensis Grosscurdy, Bixa urucurana, Bixa urucurana Willd., Bixaceae
(family), bixin, brickdust, butter color, BXN, calcium sulfate, carotenoids, chalk,
changuarica (Spanish—Mexico), colcothar, E160b, E number E160b, eroya,
essential oil, false damiana, farinaceous matter, fat-soluble color, fatty acid, fiber,
flag annotta, gypsum, ishwarane, jafara, kasujmba-kelling, kham thai, k’u-zub
(Spanish—Mexico), lipstick tree, natural color, natural food color, norbixin,
occidentalol, occidentalol acetate, ochre, onoto (Spanish—Venezuela), orellana,
Orellana americana, Orellana americana Kuntze, Orellana orellana, Orellana
orellana (L.) Kuntze, orellin, orleana, Orleanstrauch (German), orucu-axiote,

Address correspondence to: Catherine Ulbricht, Massachusetts General Hospital, 55 Fruit Street, Boston,
MA 02114, USA (E-mail: ulbricht@naturalstandard.com).
(Received 23 December 2011; accepted 28 December 2011)

57
58 Ulbricht et al.

phosphoric acid, potassa, powdered bricks, pumacua (Mexico), red ochre,

rocou (Dutch, French), roucou (French—Dominica and the French West
Indies), roucouyer, ruku (Hungarian), sand, sand gypsum, silica, spathulenol,
starchy bodies, sulfuric acid, terebinthinous body, tomentosic acid, Ultrabix,
unane, urucu (Portuguese—Brazil), urucum (Portuguese), urucu-üva, uruku,
water-soluble color, (Z,E)-farnesyl acetate.

CLINICAL BOTTOM LINE

Brief Background
• Achiote (Bixa orellana) is a tree or shrub native to the tropics of North and South
America, the Caribbean, and the East Indies. It is most abundant from Mexico to
Ecuador, as well as Brazil, Bolivia, Venezuela, and several other South American
countries. Bixa orellana is cultivated in South America and also in southeastern
Asia, where it was introduced by Spaniards in the 17th century.
• Annatto is a pigment produced from the seed of the achiote tree (Bixa orellana).
Annatto is commonly used as a coloring agent for pharmaceutical ointments and
plasters. It contains the pigment bixin, which is commonly used in the food and
cosmetics industries to add yellow or red colors (Rodrigues et al., 2007). Annatto
has also long been a staple in Latin American cooking and Caribbean cuisine as a
coloring and flavoring agent, and it is sometimes used as a substitute for saffron.
Annatto adds a slightly sweet and peppery taste.
• Annatto has traditionally been used for diabetes and snakebites. Annatto has
recently been used as an ingredient in weight-loss products. Human study has
shown that annatto may not effectively treat urinary disorders associated with
benign prostatic hyperplasia (BPH). At this time, there is insufficient available
evidence in humans to support the use of achiote (Bixa orellana) or annatto for
any indication.

Scientific Evidence for Common/Studied Uses

Urinary disorders (BPH) D

Historical or Theoretical Uses That Lack Sufficient Evidence

• Analgesic (Shilpi et al., 2006), antacid, anticoagulant, anticonvulsant (Shilpi
et al., 2006), antidote to poisons, antifungal (Braga et al., 2007), anti-
inflammatory (Reddy, Alexander-Lindo, & Nair, 2005), antimicrobial (Caceres
et al., 1995; Castello, Phatak, Chandra, & Sharon, 2002; Fleischer, Ameade,
Mensah, & Sawer, 2003; Galindo-Cuspinera, Westhoff, & Rankin, 2003; Shilpi
et al., 2006), antioxidant (Antunes, Pascoal, Bianchi, & Dias, 2005; Junior et al.,
2005; Kovary et al., 2001; Martinez-Tome et al., 2001; Shilpi et al., 2006), antipar-
asitic, antipyretic, antiseptic, antivenom (Nunez et al., 2004; Otero et al., 2000),
aphrodisiac (‘Feature photograph’, 2009), apnea, ascaridiasis, asthma, astringent
(‘Feature photograph’, 2009), bacterial skin infections, blisters, blood cleanser,
burns (‘Feature photograph’, 2009), cancer (Antunes et al., 2005; Reddy et al.,
2005; Ribeiro, Mantovani, Ribeiro, & Salvadori, 2006), cardiotonic, cataracts,
 Evidence-Based Systematic Review of Annatto 59

cicatrizant (scar formation), colic, conjunctivitis (‘Feature photograph’, 2009),

constipation, cosmetic uses (Rodrigues et al., 2007), coughs, cuts, cystitis (‘Fea-
ture photograph’, 2009), diabetes (Fernandes et al., 2002; Lans, 2006; Morrison,
Thompson, Pascoe, West, & Fletcher, 1991; Russell, Morrison, & Ragoobirsingh,
2005; Russell, Omoruyi, Pascoe, & Morrison, 2008), diabetic complications
(Terashima, Shimizu, Horie, & Morita, 1991), diabetic neuropathy, diarrhea
(Shilpi et al., 2006), digestive problems (‘Feature photograph’, 2009), diuretic,
dysentery (‘Feature photograph’, 2009), edema, enhanced immune function,
epilepsy (‘Feature photograph’, 2009), eye infections, fever, food preservation,
food uses (coloring, flavoring, fermentation) (Scotter, 2009), gonorrhea (Caceres
et al., 1995), hair tonic, headaches, heartburn, hemorrhage, hemorrhoids, hep-
atitis, hepatoprotection, high cholesterol, hyperglycemia, hypertension (Lans,
2006), infections, inflammation, influenza, insect repellent, insecticide, irritable
bowel syndrome (IBS) (Floch, 2009; Stein, 2009), jaundice (Lans, 2006), kidney
disorders, laxative, leprosy, liver disorders, measles, mouth and throat inflamma-
tion, muscle relaxant, nausea, pleurisy, prostate health, rectal complaints, renal
impairment, respiratory distress, sedative (Shilpi et al., 2006), skin disorders,
solar ultraviolet protection, sore throat, stomach acid reduction, stomach disor-
ders, stomachache, styptic, sunstroke, tonic, tonsillitis, urinary retention, uterine
disorders, vaginitis, venereal diseases, vomiting, weight loss, wound healing.

