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Indigo

Scientific Name(s): Baphicacanthus cusia Brem. (Thailand), Indigofera anil L., Indigofera arrecta. (Bengal, Natal), Indigofera tinctoria (France)., Isatis indigotica Fortune ex Lindl., Isatis tinctoria L. subspecies villarsii, Persicaria tinctoria. (Japan), Polygonum tinctorium, Strobilanthes cusia (Neess) Kuntze, Indigofera suffruticosa Mill. (Guatemala)
Common Name(s): Common indigo, Indian indigo, Indigo naturalis, Qing dai (traditional Chinese medicine)

Medically reviewed by Drugs.com. Last updated on Dec 18, 2023.

Clinical Overview

Use

Indigo is mostly used as a source of dye. It has been evaluated for treatment of psoriasis and other dermatological conditions as well as GI diseases such as ulcerative colitis. However, clinical information is lacking to recommend use for any indication.

Dosing

Clinical evidence is lacking to provide dosing recommendations for indigo.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Indigo naturalis has been reported to cause mild liver dysfunction, abdominal pain, and headache. It may also cause colitis and pulmonary arterial hypertension. Topical indigo naturalis may cause pruritus, rash, erythema, and nasopharyngitis. One case report describes development of pancreatitis with use of oral indigo naturalis; another describes colitis and pulmonary hypertension with a supplement containing qing dai.

Toxicology

No data.

Scientific Family

Botany

"Indigo" can refer to several species of Indigofera (eg, I. anil L, I. suffruticosa Mill.) that are known for the natural blue colors obtained from their leaflets and branches.Simon 1984 Indigofera plants are perennial shrubs that reach 1 to 2 m in height. The French and Guatemalan varieties differ in shape and size of the leaflets and pods. Indigo naturalis or qing dai is a dried pigment obtained from the leaves and branches of indigo-producing plants such as B. cusia, I. tinctoria, P. tinctorium, Strobilantes formosanus Moore, and I. indigotica.Chiang 2013 I. indigotica is a biennial or perennial herb native to Ukraine that is widely distributed in Europe and is an invasive species in the United States. I. indigotica can reach 50 to 140 cm in height, is bluish in color, and has yellow flowers gathered in inflorescences.Kell 2011, Stasiak 2014

History

Indigo is one of the oldest known natural dyes and is formed through fermentation of a variety of plants. It has been used in traditional Chinese medicine for centuries where it is known as indigo naturalis or qing dai.Chiang 2013, Gamret 2018 The word "indigo" comes from the Greek word "indikón," meaning "Indian."Stasiak 2014 Before the development of synthetic aniline and indigo dyes, indigo plants were grown commercially in the East Indies, South America, and Central America. Indigo was a popular dye during the Middle Ages.Simon 1984, Stasiak 2014 Indigo naturalis is thought to alleviate pain and have antipyretic, anti-inflammatory, antiviral, antimicrobial, antitumor, and detoxifying properties. For decades, it has been widely used to treat psoriasis and other infections and inflammatory diseases in China and Taiwan.McDermont 2016, Simon 1984 Extracts of I. tinctoria reportedly have nematicide activity; the leaf and plant juice have also been used to treat certain cancers.Duke 1985 Other uses include as an emetic and for the treatment of numerous ailments ranging from hemorrhoids to scorpion stings.Duke 1985, Singh 2012

Chemistry

Indigo dye has the chemical formula C16H10N2O2 and a molecular weight of 262.26.Stasiak 2014 The blue dye is produced during the fermentation of the leaves of indigo-producing plants, which is commonly accomplished with caustic soda or sodium hydrosulfite.Simon 1984 A paste exudes from the fermenting plant material and is processed into cakes that are finely ground. The blue color develops as the powder is exposed to air. Indirubin, 3,2-bisindole of indigo naturalis, is the red isomer of the blue indigo pigment and has been isolated from B. cusia.Chanayatht 2002, McDermott 2016 Other major active components associated with indigo naturalis include indigo (the major component), tryptanthrin, and isatin.Chiang 2013

