Therapeutic Potential of Curcumin and Novel Formulations in Psoriasis Treatment: Evidence and Future Prospects

Introduction

Psoriasis is a chronic, immune-mediated inflammatory skin disease that affects approximately 2–3% of the global population.¹ It has been recognized by the World Health Organization as a serious non-communicable disease.² Psoriasis is classified into several types: plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, and erythrodermic psoriasis.³ Plaque psoriasis, or psoriasis vulgaris, is the most prevalent form, characterized by circumscribed, thickened, scaly, and itchy plaques commonly found on the elbows, knees, scalp, and lower back, though it can appear on any skin surface.⁴ Additionally, psoriasis is frequently associated with comorbidities such as psoriatic arthritis, metabolic syndrome, cardiovascular disease, and psychosocial disability, all of which significantly reduce patients’ quality of life and well-being.⁵ Moreover, several psoriasis patients still face challenges, including variable treatment responses, limited healthcare access, and social stigma.⁴

The pathogenesis of psoriasis is primarily driven by immune cell dysregulation, particularly involving T cells and dendritic cells, alongside keratinocyte hyperproliferation. This process unfolds in two main stages: the initial activation stage and the psoriasis stage. In the initial stage, keratinocytes are activated by various factors, including genetic predisposition and environmental triggers such as infections, medications, and trauma.⁶ These stimuli activate immune responses, leading to the recruitment and activation of dendritic cells.⁷ Activated dendritic cells then release pro-inflammatory cytokines like interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β, which drive an inflammatory cascade.⁸ This cascade promotes activation and migration of T helper cell (Th) 1 (Th1) and Th17 cells, resulting in the release of additional psoriasis-related pro-inflammatory cytokines, including IL-17, IL-22, IL-23, TNF-α, and IFN-γ. These cytokines activate keratinocytes, setting off further events that culminate in hyperproliferation and abnormal differentiation, which are hallmark features of the psoriasis stage.⁹ This cytokine-mediated feedback loop further exacerbates the disease by sustaining chronic inflammation, ultimately resulting in thickened, scaly plaques and erythema observed in psoriatic lesions.¹⁰

Treatment for psoriasis includes various therapeutic approaches aimed at reducing inflammation, alleviating skin lesions, and improving patients’ quality of life.¹¹ The choice of treatment depends on the location and severity of the disease.⁹ For mild to moderate psoriasis, topical treatments such as corticosteroids, vitamin D3 analogs, and calcineurin inhibitors are commonly used.¹² In cases of insufficient response, phototherapy approaches, including ultraviolet B (UVB) and psoralen plus ultraviolet A (PUVA) therapies, may be considered adjunctive treatments.^13,14 For moderate to severe psoriasis, management typically includes systemic agents such as methotrexate, cyclosporine, and acitretin, as well as biologics like adalimumab (a TNF-α inhibitor), ustekinumab (an IL-12,23 inhibitor), secukinumab (an IL-17 inhibitor), and guselkumab (an IL-23 inhibitor).^2,12–16 However, patients receiving systemic agents should be closely monitored for adverse effects and potential drug-drug interactions, which can limit long-term use.¹⁷ Consequently, exploring alternative treatments for psoriasis is imperative, with a focus on ensuring both safety and efficacy.

Recently, herbal medicine has gained significant interest as an alternative treatment for psoriasis due to its potential to offer a lower risk of adverse effects compared to synthetic medications, while still providing effective therapeutic outcomes.¹⁷ Several herbs such as Capsicum annuum, Aloe vera, Nigella sativa, and Matricaria recutita have been traditionally used in the management of psoriasis.¹⁸ Among these options, curcumin, the principal bioactive compound in Curcuma longa Linn. (turmeric), stands out as the most extensively evidenced compound for psoriasis management due to its well-documented antioxidant, anti-inflammatory, immunomodulatory, anti-proliferative, and anti-angiogenic activities.^19–25 Furthermore, curcumin demonstrates superior versatility in pharmaceutical development, with a wide range of formulations such as oral, topical, and advanced delivery systems enhancing its therapeutic potential compared to other herbal treatments.²⁵ Notably, curcumin constitutes approximately 76.9% of the total curcuminoid content, while demethoxycurcumin and bisdemethoxycurcumin make up around 17.6% and 5.5%, respectively.²⁶ Ongoing research endeavors aim to elucidate the mechanisms of action of curcumin in its anti-psoriatic effects, evaluate its safety and efficacy for psoriasis treatment, and address limitations in its practical application by developing novel formulations. This review article aims to comprehensively evaluate the anti-psoriatic activity, efficacy, and safety profiles of curcumin and its novel formulations in psoriasis treatment, based on non-clinical and clinical trial data. It explores future directions to enhance their potential as an alternative treatment for psoriasis.