Expert Opinion and Historic/Folkloric Precedent

• Bixa orellana has traditionally been used for a variety of ailments and conditions
worldwide, most prominently in South America, Mexico, and the Caribbean. All
parts of the plant have been used, including the dried pulp of the fruit, roots,
leaves, and seeds.
• Bixa orellana has been used in the Caribbean as a folk remedy and as part of West
Indian folk medicine to treat diabetes mellitus (Morrison et al., 1991; Russell
et al., 2005, 2008). In a survey of ethnomedicines used in Trinidad and Tobago,
annatto was reportedly used to treat diabetes, jaundice, and hypertension (Lans,
2006). Traditional healers in Colombia have used annatto as an antivenin for
snakebites (Otero et al., 2000). The seeds are believed to be an expectorant,
while the roots are thought to be a digestive aid and a cough suppressant.
• Bixa orellana seed extract (annatto) is used widely in Brazilian cuisine. Brazil-
ians also purportedly use the Bixa orellana leaf to provide relief from heartburn
and indigestion. There is a purported increased incidence of new cancer cases in
Brazil, and it has been proposed that the use of annatto may be a viable chemo-
preventive strategy for Brazilians (Ribeiro et al., 2006). Curanderos (traditional
healers) in the Peruvian Amazon squeezed the juice from the fresh leaves and
applied it to the eye to treat inflammation and eye infections. For epilepsy, the
juice is used in a combination of 12 fruits and taken twice daily for 5 days. In Peru,
Bixa orellana leaf was used to treat mild indigestion and to strengthen the liver.
A tea made with the young shoots was used as an aphrodisiac and astringent, and
to treat skin problems, fevers, dysentery, and hepatitis. According to secondary
sources, in order to help bowel elimination and decrease mucus production in
newborn babies, the Cojedes tribe of South America employs an infusion of
60 Ulbricht et al.

Bixa orellana flowers. According to secondary sources, Native Americans used a

decoction of Bixa orellana leaves to support healthy respiration. In Suriname,
Bixa orellana tea was drunk to treat nausea.
• Bixa orellana products are often marketed as herbal treatments for liver con-
ditions, urinary conditions, heartburn, digestive and prostate problems, internal
inflammation, arterial hypertension, high cholesterol, cystitis, obesity, and renal
insufficiency, and to strengthen the immune system. Bixa orellana is also used in
multi-ingredient weight-loss products.
• The effect of base media (palm kernel oil or paraffin wax) on the color stabil-
ity of annatto dye in industrial products has been examined (Adetuyi, Lajide,
& Popoola, 2006). A method has been described for a unique drying process
for annatto that minimizes the introduction of oxygen into the annatto, reduc-
ing the risk of color fade (‘Showcase’, 2006). A method has been described for
isolation of large full-length cDNA from Bixa orellana mature tissues contain-
ing large quantities of pigments, phenols, and polysaccharides (Rodriguez-Avila,
Narvaez-Zapata, Aguilar-Espinosa, & Rivera-Madrid, 2009).
• According to the US Food and Drug Administration (FDA), the toxicology pro-
file of annatto seeds and extract has been fully investigated for annatto’s use as
a food additive. Annatto is specified in the Food Chemical Codex (No. 73.30,
73.1030, and 73.2030) and is generally recognized as safe (GRAS) for human
consumption in food products. There is a lack of available information about the
GRAS status for the medicinal use of annatto. The European Union uses “E
numbers” to identify food additives. E stands for “Europe.” Annatto food color-
ing has the E number E160b (Scotter, 2009).

Brief Safety Summary

• Likely safe: When used orally in food amounts in nonsensitive individuals.
• Possibly safe: When used medicinally in small dosages of 10–20 mg of powdered
Bixa orellana leaf tablet daily for up to 2 weeks, based on expert opinion and
animal study (Agner, Barbisan, Scolastici, & Salvadori, 2004).
• Possibly unsafe: When used in patients with bleeding disorders or those using
anticoagulants (secondary sources). When used in patients with impaired kid-
ney function (Bautista, Moreira, Batista, Miranda, & Gomes, 2004). When used
in patients taking mutagenic agents, such as cyclophosphamide (Alves de Lima,
Azevedo, Ribeiro, & Salvadori, 2003). When used in patients taking diuretics
(anecdote). When used in patients taking antihypertensive agents (theoretical).
When used in patients using cytochrome P450 1A or 2B substrates (De Oliveira,
Silva, Manhaes-Rocha, & Paumgartten, 2003). When used in patients with a his-
tory of constipation or those who are using laxatives (Shilpi et al., 2006). When
used in patients with diabetes or those using antidiabetic agents (Fernandes
et al., 2002; Morrison et al., 1991; Russell et al., 2005, 2008). When used in patients
using CNS depressants (Shilpi et al., 2006). A methanol extract of Bixa orellana
leaves reduced gastrointestinal motility (Shilpi et al., 2006) and theoretically may
alter the absorption of concomitantly administered drugs.
• Likely unsafe: When used by individuals who may be or are allergic or hyper-
sensitive to Bixa orellana, Bixa orellana seeds, constituents of Bixa orellana, or
 Evidence-Based Systematic Review of Annatto 61

any member of the Bixaceae family (Lucas, Hallagan, & Taylor, 2001; Nish,
Whisman, Goetz, & Ramirez, 1991; Taylor & Hefle, 2001).

DOSING/TOXICOLOGY

General
• Doses may be based on those most commonly used in available trials, or on his-
torical practice. However, with natural products, it is often not clear what the op-
timal doses are to balance efficacy and safety. Preparation of products may vary
from manufacturer to manufacturer, and from batch to batch within one manu-
facturer. Because it is often not clear what the active component(s) of a product
is, standardization may not be possible, and the clinical effects of different brands
may not be comparable.

Standardization
• There is no well-known standardization for Bixa orellana.

Adult (Age ≥ 18)

Oral
• Tablets/capsules: Traditionally, a typical oral dose is 1–2 g of the powdered Bixa
orellana leaf in tablets or capsules twice daily.
• Tea: Although not widely available in the United States, standard decoctions of
Bixa orellana leaves have been taken by the half-cupful two or three times daily
for prostate and urinary difficulties, as well as for high cholesterol and hyperten-
sion. Ground Bixa orellana seed powder has also been used in small dosages of
10–20 mg daily.
• Tincture: Based on anecdote, Bixa orellana has been used historically as a 4:1
tincture in a dose of 2–4 mL twice daily.
• Urinary disorders (BPH): 250 mg of encapsulated dried Bixa orellana leaf three
times daily for 12 months has been used without evidence of benefit (Zegarra
et al., 2007).

Pediatric (Age < 18)

• Insufficient available evidence.

