Indigo naturalis (IN), also known as “Qingdai” in Chinese, is a dried, dark blue powder derived from the leaves and stems of plants such as
Modern pharmacologic research has isolated many active compounds from IN, the most clinically relevant of which are indirubin, indigo, isatin, and tryptanthrin. These constituents have been found to exhibit a wide range of biologic activities, including antiviral, antibacterial, anti-inflammatory, antiangiogenic, antioxidant, and immune modulating effects. Indirubin and tryptanthrin have been of particular interest for their potential antitumor effects, suggesting possible roles in future chemotherapeutic development.2 Notably, IN has demonstrated therapeutic success in ulcerative colitis through its role as a human aryl hydrocarbon receptor (AhR) ligand,4 and in acute promyelocytic leukemia by suppressing key cyclin-dependent kinases and inhibition of the JAK/STAT signaling pathway.5 Collectively, these active compounds have made IN a promising candidate for incorporation into the modern medicinal canon.
These pharmacologic properties have sparked growing interest in evaluating the efficacy and safety of IN-based therapies for a variety of dermatologic conditions. Although clinical trials in dermatologic contexts remain limited, existing studies have yielded promising results, indicating that IN may help to alleviate symptoms while maintaining a favorable safety profile. Despite these encouraging findings, widespread clinical adoption of IN for topical use has been limited by practical challenges, particularly its characteristic dark blue color and tendency to stain clothing. To address these barriers, ongoing research has focused on improving its clinical applicability through methods such as compound refinement or incorporation into nanofiber patches.6,7
While the current literature on the dermatologic applications of IN is still developing, its pharmacologically active compounds and early clinical findings point to significant potential for future investigation.
The majority of clinical research on IN in dermatology has focused on its role in psoriasis. One of the earliest randomized controlled trials evaluating its efficacy was conducted by Lin et al, who performed a 12-week intra-patient study in 42 participants with recalcitrant plaque-type psoriasis. Participants were instructed to apply IN ointment to a plaque on one side of their body, and vehicle ointment on a contralateral symmetrical lesion. Treatment with IN resulted in statistically significant improvements in scaling, erythema, induration, and lesion area compared to vehicle, with 74% of patients achieving clearance or near-clearance of treated plaques.8 Additionally, the efficacy of the IN treatment increased with the duration of treatment, and no serious adverse events were reported. However, participant compliance was slightly hindered due to reports of the blue dye of the IN ointment staining clothes and skin. (Please see Figure 2.)
In a follow-up study published in 2012, the investigators reformulated the IN ointment by removing the blue color, resulting in a purple-red product that was less prone to staining clothing. Using olive oil as an extraction solvent, the researchers were able to isolate and remove the indigo pigment through filtration, retaining the lipophilic indirubin and other important active compounds (Lindioil™). In an 8-week randomized, intra-patient trial, 35 participants with plaque psoriasis applied the new reformulated ointment to one lesion and the crude ointment to a contralateral lesion. Both formulations achieved significant improvements in psoriasis severity index (PSI) and clearing percentage compared to baseline.9 At the end of the trial, 31 of the 35 participants reported a preference for the refined ointment.
Building on their previous work, Lin et al (2014) next investigated the potential of IN in nail psoriasis, a notoriously difficult manifestation characterized by pitting, discoloration, and subungual hemorrhage. To evaluate the efficacy of an indigo naturalis extract (Lindioil™) for nail psoriasis, Lin et al conducted a 24-week, randomized, intra-subject trial involving 31 patients. Participants applied IN extract twice daily to the nails of one hand and olive oil to the contralateral nails for 12 weeks as a control, followed by IN extract treatment to both hands for another 12 weeks. Compared to olive oil, IN extract ointment produced significantly greater improvements in Nail Psoriasis Severity Index (NAPSI) scores.10 The authors noted that the IN formulation was comparable to other routine topical agents, such as steroids, and had no reported adverse events.
In a subsequent 24-week randomized trial, Lin et al (2015) compared IN ointment with topical calcipotriol, a conventional therapy for psoriasis. Among 33 patients, the IN preparation demonstrated significantly greater improvements in NAPSI scores compared to calcipotriol, and was found to be particularly effective at treating onycholysis and subungual hyperkeratosis.11 Furthermore, the majority (82%) of patients expressed a preference for the IN preparation over calcipotriol.
As IN continued to demonstrate effective results as a treatment for psoriasis, researchers sought to determine the optimal concentration of indirubin, thought to be its primary active component. In a randomized, double-blind, controlled trial published in 2018, 100 participants with plaque psoriasis were assigned to receive Lindioil™ ointment containing one of four indirubin concentrations (10 μg g−1, 50 μg g−1, 100 μg g−1, and 200 μg g−1) applied twice daily for 8 weeks. Clinical outcomes were assessed using the Psoriasis Area and Severity Index (PASI) and clearance rates. Results demonstrated a dose-response with the highest concentration (200 μg g−1) being most effective at reducing PASI scores, followed by the 100 μg g−1, 10 μg g−1, and 50 μg g−1 groups.12 Importantly, no serious adverse events were observed, and treatment was well tolerated across all groups. These findings further support the efficacy of IN in the treatment of psoriasis and suggest a dose-response effect in reducing disease severity, providing important guidance for future clinical studies.