Therapeutic Potential of Curcumin in Psoriasis Treatment and Its Potential Mechanism of Action

Curcumin exhibits anti-psoriatic effects through various mechanisms, including inhibiting cell proliferation, inducing apoptosis, suppressing pro-inflammatory cytokine levels, and enhancing the expression of skin barrier proteins.^27–31 Table 1 summarizes the anti-psoriatic effects of curcumin in non-clinical studies, while Figure 1 illustrates its potential mechanisms based on currently available evidence.

Table 1 Anti-Psoriatic Effects of Curcumin: Findings from Non-Clinical Studies

Figure 1 The mechanisms underlying curcumin’s anti-psoriatic effects are supported by scientific evidence. Abbreviations: Act, Act 1 adaptor protein; Cur, Curcumin; c-Fos, Fos proto-oncogene; c-Jun, Jun proto-oncogene; ERK, Extracellular signal-regulated kinase; IKK, Inhibitor of kappa B kinase; IκBα, Inhibitor of kappa B alpha; IL-17, Interleukin 17; JNK, c-Jun N-terminal kinase; MAPK, Mitogen-activated protein kinase; MyD88, Myeloid differentiation primary response gene 88; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; p, phosphorylated; p38, p38 MAPK; STAT3, Signal transducer and activator of transcription 3; TAK1, TGF-beta-activated Kinase1; TNF-α, Tumor necrosis factor-alpha; TRAF6, TNF-α receptor-associated factor 6; TIRAP, TIR-domain-containing adaptor protein; TYK, Tyrosine kinase.

In vitro Studies

In vitro studies typically evaluate the anti-psoriatic activity of curcumin using skin cell lines, such as immortalized human keratinocytes (HaCaT), induced by immune-stimulating agents like TNF-α, IL-22, and imiquimod (IMQ), which mimic psoriatic conditions. One study demonstrated that curcumin, at a concentration of 7.37 µg/mL, inhibited cell proliferation by suppressing cell cycle proteins, specifically cyclin D1 and cyclin E.³⁰ It also induced apoptosis by increasing the expression of TNF-related apoptosis-inducing ligand (TRAIL) and reducing anti-apoptotic proteins, including inhibitor of apoptosis (IAP) 1, IAP2, and B-cell lymphoma extra-large (Bcl-XL), in TNF-α induced HaCaT cells.²⁷ These effects help manage psoriasis signs and symptoms by reducing hyperproliferation and eliminating dysfunctional keratinocytes, thereby minimizing the formation of thickened, itchy, scaly plaques characteristic of the disease.

Curcumin is well known for its anti-inflammatory properties. Several studies have shown that curcumin, at concentrations ranging from 5 to 100 µM, effectively reduces the expression of pro-inflammatory cytokines, including IL-6, IL-17, IL-22, IFN-γ, and TNF-α, which play roles in the pathogenesis and progression of psoriasis.^27–29 The anti-inflammatory activity of curcumin could be attributed to its modulation of multiple intracellular signaling pathways, such as Nuclear Factor-Kappa B (NF-κB), Mitogen-Activated Protein Kinase (MAPK), and Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) pathways.^27,29 These pathways are central to driving skin inflammation, hyperproliferation, and keratinocyte differentiation in psoriasis.⁶ Additionally, curcumin was reported to regulate inflammatory cytokines and inhibit T-cell proliferation by blocking the potassium channel subtype Kv1.3.³² In addition, curcumin enhances the levels of skin barrier proteins, including involucrin and filaggrin, suggesting that it may improve the protective function of psoriatic skin and reduce transepidermal water loss.²⁸