Toxicology
• In animal studies, annatto at doses as high as 2,000 mg/kg daily was not toxic;
specifically, it was not genotoxic or carcinogenic (Agner et al., 2004; Alves de
Lima et al., 2003; Bautista et al., 2004; Fernandes et al., 2002; Hagiwara et al.,
2003; Paumgartten et al., 2002). Although annatto has not been found to be mu-
tagenic or an inhibitor of induced mutations, it should be used carefully, since
high doses may increase the effect of another mutagen (cyclophosphamide), ac-
cording to mouse study (Alves de Lima et al., 2003).
• In Sprague-Dawley rats, the no-observed-adverse-effect level (NOAEL) for
annatto extract was judged to be a dietary level of 0.1% (69 mg/kg of body
62 Ulbricht et al.

weight daily for males, 76 mg/kg of body weight daily for females) (Hagiwara
et al., 2003). The NOAEL for annatto-induced maternal and developmental
toxicity in Wistar rats was 500 mg/kg of body weight daily or greater (or
≥140 mg of bixin/kg of body weight daily) by the oral route (Paumgartten
et al., 2002).
• In human hepatoma (HepG2) cells, doses of annatto up to 10 mcg/mL were de-
void of mutagenic activity (Barcelos et al., 2009).
• In vitro, norbixin, a constituent of Bixa orellana, promoted copper(II)-induced
DNA damage on supercoiled plasmid DNA (Ouyang, Zhang, Yi, & Xi, 2008).
The mechanism may involve participation of norbixin’s long-chain conjugated
polyene unit in the reductive reaction of copper(II) ion to generate free radicals,
promoting greater DNA damage through the interactions between DNA and the
radicalized carotenoids.
• A joint Food and Agriculture Organization of the United Nations (FAO)/World
Health Organization (WHO) Expert Committee evaluated the technical, toxi-
cological, and intake data for certain food additives, including annatto extracts;
further information is not available (‘Evaluation of certain food additives 2007).

ADVERSE EFFECTS/PRECAUTIONS/CONTRAINDICATIONS

Allergy
• Avoid in patients with known allergy/hypersensitivity to Bixa orellana, its con-
stituents, or any members of the Bixaceae family.
• In one case report, annatto caused anaphylaxis with symptoms including ur-
ticaria, angioedema, and severe hypotension 20 min following ingestion of milk
and Fiber One cereal, which contained annatto dye (Nish et al., 1991). According
to expert opinion, annatto may be classified as rarely allergenic, due to its long
use primarily as a food additive (Lucas et al., 2001; Taylor & Hefle, 2001).
• There is a case report of a 58-year-old male who experienced anaphylaxis follow-
ing ingestion of annatto in a cheese product (Ebo Ingelbrecht, Bridts, & Stevens,
2009). He experienced four episodes of severe anaphylaxis with urticaria and an-
gioedema.

Adverse Effects/Postmarket Surveillance

• General: Annatto is generally well tolerated, with rare reports of adverse effects,
which have occurred primarily in individuals with sensitivities.
• Cardiovascular: Based on anecdote, annatto may lower blood pressure. A case re-
port detailed adverse reactions associated with annatto dye that included severe
hypotension and angioedema (Nish et al., 1991).
• Dermatologic: There are case reports of adverse reactions associated with an-
natto dye in food products that included urticaria and angioedema (Ebo et al.,
2009; Nish et al., 1991). Eczema may also occur.
• Endocrine: Based on animal studies, annatto may alter glycemic and insulin lev-
els (Fernandes et al., 2002; Morrison et al., 1991; Russell et al., 2005). Hyperinsu-
linemia and hypoinsulinemia have been reported in animal study using annatto
pigments.
 Evidence-Based Systematic Review of Annatto 63

• Gastrointestinal: In clinical trial, 68 patients with BPH with moderate lower uri-
nary tract symptoms using Bixa orellana complained of constipation (Zegarra
et al., 2007).
• Hepatic: In canine study, administration of annatto induced hyperglycemia but
with concurrent damage to mitochondria and endoplasmic reticulum, mainly in
the liver and pancreas (Morrison et al., 1991).
• Renal: Based on anecdote, some individuals may be highly sensitive to annatto,
and a diuretic effect may occur at low doses, such as from eating foods in which
annatto was used as a coloring or flavoring agent.

Precautions/Warnings/Contraindications
• Use cautiously in patients with bleeding disorders or those using anticoagulants;
based on secondary sources, annatto may have anticoagulant effects.
• Use cautiously in patients with impaired kidney function, as rat study found that
annatto caused kidney apoptosis, though the nature of the apoptosis was not in-
vestigated in the study (Bautista et al., 2004).
• Use cautiously in patients taking mutagenic agents, such as cyclophosphamide as,
in vitro, high doses of annatto increased the effect of cyclophosphamide (Alves
de Lima et al., 2003).
• Use cautiously in patients taking diuretics as, based on anecdote, annatto may
have diuretic effects and theoretically may increase the risk of electrolyte imbal-
ances.
• Use cautiously in patients taking antihypertensive agents, as annatto, theoreti-
cally, may potentiate the effects of antihypertensive medications.
• Use cautiously in patients using cytochrome P450 1A or 2B substrates as, in in
vitro and animal study, annatto induced these isoenzymes (De Oliveira et al.,
2003).
• Use cautiously in patients with a history of constipation or those who are using
laxative, as, based on animal study, annatto may have antidiarrheal activity and
antagonize these effects (Shilpi et al., 2006).
• Use cautiously in patients with diabetes or those using antidiabetic agents as,
based on animal studies, annatto has been shown to modulate glucose and insulin
levels (Fernandes et al., 2002; Morrison et al., 1991; Russell et al., 2005, 2008).
• Use cautiously in patients using CNS depressants as, based on animal study, a
methanol extract of Bixa orellana leaves exerted sedative effects (Shilpi et al.,
2006).
• Use cautiously in patients using orally administered drugs, as a methanol extract
of Bixa orellana leaves reduced gastrointestinal motility in animal study (Shilpi
et al., 2006) and theoretically may alter the absorption of concomitantly admin-
istered drugs.
• Avoid in pregnant or breast-feeding women and children at doses greater than
those normally found in foods. There are insufficient human clinical data to sup-
port its safety at this time, although animal study in rats suggests that annatto was
not toxic for the mother or embryo (Paumgartten et al., 2002).
• Avoid in individuals who may be or are allergic or hypersensitive to Bixa orellana
seeds, constituents of Bixa orellana, or any member of the Bixaceae family (Lucas
64 Ulbricht et al.

et al., 2001; Nish et al., 1991; Taylor & Hefle, 2001). Annatto dye may contain
contaminating or residual seed proteins to which the patient may have developed
IgE hypersensitivity. Annatto dye is a rare cause of anaphylaxis.

