Identifying immunostimulatory herbal supplements that may flare autoimmune skin diseases: a systematic scoping review

Abstract

Objective

To systematically identify herbal supplements with immunostimulatory properties that may trigger or exacerbate autoimmune skin diseases.

Methods

We conducted a systematic scoping review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. PubMed was searched for studies published before 3 August 2025 using predefined immune, herbal supplement, autoimmune, skin and interferon terms. Articles in English that described immunostimulatory effects of herbal supplements in vitro, in model organisms or in human/clinical studies were included. Data were extracted by four reviewers and synthesised qualitatively, with herbs categorised according to levels of supporting evidence for their immunostimulatory properties. A subgroup of herbs with the strongest evidence was identified based on predefined criteria.

Results

From 11 819 unique articles screened, 469 studies met inclusion criteria. Across these, 227 distinct immunostimulatory herbal supplements were identified: 79 supported by human studies, 145 by model organism studies and 148 by in vitro studies. 15 herbs demonstrated the most robust evidence across all three evidence types, supported by more than five single-ingredient studies or more than 25 references overall. These included alfalfa, ashwagandha, astragalus, chlorella, echinacea, garlic, ginseng, green tea extract, Indian mulberry, liquorice, mistletoe, reishi mushroom, skullcap, spirulina and tinospora. These herbs were widely marketed for ‘immune support’ and shared proinflammatory mechanisms, including toll-like receptor activation, NF-κB/MAPK signalling and increased production of inflammatory cytokines including IL-1β, IL-6, TNF-α, IL-12 and IFN-γ.

Conclusions

We identified 227 herbal supplements with immunostimulatory properties, of which 15 were most strongly supported by the evidence. This article may serve as a reference to help clinicians counsel patients with autoimmune skin diseases on the risks associated with use of specific herbal supplements.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Herbal supplements may possess immunostimulatory properties that can trigger or exacerbate autoimmune diseases, including those affecting the skin.

WHAT THIS STUDY ADDS

• This systematic scoping review identified 227 herbal supplements with immunostimulatory effects, including 15 with the strongest supporting evidence across human, animal and in vitro studies. Several of these have been directly associated with flares of systemic and cutaneous autoimmune diseases, including lupus.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• When patients present with the new onset or flares of autoimmune skin diseases, a thorough history of herbal supplement use should be part of the clinical evaluation. These findings provide clinicians with a reference to guide patient counselling regarding herbal supplement use, highlight the need for supplement use histories in autoimmune disease management and lay the groundwork for future in vitro and clinical research on supplement safety.

Introduction

Autoimmune skin diseases, such as dermatomyositis and lupus erythematosus, are chronic conditions characterised by dysregulated immune responses that target the skin, leading to inflammation, tissue damage and a range of debilitating symptoms.¹ While these diseases have a strong genetic component, environmental and lifestyle factors can significantly influence disease activity.^{2 3} Among these, herbal supplements have emerged as a potential trigger for disease flares due to their ability to enhance immune activity.²⁴,⁸

Despite this risk, public awareness of the potential for herbal supplements to exacerbate autoimmune skin diseases remains low. Recent studies have demonstrated a significantly higher prevalence of immunostimulatory herbal supplement use among individuals with autoimmune skin diseases compared with healthy controls.⁷ The basis for this trend is multifactorial. A key factor is the widespread misconception that ‘natural’ remedies are inherently safe.^{9 10} Additionally, many patients turn to complementary or alternative therapies due to dissatisfaction with conventional treatments, seeking greater autonomy in managing their health.^{11 12} The COVID-19 pandemic further reinforced this behaviour, driving a dramatic surge in the sales and availability of immunostimulatory herbal supplements as individuals sought to ‘boost’ their immune systems.¹³,¹⁵ This rise in herbal supplement use highlights a critical need for patient education, as increasingly many individuals with susceptibility to autoimmune diseases may unknowingly trigger their conditions by taking products marketed for immune support.

To effectively guide patients on how to avoid potentially harmful supplements, it is essential to establish which herbal products possess immunostimulatory properties that could contribute to disease flares. Prior research has identified several commonly used herbal supplements with immunostimulatory properties that may worsen autoimmune skin diseases, including spirulina, blue-green algae, elderberry, ashwagandha, echinacea, chlorella and alfalfa.^{2 8} These supplements contain bioactive compounds such as polysaccharides, flavonoids and terpenoids that have been demonstrated to stimulate various immune pathways, including type 1 interferon production via toll-like receptor four activation.^{2 6 16 17}

However, the rapidly expanding herbal supplement market presents an ongoing challenge, as new herbs and botanical blends continue to emerge with limited regulatory oversight.^{14 15 18} This has created a knowledge gap: there is no reference identifying all herbal supplements to date that are potentially harmful to patients with autoimmune skin diseases. To address this, we conducted a systematic scoping review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines to compile a comprehensive list of immunostimulatory herbal supplements that may trigger or exacerbate autoimmune skin diseases. Our goal is to provide clinicians with a resource for assessing the potential risks of herbal supplements when patients present with an unfamiliar or newly marketed product. By equipping healthcare providers with this information, we aim to improve patient counselling and mitigate the risk of disease flares in individuals with autoimmune skin conditions.