Ex vivo Studies

Findings from ex vivo studies align with in vitro results, showing that curcumin (≥ 5 µM) significantly reduces levels of pro-inflammatory cytokines, including IL-17 and IFN-γ, in peripheral blood mononuclear cells from both psoriasis patients and healthy controls.³³ Additionally, curcumin was shown to suppress phosphorylase kinase (PhK) activity, an enzyme involved in the persistence of psoriatic plaques, indicating that curcumin may help mitigate both acute and chronic phases of psoriasis.³⁴ In addition to ex vivo studies, combining curcumin with other treatments has shown potential in reducing pro-inflammatory cytokines^33,40 and inhibiting cell proliferation in psoriatic keratinocytes compared to normal cells.⁴¹

In vivo Studies

Animal studies suggest that curcumin not only modifies underlying molecular mechanisms but also alleviates signs of psoriasis. Previous studies have demonstrated that oral curcumin (40–200 mg/kg) can significantly reduce the Psoriasis Area and Severity Index (PASI) score, a standard measure for assessing psoriasis severity and therapeutic response, as evidenced by reductions in erythema, scaling, and skin thickness in IMQ-induced mice compared to the control group.^32,36,37 Additionally, curcumin significantly decreased the expression of pro-inflammatory cytokines, such as IL-17, IL-22, IL-8, IFN-γ, and TNF-α, while increasing levels of antioxidant enzymes, including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), in psoriatic lesions.^32,36 These findings highlight curcumin’s potential as a multi-target therapeutic agent for psoriasis, offering both anti-inflammatory and antioxidant effects. Moreover, adjunctive use of curcumin with another therapeutic agent, such as ustekinumab and ibrutinib, has demonstrated superiority in reducing PASI scores, oxidative stress, and levels of psoriasis-associated cytokines compared to monotherapy, suggesting a potential synergistic effect.^36,42,43 Whether used as an adjunct to conventional therapy or as a standalone intervention, curcumin may contribute to potentially improved clinical outcomes.

Challenges in the Low Bioavailability of Curcumin and Approaches to Enhance It

Curcumin is well-known for its low systemic bioavailability due to its poor solubility, low intrinsic activity, poor absorption, high metabolic rate, and rapid elimination from the body.^44,45 Thus, the doses of curcumin used in animal studies cannot be directly compared to those in vitro due to factors such as solubility and the pharmacokinetic profile of curcumin. When administered orally to Sprague-Dawley rats at a dose of 1 g/kg, a negligible amount of curcumin is detected in blood plasma, indicating poor absorption from the gut.⁴⁶ Once absorbed, curcumin undergoes rapid metabolism via conjugation processes like sulfation and glucuronidation in the liver, its major metabolism.⁴⁷ Consequently, curcumin is largely excreted in feces, with an elimination half-life of approximately 1.45 h in rats.⁴⁸ Additionally, curcumin is chemically unstable, particularly in the alkaline environment of the intestines.⁴⁹ Due to its low bioavailability, curcumin in food cannot be utilized for therapeutic purposes, despite turmeric’s widespread use as a dietary ingredient across various cultures. Furthermore, since turmeric contains curcumin at relatively low concentrations, approximately 3.14% by weight, its therapeutic potential may be limited.⁵⁰ These challenges have been identified as significant barriers to the practical application of oral curcumin in psoriasis treatment, particularly in vivo and clinical trials, where its low bioavailability limits therapeutic efficacy.