Pregnancy and Lactation

• The use of Bixa orellana during pregnancy and lactation has not been thoroughly
studied in human clinical trials. However, Bixa orellana is considered likely safe
when used orally in amounts found in foods, due to its long history of use as a
food additive. The use of medicinal amounts of annatto during pregnancy and
lactation is not recommended, due to insufficient available data.
• Information concerning the toxicology and developmental toxicology, as well as
potentially hazardous substances, of Bixa orellana is currently available in the Na-
tional Institute of Health’s Lactation and Toxicology Database (LactMed). Based
on animal study, doses of up to 500 mg of annatto per kg of body weight given
by gavage for 7 days had no adverse effects on mothers or fetuses (Paumgartten
et al., 2002). No increases in embryo lethality or reduction of fetal body weight
were observed among annatto-exposed rats. Annatto did not cause an increase in
the incidence of externally visible, visceral, or skeletal anomalies in the exposed
offspring. These findings suggest that annatto is safe for both mother and em-
bryo. Therefore, the NOAEL for annatto-induced maternal and developmental
toxicity was equal to or greater than 500 mg/kg of body weight daily (or ≥140 mg
of bixin/kg of body weight daily) orally.

INTERACTIONS

Annatto/Drug Interactions
• General: Based on mouse study, Bixa orellana leaves reduced gastrointestinal
motility (Shilpi et al., 2006). This may be significant when using oral agents as
Bixa orellana may reduce absorption.
• Aldose reductase inhibitors: In vitro, extracts of achiote (Bixa orellana) exhibited
potent inhibitory activity toward lens aldose reductase (Terashima et al., 1991).
• Analgesics: Based on mouse study, a methanol extract of Bixa orellana leaves
demonstrated analgesic properties (Shilpi et al., 2006).
• Antibiotics: Extracts of several parts of the Bixa orellana plant demonstrated
antibiotic properties, based on in vitro and animal studies (Caceres et al., 1995;
Castello et al., 2002; Fleischer et al., 2003; Galindo-Cuspinera et al., 2003; Shilpi
et al., 2006). In in vitro study, annatto extracts had an inhibitory effect on Bacillus
cereus, Clostridium perfringens, Streptococcus thermophilus, Lactobacillus casei
subsp. casei, Lactococcus lactis, Paenibacillus polymyxa, Listeria monocytogenes,
and Enterococcus durans (Galindo-Cuspinera et al., 2003).
• Anticoagulants and antiplatelets: Based on secondary sources, annatto may have
anticoagulant effects.
• Antidiabetic agents: The research in this area is conflicting, with oral administra-
tion of annatto positively and negatively affecting both glucose and insulin levels
in several animal studies (Fernandes et al., 2002; Morrison et al., 1991; Russell
 Evidence-Based Systematic Review of Annatto 65

et al., 2005, 2008). In vitro, hot-water extracts of achiote (Bixa orellana) exhibited
potent inhibitory activity toward lens aldose reductase (Terashima et al., 1991).
• Antidiarrheals: Based on mouse study, Bixa orellana leaves demonstrated an-
tidiarrheal activity (Shilpi et al., 2006). In clinical trial, patients with BPH using
Bixa orellana complained of constipation (Zegarra et al., 2007).
• Antifungals: In vitro, Bixa orellana fruit extract exhibited antifungal activity
against Cryptococcus neoformans (minimum inhibitory concentration, MIC =
0.078 mg/mL) (Braga et al., 2007).
• Antihypertensives: Theoretically, annatto may potentiate the antihypertensive
effects of medication used to treat hypertension.
• Anti-inflammatory agents: In in vitro study, bixin isolated from Bixa orellana
demonstrated COX-1 and COX-2 inhibitory properties (Reddy et al., 2005).
• Antineoplastic agents: Based on in vitro studies, bixin demonstrated antineo-
plastic activity (Antunes et al., 2005; Reddy et al., 2005). In vitro, an increased
frequency of micronucleated cells has been observed at a high concentration of
annatto (10,670 ppm) when it was administered simultaneously with cyclophos-
phamide (Alves de Lima et al., 2003).
• Antiprotozoals: In vitro, Bixa orellana methanol seed extract inhibited the
growth of Leishmania amazonensis (Braga et al., 2007).
• CNS depressants: Based on mouse study, Bixa orellana leaves decreased locomo-
tor activity (Shilpi et al., 2006).
• Cytochrome P450-metabolized agents: Based on in vitro and animal study, an-
natto may induce CYP1A1 and 2B isoenzymes; however, bixin, which makes up
approximately 28% of annatto, may not be responsible for the CYP induction
shown by annatto administration (De Oliveira et al., 2003).
• Diuretics: Based on anecdote, some individuals may be highly sensitive to annatto
and experience a diuretic effect at low doses, such as when eating foods in which
annatto was used as a coloring or flavoring agent.
• Sedatives: Based on mouse study, Bixa orellana leaves had dose-dependent seda-
tive effects (Shilpi et al., 2006).

Annatto/Herb/Supplement Interactions
• General: Based on mouse study, Bixa orellana leaves reduced gastrointestinal
motility (Shilpi et al., 2006). This may be significant when using oral herbs and
supplements as Bixa orellana may reduce absorption.
• Aldose reductase inhibitors: In vitro, extracts of achiote (Bixa orellana) exhibited
potent inhibitory activity toward lens aldose reductase (Terashima et al., 1991).
• Analgesics: Based on mouse study, Bixa orellana leaves demonstrated analgesic
properties (Shilpi et al., 2006).
• Antibacterials: Extracts of several parts of the Bixa orellana plant demonstrated
antibacterial properties, based on in vitro and animal studies (Caceres et al., 1995;
Castello et al., 2002; Fleischer et al., 2003; Galindo-Cuspinera et al., 2003; Shilpi
et al., 2006). In in vitro study, annatto extracts had an inhibitory effect on Bacillus
cereus, Clostridium perfringens, Streptococcus thermophilus, Lactobacillus casei
subsp. casei, Lactococcus lactis, Paenibacillus polymyxa, Listeria monocytogenes,
and Enterococcus durans (Galindo-Cuspinera et al., 2003).
66 Ulbricht et al.