In a randomized, double-blind, placebo-controlled trial of IN, 24 participants with plaque psoriasis were assigned to apply either IN ointment or a placebo ointment twice daily for up to 8-week or until skin clearance was achieved. At week 8, the IN-treated group showed a statistically significant improvement in PASI scores compared to placebo, accompanied by visible improvements in erythema and plaque thickness.13 The authors emphasized that earlier intra-patient studies risked cross-contamination between treatment and control sites, making this trial an important step in confirming IN’s clinical efficacy. Mechanistic analyses further revealed that IN exerted its therapeutic effects by downregulating interleukin-17A (IL-17A) and related cytokines, suppressing the Th17 pathway.
Due to concerns regarding the texture, color, and absorption of IN, recent research has tried to find alternative routes of administration. One study by Zhao et al developed an IN-poly(ε-caprolactone)/poly(ethylene oxide) (IN-PCL/PEO) nanofibrous patch and tested its efficacy in a randomized, positive drug-controlled clinical trial. Thirty patients with plaque psoriasis received both treatments on symmetrical lesions: one lesion was treated with the IN patch once daily for 30 minutes, while the contralateral lesion received topical calcipotriol ointment. After the 4-week trial, both treatments significantly reduced PASI scores, with no meaningful difference in overall efficacy.14 Importantly, the IN-PCL/PEO nanofibrous patches demonstrated superior tolerability and were rated more favorably by participants due to lack of skin irritation compared to calcipotriol. Such findings suggest that IN nanofibrous patches may provide an effective and cosmetically preferable alternative for psoriasis management.
Although research on IN for atopic dermatitis (AD) remains limited, interest in its therapeutic potential has recently grown. In one study, 48 participants with AD were randomized to receive either IN extract oil ointment or a placebo vehicle, applied twice daily to affected areas over a six-week period. Treatment efficacy was primarily assessed using the Eczema Area Severity Index (EASI), with secondary outcomes including the Investigator’s Global Assessment (IGA), Body Surface Area (BSA) involvement, Visual Analogue Scale (VAS), and Dermatology Quality of Life Index (DLQI). IN extract ointment was effective at relieving all measurable symptoms of AD and demonstrated superior effectiveness compared to the placebo.7
In another trial, researchers compared the IN extract ointment to tacrolimus, a topical calcineurin inhibitor widely used to manage AD. In addition to previously mentioned metrics, this trial included the pruritus Numeric Rating Scale (NRS), Subject’s Global Assessment (SGA), and analysis of skin microbiota via 16S rRNA sequencing, with particular attention to
A meta-analysis synthesized data from eight randomized controlled trials involving 688 participants to evaluate the efficacy and safety of combining compound indigo naturalis with narrow-band ultraviolet B (NB-UVB) for treating pityriasis rosea (PR). All trials were conducted in China and published in Chinese journals. Across studies, the combination therapy demonstrated significantly higher cure rates overall effectiveness compared to either indigo naturalis or NB-UVB monotherapy.16 Reported adverse events, including erythema, thermalgia, pruritus, and diarrhea, were mild and occurred at similar rates between groups. While these findings suggest that the combination regimen is more effective than monotherapy, the analysis was limited by small sample sizes, methodological variability and potential publication bias. Larger, high-quality randomized trials are warranted to confirm these results. (See Table.)
TABLE: Summary of Studies Using Indigo Naturalis to Treat Dermatologic Conditions
Study
Type of Study
N
Findings
Psoriasis
Lin, et al. 2008
Randomized, observer-blind, placebo-controlled, intra-patient comparison study
42
Indigo naturalis showed statistically significant improvement in the scaling, erythema, and induration of psoriasis compared to placebo (P<0.001)
Lin, et al. 2012
Randomized, observer-blind, controlled, intra-patient clinical trial
35
Refined IN (P<0.001) was found to be equally effective at treating as crude IN (P<0.001). Refined IN was closer to human skin tones and less likely to stain clothes.
Lin, et al. 2014
Randomized, observer-blind, placebo-controlled, intra-subject clinical trial
31
IN extract oil was found to be more effective than olive oil at reducing the severity of nail psoriasis. IN was more effective at improving single-hand Nail Psoriasis Severity Index (shNAPSI) (P<0.0001) and modified target Nail Psoriasis Severity Index (mtNAPSI) (P<0.0001)
Lin, et al. 2015
Randomized, rater-blinded, active-controlled, clinical trial
33
IN formulation demonstrated a statistically significant improvement in single-hand Nail Psoriasis Severity Index (shNAPSI) compared to calcipotriol (P<0.001)
Lin, et al. 2018
Randomized, double-blind, parallel, dosage-controlled, clinical trial.