Methods

We conducted a systematic scoping review in accordance with PRISMA-ScR guidelines.¹⁹ A standard string structured as [Immune Terms] AND [Herbal Supplement Terms] AND ([Autoimmune Terms] OR [Skin Terms] OR [Interferon Terms]) was used to search PubMed (online supplemental material 1). Articles published any time before 3 August 2025 were selected for study inclusion after an initial title/abstract screen followed by full-text review. Inclusion criteria were for articles written in English that described herbal supplements with immunostimulatory properties based on clinical, model organism or in vitro studies. Exclusion criteria were for articles that were not written in English, described outcomes unrelated to immune stimulation or flaring of immune-mediated disease, described herbal supplements with anti-inflammatory properties, did not include herbal supplements or were about a type 1 hypersensitivity reaction or contact dermatitis.

Title and abstract screening were conducted by JDW, AH and CS. An article required approval from at least two reviewers to proceed to full-text review. Full-text review was performed by JDW, AH and CS, with inclusion requiring consensus among all three reviewers.

Data extraction was evenly distributed among four reviewers: JDW, AH, CS and AO. Extracted data were synthesised qualitatively by compiling a list of all herbs identified as immunostimulatory, along with their corresponding references. Additionally, the level of evidence supporting each herb’s immunostimulatory properties (in vitro, model organism and/or human/clinical) was documented. For supplement blends, we searched for the product’s ingredients and listed each herbal component separately in our results. Herbs that only had evidence supporting their immunostimulatory properties as part of blends were marked accordingly. Some papers referred to the same herbs by different names. In these cases, we picked the English name, or if no English name was available, the most common name for the herb, and reported the results from all corresponding papers under that name.

After data extraction, we identified the herbs with the most substantial evidence for being immunostimulatory. This selected cohort consisted of herbs with immune stimulation evidence at all three levels (in vitro, model organism and human/clinical) that either had all single-ingredient evidence and more than five total references or had a mix of single-ingredient and blend-based evidence provided they had more than 25 total references. For this cohort, we identified botanical names using the NCBI’s Taxonomy Database. We also determined what types of commercially available products commonly contain these herbs and how they are marketed by searching their names on the websites of large retail vendors of herbal products in the USA, including Amazon, Walmart, iHerb, ActiveHerb and Vitacost.

Patient and public involvement

This study was motivated by conversations with patients with autoimmune skin diseases, who frequently asked about the safety of herbal supplements during clinic visits and at patient-focused conferences. Patients also helped guide the herbal supplement terms used in the search strategy by sharing the supplements they most commonly take in conversations leading up to this study. We plan to collaborate with patients and advocacy groups to disseminate the findings through educational resources, social media and outreach efforts.

Results

The PRISMA flow diagram for identification of included studies is shown in figure 1. The search of the peer-reviewed literature resulted in 11 819 unique articles after removing duplicates. After abstract screening, 531 full-text studies were assessed for eligibility. 62 studies were excluded (n=17 not in English, n=17 outcome not related to immune activity or flaring of immune-mediated disease, n=15 herbal supplement anti-inflammatory, n=5 herbal supplement not part of study, n=4 type 1 hypersensitivity reaction or contact dermatitis, n=4 unable to obtain full text of article). This resulted in 469 full-text studies included.²⁴,^{8 16 20}

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

From the included studies, we identified 227 different immunostimulatory herbal supplements. Online supplemental material 2 provides an alphabetised comprehensive list of these herbs categorised according to the available evidence from human, model organism and in vitro studies. Of these, 79 herbs were supported by human clinical studies or case reports, 145 by model organism studies and 148 by in vitro research. Some herbs were supported by multiple types of evidence, while others had only one type. Additionally, 10 studies documented instances in which herbal supplements triggered autoimmune diseases or immune stimulation, but the specific herbs involved were unable to be identified.

Applying our predefined criteria, we identified a cohort of 15 herbs with the most substantial evidence for immune stimulation, characterised by numerous supporting references across in vitro, model organism and human/clinical studies. These included alfalfa, ashwagandha, astragalus, chlorella, echinacea, garlic, ginseng, green tea extract, Indian mulberry, liquorice, mistletoe, reishi mushroom, skullcap, spirulina and tinospora. Online supplemental material 3 summarises the common and botanical names for these 15 herbs, evidence for their immunostimulatory properties, the types of products in which they are commonly found and how they are marketed. A closer look at these herbs shows convergent, proinflammatory mechanisms. Most contain polysaccharides that activate innate immunity via toll-like receptors and downstream NF-κB/MAPK signalling, driving IL-1β, IL-6 and TNF-α production with a slight Th1 tilt (increased IL-12, IFN-γ, IL-2), enhanced dendritic-cell maturation/antigen presentation, higher NK-cell cytotoxicity and adjuvant-like effects. Across major US retailers, these herbs were widely available, most commonly as capsules/tablets, powders, teas, liquid extracts/tinctures, gummies/chews, traditional herbal blends, or multi-ingredient ‘greens’ blends. Notably, all of these herbs were marketed for ‘immune support’ in addition to their other general wellness claims.