• Anticoagulants and antiplatelets: Based on secondary sources, annatto may have

anticoagulant effects.
• Antidiarrheals: Based on mouse study, Bixa orellana leaves demonstrated an-
tidiarrheal activity (Shilpi et al., 2006). In clinical trial, patients with BPH using
Bixa orellana complained of constipation (Zegarra et al., 2007).
• Antifungals: In vitro, Bixa orellana fruit extract exhibited antifungal activity
against Cryptococcus neoformans (MIC = 0.078 mg/mL) (Braga et al., 2007).
• Anti-inflammatory herbs: Based on in vitro study, bixin isolated from Bixa orel-
lana demonstrated COX-1 and COX-2 inhibitory properties (Reddy et al., 2005).
• Antineoplastics: Based on in vitro studies, bixin may have antineoplastic activ-
ity (Antunes et al., 2005; Reddy et al., 2005). In vitro, an increased frequency
of micronucleated cells has been observed at a high concentration of annatto
(10,670 ppm) when it was administered simultaneously with cyclophosphamide,
so it should be used carefully, as high doses may increase the effect of mutagens
(Alves de Lima et al., 2003).
• Antioxidants: Based on in vitro and animal studies, annatto and Bixa orellana
leaves demonstrated antioxidant activity (Antunes et al., 2005; Junior et al., 2005;
Kovary et al., 2001; Martinez-Tome et al., 2001; Shilpi et al., 2006).
• Antiparasitics: In vitro, Bixa orellana methanol seed extract inhibited Leishma-
nia amazonensis (Braga et al., 2007).
• Cytochrome P450-metabolized herbs and supplements: Based on in vitro and an-
imal study, annatto induced CYP1A1 and 2B isoenzymes; however, bixin, which
is approximately 28% of annatto, may not be responsible for the CYP induction
shown by annatto administration (De Oliveira et al., 2003).
• Diuretics: Based on anecdote, some individuals may be highly sensitive to an-
natto, and a diuretic effect may occur at low doses, such as by eating foods in
which annatto was used as a coloring or flavoring agent.
• Hypoglycemics: The research in this area is conflicting, with oral administration
of annatto positively and negatively affecting both glucose and insulin levels in
animal studies (Fernandes et al., 2002; Morrison et al., 1991; Russell et al., 2005,
2008). In vitro, hot-water extracts of achiote (Bixa orellana) exhibited potent in-
hibitory activity toward lens aldose reductase (Terashima et al., 1991).
• Hypotensives: Theoretically, annatto may potentiate the antihypertensive effects
of herbs and supplements used to treat hypertension.
• Sedatives: Based on mouse study, Bixa orellana leaves had dose-dependent seda-
tive effects (Shilpi et al., 2006).

Annatto/Food Interactions
• Insufficient available evidence.

Annatto/Lab Interactions
• Blood cultures: Extracts of several parts of the Bixa orellana plant demonstrated
antibacterial properties, based on in vitro and animal studies (Caceres et al., 1995;
Castello et al., 2002; Fleischer et al., 2003; Galindo-Cuspinera et al., 2003; Shilpi
et al., 2006). In in vitro study, annatto extracts had an inhibitory effect on Bacillus
cereus, Clostridium perfringens, Streptococcus thermophilus, Lactobacillus casei
 Evidence-Based Systematic Review of Annatto 67

subsp. casei, Lactococcus lactis, Paenibacillus polymyxa, Listeria monocytogenes,

and Enterococcus durans (Galindo-Cuspinera et al., 2003).
• Blood pressure: Theoretically, annatto may potentiate the antihypertensive ef-
fects of herbs and supplements used to treat hypertension.
• Electrolytes: Based on anecdote, annatto may have diuretic properties and theo-
retically may cause electrolyte imbalances.
• Insulin levels: The research in this area is conflicting, with oral administration
of annatto positively and negatively affecting both glucose and insulin levels in
animal studies (Fernandes et al., 2002; Morrison et al., 1991; Russell et al., 2005,
2008).
• Serum glucose levels: The research in this area is conflicting, with oral admin-
istration of annatto positively and negatively affecting both glucose and insulin
levels in animal studies (Fernandes et al., 2002; Morrison et al., 1991; Russell
et al., 2008). In vitro, hot-water extracts of achiote (Bixa orellana) exhibited po-
tent inhibitory activity toward lens aldose reductase (Terashima et al., 1991).
• Serum levels of cytochrome P450-metabolized agents: Based on in vitro and an-
imal study, annatto induced CYP1A1 and 2B isoenzymes; however, bixin, which
is approximately 28% of annatto, may not be responsible for the CYP induction
shown by annatto administration (De Oliveira et al., 2003).
• Serum levels of oral drugs: Based on mouse study, Bixa orellana leaves reduced
gastrointestinal motility (Shilpi et al., 2006).

Annatto/Nutrient Depletion
• Glucose: The research in this area is conflicting, with oral administration of an-
natto positively and negatively affecting both glucose and insulin levels in animal
studies (Fernandes et al., 2002; Morrison et al., 1991; Russell et al., 2005, 2008).

MECHANISM OF ACTION

Pharmacology
• Constituents: Achiote (Bixa orellana) seeds have a high phosphorus and low cal-
cium content (Bressani et al., 1983). The seeds also contain a high amount of
protein (15%–17%), which includes typical levels of tryptophan and lysine, but
low levels of methionine, isoleucine, leucine, phenylalanine, and threonine.
• Thirty-five components of Bixa orellana have been identified, of which (Z,E)-
farnesyl acetate (11.6%), occidentalol acetate (9.7%), spathulenol (9.6%), ish-
warane (9.1%), bixin, and norbixin are major constituents (De Oliveira et al.,
2003; Oyedeji, Adeniyi, Ajayi, & Konig, 2005; Pino & Correa, 2003).
• The floral scent of the seed is caused by a tricyclic sesquiterpene hydrocarbon,
ishwarane. The total amount of bixin and norbixin varies greatly; common val-
ues range from 2% to 5%, but the content may reach up to 7% of the dry seeds’
mass (Mercandante, Steck, Rodriguez-Amaya, Pfander, & Britton, 1996). Other
constituents of annatto include acetone, geranyl geraniol, achiotin, tomentosic
acid, carotenoids, a methyl ester, trans-bixin, apocarotenoids, and orellin (Ciscar,
1965; Morrison et al., 1991; Schneider, Caron, & Hinman, 1965; Teixeira, Durán,
& Guterres, 2008; Uematsu, Hirata, Suzuki, Iida, & Kamata, 2002). Besides these
68 Ulbricht et al.