100
The highest concentration group of indirubin showed the greatest reduction in PASI score (P=0.0445)
Cheng, et al.
Randomized, double-blind, placebo-controlled, clinical trial
24
IN patients showed a statistically significant improvement in Psoriasis Area and Severity Index (PASI) compared to placebo (P=0.01)
Zhao, et al.
Randomized, semi-compartmental paired, positive drug-controlled clinical trial
30
Novel IN-PCL/PEO nanofibrous patches exhibited comparable therapeutic efficacy to calcipotriol ointment for psoriasis patients.
Atopic Dermatitis
Lin, et al. 2020
Randomized, double-blind, placebo-controlled, clinical trial
48
IN formulation showed a statistically significant improvement in eczema area and severity index (EASI) in comparison to placebo (P=0.0235)
Yang, et al.
Randomized, evaluator-blind, controlled trial
22
IN ointment and tacrolimus both effectively alleviated atopic dermatitis symptoms. Lindioil significantly reduced EASI (P=0.017) as well as other secondary measurement points
Pityriasis Rosea
Wang, et al.
Meta-analysis
N/A
IN in combination with NB-UVB was significantly more effective than IN monotherapy (P<0.0001) or NB-UVB monotherapy (P<0.00001) at treating pityriasis rosea
Several formulations of indigo naturalis have been evaluated, each with distinct practical and clinical implications. Crude indigo naturalis ointments contain the full pigment profile and demonstrate clinical efficacy but are associated with prominent blue discoloration, staining of skin and clothing, and lower cosmetic acceptability. Refined preparations, most notably the indigo naturalis extract in oil (Lindioil™), remove the indigo pigment while retaining the bioactive compounds, including indirubin, resulting in improved tolerability, reduced staining, and greater patient preference with comparable efficacy. More recently, nanofibrous patch formulations incorporating indigo naturalis have been developed to optimize drug delivery and minimize local irritation, offering a more practical alternative. As new approaches continue to be developed, further studies are needed to define the optimal formulation for routine clinical practice.
Across dermatologic trials, topical indigo naturalis formulations have generally been well tolerated, with most adverse events limited to mild, transient local reactions such as irritation, pruritus, erythema, or nasopharyngitis. Cosmetic drawbacks, particularly blue staining of skin and clothing, were frequently cited as barriers to adherence in early studies using crude preparations, prompting the development of alternative delivery systems. Although serious adverse events have not been observed in dermatologic trials, a report by Lin et al (2018) noted that the long-term oral use of indigo naturalis can cause irritation to the gastrointestinal tract and hepatotoxicity, underscoring the importance of distinguishing systemic from topical exposure. In dermatologic use, allergic contact dermatitis has been reported infrequently, with one participant discontinuing treatment due to treatment-related reaction.12 Combination therapies, including the use of NB-UVB, have demonstrated safety profiles comparable to indigo naturalis monotherapy.16 Importantly, long-term safety data beyond six to twelve months of continuous use are lacking, highlighting the need for extended follow-up.
Several limitations characterize the current evidence base evaluating indigo naturalis in dermatology. Most available studies are limited by relatively small sample sizes and are conducted as single-center designs, predominantly in East Asia, raising concerns about generalizability and geographic biases. In addition, much of the clinical literature originates from a limited number of investigative groups, raising the possibility of publication bias and emphasizing the need for further independent replication studies. The heterogeneity in formulation, extraction methods, and concentrations further complicates direct comparison across studies. Additionally, this can present challenges in standardization for use in clinical practice. As a botanical therapy, indigo naturalis is subject to variability in sourcing of the plant, processing, and quality control, which may impact the consistency of formulation. Although no significant contamination-related adverse events have been reported, it is important to consider the theoretical risk of contamination with other potentially offending agents. These limitations highlight the need for larger, multicenter trials with standardized formulation and quality assurance.
Indigo naturalis has emerged as a promising alternative or adjunctive therapy in dermatology, with growing clinical evidence supporting its effectiveness in managing psoriasis, pityriasis rosea, and atopic dermatitis. Its safety profile appears favorable, as most formulations are well tolerated and associated with fewer adverse events than many conventional treatments. The anti-inflammatory, antiproliferative, and immunomodulatory properties of indirubin and other active constituents underscore its therapeutic versatility, warranting further investigation into broader clinical implications. Future research should also prioritize developing a standardized formulation to ensure consistent use in clinical settings. Collectively, these findings position indigo naturalis as a multifaceted therapeutic agent in dermatology and support continued investigation and integration into evidence-based clinical practice.
You may also start an advanced similarity search for this article.
Email
X
Facebook
LinkedIn