Transdermal drug delivery is a promising strategy for enhancing the therapeutic potential of curcumin in psoriasis treatment. By bypassing the gastrointestinal tract and hepatic first-pass metabolism, this approach delivers the drug directly to the target site, potentially improving its effect.⁵¹ Studies have shown that topical curcumin formulations (0.5 to 4 g/kg/d) alleviate psoriatic signs, as evidenced by reduced PASI scores and lowered inflammatory cytokine levels in psoriasis mouse models after 6–14 days of treatment.^35,38,39 Furthermore, topical curcumin significantly decreases the expression of proliferating cell nuclear antigen (PCNA) and immune factors such as cytokeratin 16 (CK16), cytokeratin 17 (CK17), Toll-like receptor 2 (TLR-2), and TLR-4,³⁸ all of which are associated with epidermal cell hyperproliferation and abnormal differentiation.³⁵ Additionally, it inhibits C-C chemokine receptor 6 (CCR6), a marker for IL-17A-producing cells in psoriatic skin.³⁹ These findings confirm that curcumin can effectively alleviate psoriasis signs in animal models through topical administration. However, the efficacy of transdermal delivery depends on the drug’s physicochemical properties.⁵² The hydrophobic nature, low solubility, instability, and large molecular size of curcumin present significant challenges to its effective delivery through the skin, limiting its potential as a topical agent.⁵³ Consequently, numerous efforts have been made to enhance the bioavailability of curcumin, primarily through, at least, two strategies: (1) inhibition of metabolic pathways via co-administration with adjuvants such as piperine, and (2) improvement of physicochemical properties through advanced delivery systems, structural modifications, and prodrug development,^47,54 thereby enhancing curcumin’s bioavailability and therapeutic effect.

Novel Curcumin Formulations to Enhance Anti-Psoriatic Effects

To address the challenges of poor bioavailability and limited skin penetration, novel curcumin formulations, such as liposomes, polymeric nanoparticles, hydrogels, and nanostructured lipid carriers, have been developed to improve their anti-psoriatic effects.⁵⁵ The anti-psoriatic effects of these formulations are detailed in Table 2.

Table 2 Anti-Psoriatic Effects of Novel Curcumin Formulations: Findings from Non-Clinical Studies

In vitro and ex vivo Studies of Novel Curcumin Formulations

Most in vitro and ex vivo studies demonstrated that these novel formulations significantly enhance the anti-psoriatic effects of curcumin compared to conventional formulations.^56,57,59,60 For example, ionic liquid liposomes significantly improved curcumin’s ability to inhibit cell proliferation and reduce pro-inflammatory cytokine levels, including IL-1β, IL-17, IL-22, IFN-γ, and TNF-α, in psoriatic-like HaCaT cells compared to a curcumin solution at the same concentration.⁵⁶ Another study found that ethosomes could enhance the free radical-scavenging effects of curcumin combined with glycyrrhetinic acid.⁵⁸ In addition to ex vivo findings, curcumin-loaded niosomal gel significantly reduced gene expression levels of pro-inflammatory cytokines, including IL-17, IL-22, IL-23, and TNF-⍺, as well as inflammatory antimicrobial peptides such as S100A7, S100A12, and Ki67, in skin biopsies from psoriasis patients compared to the placebo group.⁴⁰ The enhanced anti-psoriatic effects of these formulations can be attributed to increased cellular uptake through multifaceted mechanisms, including endocytosis, phagocytosis, and pinocytosis, rather than the simple diffusion observed with conventional small molecules.⁷⁶ However, this enhancement not only enhances curcumin’s bioactivity but also amplifies its cytotoxic potential, posing a dual-faceted challenge. Additionally, encapsulating curcumin within these systems provides protection from degradation and enables sustained release, resulting in higher drug concentrations at target sites.⁷⁷

Although these formulations enhance the bioactivity of curcumin, they may present limitations, such as challenges with drug loading capacity, potential drug leakage, and release profiles, which could impact their stability and overall effectiveness. Therefore, it is essential to ensure that the concentration of curcumin released from the carrier is sufficient to exert the desired anti-psoriatic effects and that the formulation has good long-term stability to maintain consistent therapeutic effects.

In vivo Studies of Novel Curcumin Formulations

The stratum corneum, the outermost layer of the skin, presents a significant barrier to transdermal drug delivery.⁷⁸ Effective transdermal delivery requires drug molecules to have a low molecular weight (less than 500 Daltons) and balanced solubility in both water and oil.⁷⁹ However, due to its poor solubility and hydrophobic nature, curcumin struggles to penetrate deeper skin layers, remaining primarily within the stratum corneum.⁴⁷

Studies on novel topical formulations have shown significant effects in alleviating psoriasis signs, reducing pro-inflammatory cytokines, increasing antioxidant enzymes, and enhancing skin barrier protein levels in psoriasis-induced mice compared to conventional formulations.^67,68,70,72 Some novel curcumin formulations, specifically lipid-polymer hybrid nanoparticles, exhibited superior efficacy in improving psoriasis signs compared to 0.1% betamethasone valerate, a commonly used positive control.^61,64,66,74 This enhanced anti-psoriatic effect may be attributed to the ability of these novel formulations to improve skin penetration and retention, ensuring more effective delivery of curcumin to the target site within the skin.