compounds, annatto has also been reported to contain a terebinthinous body and
fatty acids; the seeds contain phosphoric acid, silica, and potassium. Many tech-
niques (spectrophotometry, nuclear magnetic resonance, chromatography, and
mass spectrometry) have been described for the extraction, detection (such as
in foods), and characterization of annatto, bixin, and norbixin (Cunha, Santos,
Ataide, Epstein, & Barrozo, 2009; McCullagh & Ramos, 2008; Noppe et al., 2009;
Scotter, 2009). Methods for the encapsulation of Bixa orellana seed components
have been reviewed (Coleman, 2008).
• Analgesic effects: After administration of the methanol extract of Bixa orel-
lana leaves, mice exhibited a reduced writhing reflex in the acetic-acid-induced
writhing test (Shilpi et al., 2006).
• Anticarcinogenic effects: Although annatto contains carotenoids, animal studies
have not found anticarcinogenic effects from dietary annatto (Agner et al., 2004;
Hagiwara et al., 2003). Another animal study found that annatto did not have a
significant effect on the initiation stage of colon carcinogenesis, but it did modu-
late cryptal cell proliferation later (Agner, Bazo, Ribeiro, & Salvadori, 2005).
In in vitro study, bixin isolated from Bixa orellana showed a dose-dependent
growth inhibition against MCF-7 (breast), HCT-116 (colon), AGS (stomach),
CNS (central nervous system), and NCI-H460 (lung) tumor cell lines (Reddy et
al., 2005). In human hepatoma (HepG2) cells, annatto exhibited antimutagenic
activity against micronuclei induced by benzo(a)pyrene and doxorubicin but not
methyl methanesulfonate; treatment with amounts higher than 10 mcg/mL de-
creased cell viability (Barcelos et al., 2009).
• Anticlastogenic effects: In in vitro study, bixin exhibited statistically significant
anticlastogenic activity (Antunes et al., 2005).
• Anticoagulant effects: Based on secondary sources, annatto may have anticoag-
ulant effects.
• Antidiabetic effects: In streptozotocin-induced diabetic dogs as well as in fasting
normoglycemic dogs, an annatto extract lowered blood glucose by stimulating
peripheral utilization of glucose (Russell et al., 2008). Extracts of Bixa orellana
exhibited potent inhibitory activity toward lens aldose reductase (Terashima
et al., 1991).
• Antidiarrheal effects: In a castor-oil-induced diarrhea model, mice administered
with an extract of Bixa orellana leaves showed a statistically significant decrease
in the total number of stools (including wet stools) (Shilpi et al., 2006). In a clin-
ical trial involving patients with BPH, 2 out of 68 patients from the Bixa orellana
group complained of constipation (Zegarra et al., 2007).
• Antimicrobial effects: Extracts of several parts of the Bixa orellana plant have
shown antimicrobial properties in vitro (Castello et al., 2002; Fleischer et al.,
2003). In vitro, an extract of Bixa orellana bark showed activity against Neisseria
gonorrhea (Caceres et al., 1995). The methanol extract of Bixa orellana leaves
showed antibacterial effects against agents that may cause diarrhea and dysen-
tery, such as Shigella dysenteriae (Shilpi et al., 2006).
• In in vitro study, annatto extracts had an inhibitory effect on Bacillus cereus
[MIC = 0.08% (vol/vol)], Clostridium perfringens [MIC = 0.31% (vol/vol)],
Streptococcus thermophilus, Lactobacillus casei subsp. casei, Lactococcus lac-
tis, Paenibacillus polymyxa, Listeria monocytogenes [MIC = 1.25% (vol/vol)],
 Evidence-Based Systematic Review of Annatto 69

and Enterococcus durans [MIC = 2.5% (vol/vol)]; no activity was detected

against Lactobacillus plantarum, Bifidobacterium bifidum, yeasts, or selected
gram-negative bacteria (Galindo-Cuspinera et al., 2003). Bixa orellana exhib-
ited antifungal activity against Cryptococcus neoformans (MIC = 0.078 mg/mL)
(Braga et al., 2007).
• Bixa orellana was found to have a lower MIC against Escherichia coli (0.8
mcg/mL) compared with gentamicin sulfate (0.98 g/mL), although Bixa orellana
exhibited a better MIC against Bacillus cereus (0.2 mcg/mL) than gentamicin sul-
fate (0.5 mcg/mL) (Rojas, Ochoa, Ocampo, & Munoz, 2006).
• Antioxidant effects: Bixa orellana extract has been found to contain carotenoids,
which are particularly effective at eliminating free radicals (Junior et al., 2005).
In in vitro studies, annatto showed antioxidant activity (Antunes et al., 2005; Ko-
vary et al., 2001; Martinez-Tome et al., 2001). The methanol extract of Bixa orel-
lana leaves showed radical-scavenging properties in the DPPH (1,1-diphenyl-2-
picrylhydrazyl) assay (IC50 = 22.36 mcg/mL) (Shilpi et al., 2006). However, in
another in vitro study, bixin isolated from Bixa orellana did not inhibit lipid per-
oxidation (Reddy et al., 2005).
• Antiprotozoal effects: In vitro, Bixa orellana methanol seed extract inhibited
Leishmania amazonensis (Braga et al., 2007).
• Antivenom effects: In mouse studies, an extract of Bixa orellana leaves and
branches showed strong antivenom activity against both Bothrops asper venom
and Bothrops atrox viper venom (Nunez et al., 2004; Otero et al., 2000).
• Cyclooxygenase (COX) inhibition effects: In in vitro study, bixin isolated
from Bixa orellana showed COX-1 and COX-2 inhibition (Reddy et al.,
2005).
• Diuretic effects: Based on anecdote, some individuals may be highly sensitive to
annatto and experience a diuretic effect at low doses, such as when eating foods
in which annatto was used as a coloring or flavoring agent. The exact mechanism
of action, however, is unclear.
• Gastrointestinal effects: In mouse study, 500 mg/kg doses of the methanol extract
of Bixa orellana leaves statistically significantly delayed the passage of charcoal
meal (Shilpi et al., 2006).
• Hematologic effects: In vitro, 2.5 mg/mL extracts of Bixa orellana demon-
strated more than 70% inhibition of hematin polymerization (Baelmans
et al., 2000).
• Hypotensive effects: Theoretically, annatto may potentiate the antihypertensive
effects of herbs and supplements used to treat hypertension. The exact mecha-
nism of action, however, is unclear.
• Neurologic effects: Mice given an extract of Bixa orellana leaves showed a statis-
tically significant decrease in locomotor activity (Shilpi et al., 2006). In addition,
the extract increased the survival time of mice in the strychnine-induced anticon-
vulsant test.
• In a pentobarbitone-induced hypnosis test in mice, an extract of Bixa orel-
lana leaves significantly reduced the onset to sleep time at a dose of 500
mg/kg and increased the total sleeping time at 250 and 500 mg/kg doses (Shilpi
et al., 2006).
70 Ulbricht et al.