Indigo is a dark blue crystalline powder and is an alkaloid. It is insoluble in water, alcohol, and diethyl ether; however, it is soluble in dimethyl sulfoxide, chloroform, nitrobenzene, and concentrated sulfuric acid.Stasiak 2014

Indigo dye is a derivative of indican, a glucosideChanayatht 2002, Duke 1985 component of B. cusia and numerous Indigofera species. Indican is enzymatically converted to blue indigotin.Chanayatht 2002, Simon 1984 This colorfast dye is combined with stabilizers and other compounds to produce a wide range of colorants. Today, almost all indigo used commercially is produced synthetically.

Uses and Pharmacology

Antimicrobial activity

In vitro data

In an in vitro study, an ethyl acetate extract of indigo naturalis prepared from S. formosanus Moore inhibited Staphylococcus aureus, Staphylococcus epidermidis, and methicillin-resistant S. aureus. It also mildly inhibited Aspergillus fumigates and Candida albicans, pathogens associated with nondermatophytic onychomycosis. Tryptanthrin and isatin were isolated as the antimicrobial components of indigo naturalis.(Chiang 2013)

GI effects

Indigo naturalis contains ligands for the aryl hydrocarbon receptors and promotes production of IL-22 to yield mucosal healing.(Naganuma 2018)

Animal and in vitro data

In a murine model of oxazolone-induced colitis, indigo naturalis treatment exacerbated mucosal damage associated with colitis despite a reduction in levels of IL-13 (an important cytokine in colitis). However, it was determined that indigo naturalis dramatically altered gut flora; when gut flora were depleted with antibiotics prior to oxazolone-induced colitis, aggravation of colitis in the indigo naturalis–treated group was no longer observed.(Adachi 2017)

In another murine model of colitis, both indigo naturalis and indigo, a major component of indigo naturalis, reduced colitis severity through activation of aryl hydrocarbon receptor signaling. Additionally, both increased expression of anti-inflammatory cytokines.(Kawai 2017)

In a murine model of ulcerative colitis, indigo naturalis significantly reduced Disease Activity Index scores and histopathologic scores compared with the model (control) group (P<0.05 and P<0.01, respectively). Additionally, indigo naturalis reduced congestion, edema, and infiltration of inflammatory cells.(Wang 2017)

An in vitro study demonstrated that qing dai suppressed the production of oxygen reactive species caused by nonsteroidal anti-inflammatory drugs (ie, indomethacin, aspirin) in GI epithelial cells.(Saito 2015)

Clinical data

In a randomized, double-blind, placebo-controlled clinical trial in 86 Japanese patients with active ulcerative colitis, the effect of indigo naturalis on clinical response was assessed. Active ulcerative colitis was defined as having a Mayo score of 6 or higher. Patients were randomized to receive 0.5, 1, or 2 g/day of indigo naturalis or placebo for 8 weeks. The primary outcome was the rate of clinical response (defined as a decrease of 3 points in Mayo score and decrease of at least 30% from baseline, with a reduction of at least 1 point on the rectal bleeding subscore or an absolute rectal bleeding score of 0 to 1) following 8 weeks of treatment. Dose-dependent clinical response rates were noted with indigo: 69.6% for the 0.5 g group, 75% for the 1 g group, 81% with the 2 g group, and 13.6% for the placebo group. The trial was terminated early because one patient who used self-purchased indigo naturalis for 6 months developed pulmonary arterial hypertension.(Naganuma 2018)

In a randomized, placebo-controlled study in patients with ulcerative colitis, qing dai significantly decreased clinical activity index (CAI) scores over 24 months of administration (P<0.001). After 3 to 6 months of qing dai administration, mucosal healing was noted, and persisted for up to 30 months.(Suzuki 2018)