Novel formulations such as nanostructured lipid carriers, mesoporous silica gel, nanoemulgel, liposome, ethosomes, and invasome gel have shown promise in enhancing the transdermal delivery of curcumin.^{42,43,58,62,65,67–69,71,73,75} These formulations increase cumulative curcumin permeation, permeation rate, permeation coefficient, and the amount of curcumin deposited within the skin, outperforming curcumin solution in modified Franz diffusion cell assays. Improved skin penetration may result from the small particle size, which increases surface area and solubility, as well as the proper particle charge.⁸⁰ Additionally, some formulations provide a lipid matrix that integrates effectively with the stratum corneum. Consequently, increased transdermal delivery of curcumin has led to enhanced anti-psoriatic effects in animal studies.

However, the permeability and retention of these formulations in psoriatic skin remain unclear, as most studies use healthy mouse models that may not accurately represent the characteristics of psoriasis skin, such as a weakened barrier, thickened stratum corneum, and scaling plaques. Another potential concern is that novel topical formulations may have unintended systemic effects. Studies have shown that these formulations can reduce the spleen-to-body weight ratio, alter serum inflammatory cytokine levels, and increase serum antioxidant enzyme levels,^{42,43,58,61,72} suggesting potential penetration into deeper skin layers and entry into the bloodstream, which may affect other organs. Since the local and systemic effects of these novel curcumin formulations have not been fully evaluated, further research is needed for a comprehensive assessment.

Clinical Efficacy of Curcumin Administration in the Treatment of Psoriasis in Humans

Oral Administration

To date, rigorous clinical trials evaluating curcumin’s efficacy for psoriasis treatment remain limited. The diverse clinical presentations and complex pathophysiology of psoriasis pose significant challenges in establishing standardized treatment protocols and outcome assessment. Table 3 summarizes the efficacy of oral curcumin in psoriasis-related outcomes in humans. Although oral curcumin has demonstrated the ability to alleviate psoriasis signs in animal models, clinical evidence supporting its use as a monotherapy is sparse. It is primarily used as an adjunct therapy for managing psoriasis.

A prospective Phase II, open-label clinical trial by Kurd et al (2008) investigated the efficacy of 4.5 g/day of curcuminoid (Curcumin C3 complex^®) capsules in 12 patients with moderate to severe psoriasis.⁸¹ The study reported a low overall response rate for achieving at least a “good” Physician Global Assessment (PGA) score (50–74% improvement), with rates of 16.7% in the intention-to-treat analysis and 25% in the per-protocol analysis. This outcome is likely attributed to poor bioavailability, suggesting that oral curcumin alone may not provide sufficient efficacy in managing psoriasis.

Most clinical studies have evaluated oral curcumin in combination therapies, underscoring the need for dose adjustments when used alongside other treatments. For instance, one study in patients with mild to moderate psoriasis demonstrated that a 12-week regimen combining 2 g/day of oral curcumin with 0.1% mycophenolic acid ointment significantly reduced median PASI values from 5.6 to 1.3, and decreased serum IL-22 levels from 35.2 ± 9.5 pg/mL to 21.1 ± 7.5 pg/mL, compared to monotherapy with mycophenolic acid.⁸² Additionally, the efficacy of novel oral formulations has been documented in recent studies. In one example, 3 g/d of curcumin nanoparticles were administered orally to patients with moderate-to-severe psoriasis (PASI ≥ 10) alongside acitretin treatment.⁸³ After 12 weeks, the combination therapy resulted in superior efficacy in reducing psoriasis severity, as evidenced by a greater reduction in median PASI scores from 16.4 to 3.4, compared to acitretin monotherapy, which reduced PASI scores from 14.8 to 6.8. These findings suggest that curcumin, when used as an adjunctive therapy, may offer a more effective and better-tolerated approach for managing psoriasis than high-dose monotherapy.