Discussion

This systematic scoping review identified 227 herbal supplements with immunostimulatory properties that may pose a risk to individuals with autoimmune skin diseases. Among these, 15 herbs—alfalfa, ashwagandha, astragalus, chlorella, echinacea, garlic, ginseng, green tea extract, Indian mulberry, liquorice, mistletoe, reishi mushroom, skullcap, spirulina and tinospora—were supported by the most robust evidence across human, animal and in vitro studies. These herbs were also implicated in the onset or flaring of a variety of both cutaneous and systemic autoimmune diseases, including dermatomyositis, cutaneous and systemic lupus erythematosus, autoimmune blistering diseases, autoimmune haemolytic anaemia, autoimmune hepatitis, acute disseminated autoimmune demyelinating disorders, erythema multiforme, erythema nodosum and recurrent inflammatory papules.²⁴,8 42 44 66 177 186 196 198 203 215 271 283 333 357 390 480

The immunostimulatory effects of these herbs are mediated through mechanisms that overlap with those involved in the pathogenesis of both systemic autoimmunity and autoimmune skin diseases. They activate the innate immune system via toll-like receptor signalling and macrophage activation, leading to the production of pro-inflammatory cytokines.^{2 4 6 16 22 43 86 111 139 149 156 184 190 246 260 297 385 390 422} This, in turn, modulates adaptive immunity by stimulating dendritic cells, T-cells and B-cells, resulting in enhanced immunoglobulin production and promoting cytotoxic immune responses, including NK cell activation and tumour cell killing.^{2 4 6 27 43 111 139 149 156 190 246 260 321 390 422} Similarly, autoimmune diseases like dermatomyositis and cutaneous and systemic lupus erythematosus are driven by innate immune activation via pattern recognition receptors such as toll-like receptors, leading to type 1 interferon production and pro-inflammatory cytokines that promote inflammation and immune cell recruitment, along with dysregulated adaptive immunity involving autoreactive T-cells and B-cells that contribute to autoantibody production.⁴⁸²

As the number of commercially available herbal supplements that can stimulate the immune system continues to grow, medical providers need to be aware of the risks associated with these products for patients with personal or family histories of autoimmune diseases. When patients present with the new onset or flares of autoimmune skin diseases, a thorough history of herbal supplement use should be incorporated into the clinical evaluation. Patients should be counselled on these risks and, when possible, encouraged to review product labels to identify potential immunostimulatory ingredients. However, this may not always be feasible, and labelling practices and ingredient transparency can vary widely. Therefore, there is a need for greater accountability from the dietary supplement industry and regulatory agencies to ensure accurate labelling and clearer disclosure of active ingredients and populations to whom these products may pose a risk. Clinicians should also advise against the use of herbal blends, as some patients may be unaware of the specific herbs they are consuming.^{96 207 208 238 314 342 364} Moreover, studies suggest that combining multiple herbs can have synergistic effects, potentially leading to more pronounced immune responses.⁴³ Lastly, it is essential for clinicians to communicate that just because a substance is natural, it does not inherently equate to safety, as many patients mistakenly believe that natural products are always benign.^{9 10}

This review has several limitations that should be considered when interpreting our findings. First, the inclusion criteria for the studies reviewed were constrained by language restrictions and the available study designs, which may limit the generalisability of the results. Specifically, the lack of long-term data and randomised controlled trials for many of the herbal supplements examined restricts our ability to draw definitive conclusions about their safety and efficacy over time or in broader populations. Additionally, the variability in patient responses to these herbal supplements presents a significant challenge in identifying what constitutes a definitive trigger for autoimmune flares. The inclusion of herbs as part of herbal blends further complicates this, as it is often unclear which component within the blend is responsible for immune stimulation. Furthermore, unlike pharmaceuticals, herbal supplements are not subject to the same rigorous regulatory oversight, increasing the risk of contamination and inconsistent potency, which may alter the observed immunostimulatory effects in some studies.^{483 484}

Based on these limitations, further research is needed. First, additional in vitro studies are necessary to elucidate the specific biological effects of herbal supplements on tissue samples from patients with autoimmune skin diseases. Clinically, systematic documentation of herbal supplement use and associated adverse effects by healthcare providers would help clarify the risks of these products. Furthermore, more research on herbal blends would aid in determining which constituents contribute to their immunostimulatory effects. Finally, the development of evidence-based educational materials proven to influence patient sentiment and behaviour regarding immunostimulatory supplement use would be valuable for improving patient safety.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.