Pharmacodynamics/Kinetics
• Bioavailability: In vitro study performed in monolayers of Caco-2 cells indicated
that ingested norbixin, a constituent of Bixa orellana, was stable during gastric
and small intestinal phases of digestion when added to milk, and that both cis and
trans isomers were bioavailable (Polar-Cabrera, Huo, Schwartz, & Failla, 2010).
• Distribution and clearance: The distribution and clearance of annatto was inves-
tigated in a study where a group of seven volunteers ingested a single dose of 1
mL of commercial annatto food coloring (16 mg of cis-bixin in soybean oil) (Levy,
Regalado, Navarrete, & Watkins, 1997). The presence of bixin (cis and trans) and
norbixin (cis and trans) was demonstrated in the plasma at average levels of 11.6,
10.1, 2.8, and 0 mcg/L of bixin and 48, 58, 53, and 29 mcg/L of norbixin after 2, 4,
6, and 8 hr, respectively. Considerable individual variations were observed. Com-
plete plasma clearance generally occurred for bixin by 8 hr and for norbixin by
24 hr after ingestion of the cis isomer of bixin.
• Metabolism: Based on in vitro and animal study, annatto may induce CYP1A1
and 2B isoenzymes; however, bixin, which is approximately 28% of annatto,
may not be responsible for the CYP induction shown by annatto administration
(De Oliveira et al., 2003). Oral administration of annatto has positively and neg-
atively affected both glucose and insulin levels in animal study. In canine study,
administration of annatto induced hyperglycemia but with concurrent damage
to mitochondria and endoplasmic reticulum, mainly in the liver and pancreas
(Morrison et al., 1991). In rat study, the animals also showed hyperglycemia with
concomitant hyperinsulinemia, indicating the functionality of pancreatic beta
cells (Fernandes et al., 2002). However, in a mouse study by the same authors,
annatto induced hypoglycemia with hypoinsulinemia. In canine study, annatto
caused a decrease in blood glucose levels 1 hr after administration as compared
with the control group (Russell et al., 2005). This study also found that the
hypoglycemia persisted for an additional hour when challenged with an oral
glucose tolerance test (OGTT). In addition, plasma insulin levels measured at 1
hr showed that there was an increase in plasma insulin levels compared with the
control group. In cultured 3T3-L1 adipocytes, bixin was an agonist of peroxisome
proliferator-activated receptor (PPAR)-gamma and enhanced insulin sensitivity
(Takahashi et al., 2009). The authors suggested that bixin may be a valuable
food-derived compound as a PPAR ligand to regulate lipid metabolism and may
have a role in treating patients with metabolic syndrome.

HISTORY
• Annatto is a pigment derived from the seeds of Bixa orellana and has been used
for centuries in South America and for over 100 years in Europe. Annatto’s his-
tory of use as a food colorant is well established worldwide, and current trends
show that it is being used increasingly in body care products. Bixa orellana seeds
are used to make a brightly colored paste that is added to soups, cheeses, and
other foods to give them a bright yellow or orange color. Annatto is also used
in margarine, butter, rice, smoked fish, custard powder, candies, snack foods, soft
drinks, jams and jellies, gelatins, puddings, and pie fillings. Because of their red
 Evidence-Based Systematic Review of Annatto 71

color, annatto seeds have been used by Central and South American natives to
make body paint, fabric dye, and lip pigment. This use explains the origin of the
plant’s nickname: “lipstick tree.” Use of the dye has been traced back to the an-
cient Mayan Indians, who employed it as a principal coloring agent in foods, body
paint, arts, crafts, and murals.
• The scientific species name orellana comes from the name of Francisco de Orel-
lana, a Spanish explorer of the 16th century. Reportedly, the Aztecs put Bixa
orellana seeds in chocolate drinks and added annatto to chocolate to deepen its
color. This was also common in Europe until the 17th century.
• Spanish annatto, which is hard, brittle, and odorless, is made in Brazil. French
annatto comes from Guinea and is bright yellow, firm, and pungent, due to its
fermentation in urine.
• In 1983, world production of Bixa orellana seed was estimated at 3,000 tons and
is thought to have quickly risen to more than 10,000 tons since then, due to in-
creased interest in natural food coloring agents. About half of today’s annatto
production comes from Brazil.
• Annatto has been used in the production of dye-sensitized solar cells (Gomez-
Ortiz, Vázquez-Maldonado, Pérez-Espadas, Mena-Rejón, & Azamar-Barrios,
2010).

REVIEW OF THE EVIDENCE: TABLE

No. of
Quality of Study: Magnitude of Patients
Statistically 0–2 = poor Benefit (How Absolute Needed to
Condition Author, Significant 3–4 = good Strong is the Risk Re- Treat for 1
Treated Study Type Year N Results? 5 = excellent Effect?) duction Outcome Comments

Urinary Randomized Zegarra 136 No 4 NA NA NA 250 mg of

disorders controlled et al. encapsulated
(BPH) trial (2007) Bixa orellana
leaf three times
daily or
placebo for 12
months.

REVIEW OF THE EVIDENCE: DISCUSSION

Urinary Disorders (Benign Prostatic Hyperplasia)

• Summary: Patients with BPH with moderate lower urinary tract symptoms did
not show any benefit in receiving achiote (Bixa orellana) compared with placebo
(Zegarra et al., 2007). Additional high-quality clinical studies are needed before
a further conclusion may be drawn.
• Evidence: Zegarra et al. (2007) conducted a randomized, double-blind, placebo
controlled study to determine the efficacy of Bixa orellana in patients with BPH
with moderate lower urinary tract symptoms. One hundred thirty-six Peruvian
patients with BPH with moderate lower urinary tract symptoms were random-
ized to receive 250 mg of encapsulated dried Bixa orellana leaf (N = 68) orally
three times daily or placebo (capsules with similar form, color, smell, and flavor,
N = 68) for 12 months. Inclusion criteria were males aged 50–70 years old, in good
physical and mental condition, having at least two obstructive urinary symptoms,
72 Ulbricht et al.