Table 3 Efficacy of Curcumin in Psoriasis Treatment: Findings from Clinical Studies

Topical Administration

Topical curcumin is commonly used to manage signs and symptoms in patients with mild to moderate psoriasis, although clinical studies evaluating its efficacy remain limited. Table 3 summarizes the efficacy of topical curcumin formulations in clinical studies. Curcumin in niosome gel and microemulgel demonstrated significant efficacy in alleviating psoriasis signs, such as redness and scaling, in patients with mild-to-moderate plaque psoriasis.^40,84 These treatments resulted in an overall improvement in disease severity and enhanced patient well-being. Novel curcumin formulations thus represent promising alternative therapeutic options for managing psoriasis.

Despite promising findings, several practical challenges may hinder the broader clinical application of curcumin-based formulations. Most existing studies are limited by small sample sizes and short treatment durations. Additionally, there is a lack of clinical research directly comparing novel curcumin delivery systems with conventional formulations, particularly regarding long-term efficacy, scalability, and cost-effectiveness. From an industrial standpoint, large-scale production of advanced delivery systems, such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, require specialized equipment and stringent quality control, substantially increasing manufacturing costs.⁸⁵ Furthermore, storage stability remains a concern; for instance, liposomal formulations are susceptible to leakage or aggregation over time, potentially compromising their therapeutic efficacy.⁸⁶ Patient acceptance is another barrier, especially for topical curcumin preparations, which may cause visible yellow-orange staining and reduce adherence when used on cosmetically sensitive areas.⁸⁷ Economic considerations are also crucial in determining the clinical viability of curcumin; however, direct pharmacoeconomic evaluations of curcumin in psoriasis therapy have not yet been conducted. However, the cost of curcumin-based interventions can vary considerably depending on formulation type, the use of bioavailability-enhancing technologies, route of administration, and treatment duration, all of which should be systematically assessed in future research.

To address these challenges, well-justified and methodologically rigorous future research is warranted. Table 4 presents an overview of ongoing clinical trials investigating the efficacy of curcumin primarily in topical formulations for the psoriasis treatment. Furthermore, future efforts should prioritize large-scale, long-term clinical trials, optimization of formulations, and the development of cost-effective manufacturing strategies. A focus on patient-centered design, along with comprehensive assessments of cost-effectiveness and long-term economic sustainability, will be critical in fully realizing the therapeutic potential and practical applicability of curcumin in psoriasis management.

Table 4 Ongoing Clinical Trials on Curcumin for Psoriasis Treatment

Safety Profiles of Curcumin and Its Novel Formulations

Ensuring safety is a critical aspect of using curcumin for psoriasis treatment. Table 5 summarizes the safety profiles of curcumin and its novel formulations.

Table 5 Safety Profiles of Curcumin: Evidence from Non-Clinical and Clinical Studies

In vitro and ex vivo Studies

With the intention of using curcumin to treat psoriasis, numerous studies have evaluated its cytotoxicity in skin cell lines, specifically the immortalized human keratinocyte cell line (HaCaT) and human skin fibroblasts (HSF), to identify safe dosage levels for further investigation of curcumin’s biological activity. Varma et al (2017) reported that curcumin exhibited a half-maximal inhibitory concentration (IC₅₀) at a concentration of 219.42 µM on HaCaT cells.²⁸ Curcumin was tested for cytotoxicity in Caco-2 cells to simulate oral administration as an intestinal epithelial barrier model. Curcumin had no cytotoxic effect in Caco-2 cells at concentrations below 5 µM but caused significant cytotoxicity at 10 µM.³¹ Additionally, curcumin’s cytotoxicity was significantly enhanced when combined with other therapeutic agents, such as ibrutinib.⁴³ This might result from a synergistic effect, as indicated by a combination index value of 0.476, amplifying curcumin’s cytotoxic potential.