Psoriasis and other dermatological conditions

Animal and in vitro data

In vitro studies have suggested that the components of indigo naturalis (tryptanthrin, indigo, and indirubin) work synergistically to down-regulate keratinocyte proliferation, improve epidermal differentiation, and reduce oxidative stress and neutrophil inflammation.(McDermott 2016)

In a murine model of oxazolone-induced dermatitis, indigo reduced immune cell infiltration, interleukin 4 (IL-4), and eosinophilic recruitment.(Adachi 2017) In vivo and in vitro data found that indigo naturalis and one of its major active ingredients, tryptanthrin, inhibited vascular endothelial growth factor–induced angiogenesis and reduced the number of viable vascular endothelial cells. The antiangiogenic effects of tryptanthrin may play an important role in conditions such as psoriasis and cancer.(Chang 2015)

In vitro analysis demonstrates that indigo down-regulates IL-17 and its pathway genes.(Cheng 2017)

Clinical data

In a small, 8-week, randomized, double-blind, placebo-controlled trial involving 24 Chinese patients with moderate plaque psoriasis, the effects of topical indigo naturalis ointment applied twice daily were compared with placebo. Statistically significant improvements in mean Psoriasis Area and Severity Index (PASI) scores were noted as early as 2 weeks after initiation of indigo naturalis therapy (P=0.02 vs placebo). At week 8 of treatment, significant improvements in PASI scores were observed for the indigo naturalis–treated group compared to baseline (P=0.01) and compared to patients receiving placebo (P=0.01). Additionally, 56.3% of patients receiving indigo achieved 75% improvement in PASI scores (PASI 75) compared with 0% in the placebo group at week 8. There was also evidence that IL-17 and its pathway genes was down-regulated after indigo naturalis treatment.(Cheng 2017)

Similarly, in a randomized, double-blind, parallel-group, dosage-controlled phase 2a study, the effects of topical indigo naturalis extract in oil (ie, Lindioil formulation) on plaque psoriasis was evaluated. Patients had been diagnosed with chronic plaque psoriasis for at least 1 year, with less than 20% of body surface area affected by psoriasis. Patients were randomized to apply 0.5 g of Lindioil ointment containing 10, 50, 100, or 200 mcg/g of indirubin twice daily for 8 weeks, followed by a 12-week safety/extension period. Patients randomized to 200 mcg/g of indirubin had the greatest improvement in PASI scores (69.2%; 95% CI, 55% to 82.8%), followed by the 100 mcg/g group (63.1%; 95% CI, 52.8% to 73.5%), the 10 mcg/g group (53.4%; 95% CI, 42.8% to 64%), and the 50 mcg/g group (50.3%; 95% CI, 37.4% to 63.2%) (between-group comparison of P=0.0445). The 200 mcg/g group had the highest percentage of patients achieving PASI 75 (57%) and PASI 90 (30%).(Lin 2018)

In a small study, the effects of Lindioil were compared with calcipotriol in patients with psoriatic nails. Patients were instructed to apply 1 to 2 drops of Lindioil to one hand and 1 to 2 drops of calcipotriol to the other hand twice daily for 24 weeks. After 24 weeks of therapy, greater percentage reductions in single-hand Nail Psoriasis Severity Index (shNAPSI) scores were observed with Lindioil (51.3%; 95% CI, 40.6% to 62%) compared with calcipotril (27.1%; 95% CI, 16.2% to 38%; P<0.001). Additionally, more patients preferred Lindioil (82.1%) to treat their psoriasis compared to calcipotriol (17.9%). Both treatments were best at treating subungual hyperkeratosis and onycholysis compared with other nail features.(Lin 2015)

A 2018 systematic review of 5 clinical trials (N=215) evaluating alternative therapies for psoriasis found reasonable evidence supporting the use of topical indigo naturalis on a trial basis for patients with mild to moderate psoriasis. Its beneficial action is believed to result from an antiproliferative effect on keratinocytes and repair of the epidermal barrier.(Gamret 2018)