an average maximum urinary flow (Qmax ) of 5–15 mL/s, a postvoid residual urine
<250 mL, an increased volume of the prostatic gland, and prostate-specific anti-
gen (PSA) levels <10 ng/mL. Exclusion criteria included the presence of dysuria
or hematuria, a maximum urinary flow >15 mL/s, allergies, drug abuse, chronic
use of medicine with antiandrogenic properties, history of diseases that predis-
pose to urethral stenosis, urinary infection, invasive interventions for BPH treat-
ment, evidence of prostate cancer, history of intermittent catheterization, and
neurogenic bladder. Outcome measures included symptom score, uroflowmetry,
and postvoid residual urine variables. Thirty patients withdrew from the study:
14 from the Bixa orellana group and 16 (23.5%) from the placebo group. Two
patients from the Bixa orellana group presented with constipation, and one from
the placebo group presented with mild gastritis. Throughout the study, symptom
score, mean change in symptom score during each visit, and the final average
change were similar for both groups (Bixa orellana: 0.79 ± 1.87; placebo: 1.07 ±
1.49; p = .33). Variations of Qmax mean, Qmax average change, and final average
change were also similar (Bixa orellana: 0.44 ± 1.07; placebo: 0.47 ± 1.32; p =
.88). Variations of postvoid residual urine mean, postvoid residual urine average
change in each visit, and the final average change were similar for both groups
(Bixa orellana: 4.24 ± 11.69; placebo: 9.01 ± 18.66; p = .07). The authors con-
cluded that there was no benefit exhibited by Bixa orellana in patients with BPH
and moderate lower urinary tract symptoms. A weakness of this study is the large
number of withdrawals (22%).

FORMULARY: BRANDS USED IN CLINICAL TRIALS/THIRD-PARTY

TESTING

Brands Used in Statistically Significant Clinical Trials

• Not applicable.

Brands Shown to Contain Claimed Ingredients Through Third-Party Testing

• Consumer lab: Not applicable.
• Consumer reports: Not applicable.
• Natural Products Association: Not applicable.
• NSF International: Not applicable.
• US Pharmacopeia: Not applicable.

Select Patents Outside of the United States

• FR2693372: Tanning cream promoting moisturizing surface skin layers—contains
pure lambs’ tallow, lard, annatto oil, powdered pine resin, and extract of onion
skin.
• FR2589728: Process for obtaining a concentrate of annatto (Bixa orellana seeds),
which can be used as an agent for screening actinic radiation, and sun protection
composition based on this concentrate.
• FR2555447: Antisun cosmetic composition containing natural annatto: mixture
of four natural vegetable oils. Annatto oil, product claimed as well as the methods
of extraction.
 Evidence-Based Systematic Review of Annatto 73

United States Patents

• US3066074: Extract of Bixa orellana plant for use as a pharmaceutical.
• US2009041870: Annatto extract compositions including tocotrienols and toco-
pherols and methods of use.
• US2008031985: Annatto extract compositions, including geranyl geraniols and
methods of use.
• US2003104090: Supplements containing annatto extracts and carotenoids and
methods for using the same.

ATTRIBUTION/MONOGRAPH CURRENCY
• Last update: June 2010.
• Authors/Editors: Ashley Brigham, PharmD (Northeastern University); J.
Katherine Bryan, BA (Natural Standard Research Collaboration); Julie Con-
quer, PhD (RGB Consulting); Dawn Costa, BA, BS (Natural Standard Research
Collaboration); Nicole Giese, MS (Natural Standard Research Collaboration);
Jacquelyn Guilford PhD, MBA (Natural Standard Research Collaboration); Eliz-
abeth R.B. Higdon, PharmD (Natural Standard Research Collaboration); Kyla
Holmes, PharmDc (Appalachian College of Pharmacy); Richard Isaac (Natural
Standard Research Collaboration); Sara Jingst, PharmDc (Northeastern Univer-
sity); Juila Kats, PharmDc (Northeastern University); Laurie Peery, PharmDc
(Appalachian College of Pharmacy); Erica Rusie, PharmD (Natural Standard
Research Collaboration); Anneli Savinainen, MS (MPI); Todd Schoen, Phar-
mDc (St. John Fisher College); Tera Stock, PharmD (Massachusetts College of
Pharmacy and Health Sciences); Shaina Tanguay-Colucci, BS (Natural Standard
Research Collaboration); Catherine Ulbricht, PharmD (Massachusetts General
Hospital); Wendy Weissner, BA (Natural Standard Research Collaboration);
Regina C. Windsor, MPH (Natural Standard Research Collaboration).
• Blinded peer review: Natural Standard Editorial Board.

Declaration of interest: The authors report no conflict of interest. The authors

alone are responsible for the content and writing of this article.

ABOUT THE AUTHORS

Catherine Ulbricht, PharmD, Massachusetts General Hospital, Boston, Mas-
sachusetts, USA. Regina C. Windsor, MPH, Natural Standard Research Col-
laboration, Somerville, Massachusetts, USA. Ashley Brigham, PharmD, North-
eastern University, Boston, Massachusetts, USA. J. Katherine Bryan, BA,
Natural Standard Research Collaboration, Somerville, Massachusetts, USA.
Julie Conquer, PhD, RGB Consulting, London, Ontario, USA. Dawn Costa,
BA, BS, Natural Standard Research Collaboration, Somerville, Massachusetts,
USA. Nicole Giese, MS, Natural Standard Research Collaboration, Somerville,
Massachusetts, USA. Jacquelyn Guilford, PhD, MBA, Natural Standard Re-
search Collaboration, Somerville, Massachusetts, USA. Elizabeth R.B. Hig-
don, PharmD, Natural Standard Research Collaboration, Somerville, Mas-
sachusetts, USA. Kyla Holmes, PharmDc, Appalachian College of Pharmacy,
74 Ulbricht et al.

Oakwood, Virginia, USA. Richard Isaac, BA, Natural Standard Research

Collaboration, Somerville, Massachusetts, USA. Sara Jingst, PharmDc, Northeast-
ern University, Boston, Massachusetts, USA. Juila Kats, PharmDc, Northeastern
University, Boston, Massachusetts, USA. Laurie Peery, PharmDc, Appalachian
College of Pharmacy, Oakwood, Virginia, USA. Erica Rusie, PharmD, Natural
Standard Research Collaboration, Somerville, Massachusetts, USA. Anneli Sav-
inainen, MS, Millennium Pharmaceuticals, Inc. (MPI), Cambridge, Massachusetts,
USA. Todd Schoen, PharmDc, St. John Fisher College, Rochester, New York, USA.
Tera Stock, PharmD, Massachusetts College of Pharmacy and Health Sciences,
Boston, Massachusetts, USA. Shaina Tanguay-Colucci, BS, Natural Standard Re-
search Collaboration, Somerville, Massachusetts, USA. Wendy Weissner, BA, Nat-
ural Standard Research Collaboration, Somerville, Massachusetts, USA.

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