Studies on novel curcumin formulations, such as ionic liquid-loaded liposomes and water-responsive gel, exhibit no significant cytotoxicity in both HaCaT and HSF cells.^56,72 However, it is noteworthy that the novel formulations significantly increased the cytotoxicity of curcumin, as evidenced by a decrease in the IC₅₀ value, which dropped from 6.90 ± 0.36 μM for the curcumin solution to 3.86 ± 0.67 μM for the curcumin-loaded liposomal gel when tested on HaCaT cells.⁴³ Additionally, this result was consistent with observations from curcumin-loaded nanostructured lipid carriers.⁴² This enhancement could be attributed to increased cellular uptake, resulting in elevated concentrations of curcumin within cells and, consequently, enhanced cytotoxic effects. Therefore, optimizing the dosage and formulation of curcumin is essential to achieve a balance between its therapeutic effects and safety profile.

The ex vivo study examining curcumin and curcumin niosome formulations on peripheral blood mononuclear cells (PBMCs) from healthy volunteers showed consistently low cytotoxicity across all tested concentrations (5, 10, and 15 µM).⁴⁰ Overall, these findings affirm the safety of curcumin and its formulations in non-clinical studies, underscoring the need for further investigation in animal studies.

In vivo Studies

Oral Administration

Oral curcumin has demonstrated safety in both acute and sub-chronic toxicity animal studies, with minimal adverse effects observed. In an acute toxicity study, Swiss albino mice and Wistar albino rats were administered a 5000 mg/kg dose of curcumin over 14 days.⁸⁸ No mortality, toxic effects, or significant differences in body weight were observed. In a subchronic toxicity study, Wistar rats were fed curcumin (≥ 90% purity) at doses of 0, 130–140, 250–290, and 850–960 mg/kg body weight per day for males, and 0, 160, 310–320, and 1000–1100 mg/kg body weight/day for females over 21 weeks for the parental generation and 24 weeks for the F1 generation.⁸⁹ There were no treatment-related toxicological effects in the parental animals, and no gross or microscopic changes were observed in any organs. Reproductive parameters were unaffected, and the only effect on the offspring was a slight reduction in pre-weaning body weight gain in F2 pups at the highest dose level. Consequently, this study established the No Observed Adverse Effect Level (NOAEL) for curcumin’s reproductive toxicity to be 847–1076 mg/kg body weight/day, equivalent to an estimated human dose of 8.2–10.4 g/day for a 60 kg individual. Additionally, mutagenicity has not been observed in rodent models treated with curcumin.⁹⁰ In terms of chronic toxicity, a six-month study was conducted using curcumin-loaded nanocomplexes in rats and mice, with equivalent curcumin doses ranging from 50–450 mg/kg/day in hamsters and 25–225 mg/kg/day in mice.⁹¹ The study found that high-dose treatment significantly increased the organ-to-body weight ratios of the stomach and intestine in mice, and the lung and heart in hamsters. In mice, elevated levels of glucose, total protein, liver enzymes, and globulin were observed, while hamsters exhibited increased liver enzyme levels and decreased cholesterol levels. Importantly, these abnormalities were reversed within 28 days after treatment cessation. These findings highlight the importance of cautious administration of high doses of curcumin for long-term use.

In psoriasis mouse models, oral curcumin has also demonstrated safety. Kang et al (2016) evaluated renal histology in keratin 14-VEGF transgenic mice treated with either oral curcumin (40 mg/kg) or cyclosporine (40 mg/kg), a potent immunosuppressant approved by the United States Food and Drug Administration (FDA) for psoriasis treatment, over a 20-day period.³² This study found no significant histopathological changes in the kidneys of curcumin-treated mice compared to those treated with cyclosporine, which is known to cause significant nephrotoxicity.^92,93 However, the study’s short duration did not allow for the assessment of potential systemic adverse effects that could result from oral curcumin administration over a longer period.

Topical Administration

The safety of curcumin incorporated into nanocarriers, such as liposomes, water-responsive gel, nanosponge, nanoemulsion, and liposphere, in topical formulations has been documented, with no evidence of skin irritation or histological changes observed in animal models.^43,59,61,73 These findings underscore the potential of curcumin for safe topical application, representing a critical preliminary step prior to human clinical evaluation. However, these investigations have certain limitations. Firstly, the protocols of these animal studies have not always followed standardized guidelines for skin toxicity assessments, such as those outlined by the Organization for Economic Co-operation and Development (OECD), which may affect the reliability and reproducibility of the findings. Secondly, the treatment durations were relatively short, and thirdly, comprehensive safety assessments addressing potential systemic adverse effects were lacking. Therefore, further comprehensive safety studies adhering to standardized guidelines are essential to thoroughly evaluate the safety profiles of these novel formulations.