In a meta-analysis of 8 clinical studies involving 688 patients with pityriasis rosea, the combination of indigo naturalis and narrow-band ultraviolet B was associated with better control of pityriasis rosea, as measured by cure rate and effective rate, compared with either treatment alone.(Wang 2018)

In patients with mild to severe atopic dermatitis, topical application of indigo naturalis ointment for 6 weeks resulted in a significant improvement in area severity scores compared to vehicle controls (49.9% vs 19.6% reduction from baseline, respectively; P=0.0235). Similarly, the percent reduction as assessed by the investigator (39.3% vs 18.2%; P=0.0387) and in body surface area involved (50.4% vs 17.6%; P=0.0241) were significantly improved with indigo compared to controls. Patients were randomized 2:1 in treatment and control groups. Of the 48 patients enrolled in this double-blind, randomized, controlled trial, 16% (5) and 50% (8) discontinued treatment in the indigo and control groups, respectively. Discontinuation due to lack of efficacy and/or worsening of symptoms was reported as the reason by 4 of those in the control group and 1 in the indigo group. No treatment-related adverse effects were observed.(Lin 2020)

The joint American Academy of Dermatology and National Psoriasis Foundation (AAD-NPF) guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures (2020) states that the use of topical herbal Traditional Chines Medicine (TCM) methods, including Indigo naturalis, should only be considered if working with TCM practitioners experienced in dermatology. No evidence-based recommendations were made.(Elmets 2020)

Dosing

Clinical evidence is lacking to provide dosing recommendations for indigo.

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Indigo appears to be a mild ocular irritant. Dermatitis is common among indigo dyers, but there is no direct evidence linking this effect to indigo plant or dye exposure.Duke 1985 Adverse events reported in small studies and case reports of indigo naturalis use include phlebitis-induced colitis and reversible pulmonary arterial hypertension, as well as mild liver dysfunction, abdominal pain, and headache.Kim 2018, Matsuno 2018, Nishio 2018 Topical indigo ointment may cause pruritus, rash, erythema, and nasopharyngitis.Cheng 2017, Farahnik 2017

A case report describes the appearance of blue colorectal lesions in the sigmoid colon and rectum in a woman who took a supplement containing qing dai for ulcerative colitis.Kato 2016 Another case report describes the development of pancreatitis in an 11-year-old boy with refractory Crohn disease. After 2 doses of indigo naturalis, the patient developed epigastric pain and vomiting along with elevated lipase and amylase levels. Upon discontinuation, the patient's signs and symptoms resolved. Upon rechallenge, the same clinical presentation was noted.Kim 2018 Another case report describes 2 patients with ulcerative colitis who developed wall thickening and edema during administration of the oral powdered form of qing dai. Specifically, the patients had abdominal pain with bloody diarrhea; an abdominal computed tomography scan revealed marked wall edema impacting the large bowel.Kondo 2018 A similar case report describes a 68-year-old woman with ulcerative colitis presenting with inflammation, edema, congestion, and mucosal hemorrhage in the ascending colon following treatment with qing dai. Upon discontinuation, her condition improved but recurred upon rechallenge.Yanai 2018 A 56-year-old female with refractory ulcerative colitis reportedly developed pulmonary arterial hypertension after taking qing dai for 22 months. Three months after discontinuation of qing dai, the patient's symptoms had resolved.Misumi 2018

Toxicology

Some species are toxic. Indigofera spicata is recognized as a teratogen due to the presence of indospicine, a toxic amino acid found in Indigofera spp. Indospicine is also hepatotoxic.Hegarty 1988, Liener 1980 In animals, indospicine causes cleft palate and embryolethality.Evans 1989, Fletcher 2015 Indigofera endacaphylla (creeping indigo) has caused livestock poisonings and deaths.Simon 1984

Index Terms

References

Disclaimer

This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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