Clinical Studies

Oral Administration

The safety of oral curcumin in healthy volunteers has been well-established in clinical studies. In a study of 59 healthy young individuals, a daily dose of 200 mg of curcumin for 8 weeks caused no adverse effects, with blood counts and metabolic panels remaining within normal ranges.⁹⁴ Similarly, Lao et al (2006) evaluated curcumin’s safety in 24 healthy volunteers with doses ranging from 0.5 to 12 g of C3 Complex™ capsules, equivalent to curcumin doses of 0.38 to 9 g.⁹⁵ Over 72 hours of monitoring, seven participants experienced mild adverse effects, such as diarrhea, headache, rash, and yellowish stool. These effects were not dose-dependent, highlighting curcumin’s safety at high doses. Additionally, a prospective Phase I study by Cheng et al (2001) assessed the safety of curcumin in 25 patients who received curcumin (99.3% purity) for three months.⁹⁶ The initial dose of 0.5 g/day gradually escalated to 1, 2, 4, 8, and finally 12 g/day. However, the highest dose of 12 g/day was not well-tolerated due to the large volume of the tablets, leading to a dose reduction and discontinuation at 8 g/day. No adverse effects were observed at doses up to 8 g/day. Based on the findings, it could be implied that the safety of oral curcumin administration was assessed at doses up to 8 g/day over a period of up to three months. Regarding the long-term safety of curcumin, a study randomized thirty-six individuals with mild-to-moderate Alzheimer’s disease to receive either a placebo, 2 g/day, or 4 g/day of oral curcumin for 48 weeks.⁹⁷ The incidence of adverse events did not differ significantly between the curcumin and placebo groups. Reported adverse events included endocrine-related complaints, diarrhea, and joint pain. It can be inferred that oral curcumin, at doses up to 4 g/day, may be safe for use over a 48-week period.

Oral curcumin has been shown to be safe in psoriasis patients, with no significant systemic adverse events observed. The findings from Kurd’s study demonstrated that curcumin was safe for patients with moderate-to-severe psoriasis vulgaris who received 4.5 g/day of C3 Complex™ capsules (approximately equivalent to 3.4 g/d of curcumin) for 10 weeks, with only mild adverse events observed in a single-arm, open-label study.⁸¹ In a study by Antiga et al (2015), among 31 patients treated with oral curcumin (2 g/day) and mycophenolic acid ointment (0.1%) over 12 weeks, one patient experienced diarrhea, while the placebo group noted one case of papular eruption and two cases of nausea.⁸² Additionally, a 12-week study evaluating an oral formulation combining curcumin nanoparticles (3 g/day) and acitretin (0.4 mg/kg/day) reported mild adverse effects, such as cheilitis, and peeling of the palms and soles.⁸³ However, the study suggested that these adverse effects may be more related to acitretin rather than curcumin. Concerning the safety of adjunctive therapy, caution is warranted when curcumin is administered in combination with other therapeutic agents, particularly immunosuppressants. Due to the immunomodulatory effects of curcumin, such combinations may enhance the immunosuppressive effects, thereby increasing the risk of infections.^98,99 Furthermore, curcumin may potentially affect other therapeutic agents by modulating the cytochrome P450 enzyme system or transporters involved in drug clearance.¹⁰⁰ Such interactions may alter the pharmacokinetics of co-administered drugs, thereby contributing to therapeutic challenges and increasing the risk of adverse events.

Overall, oral curcumin is generally considered safe for psoriasis treatment, with mild and manageable adverse effects. Nevertheless, the limited sample sizes and short durations (10–12 weeks) of these studies may not adequately capture the long-term safety profile of curcumin, particularly concerning potential systemic adverse effects.

Topical Administration

To date, novel curcumin-based topical formulations have been shown to be safe and well-tolerated for psoriasis treatment with no significant adverse effects, including allergic reactions, skin irritation, or photosensitivity. A 0.1% curcumin-loaded niosome gel, applied over a 4-week period, was well-tolerated in mild-to-moderate psoriasis patients, with no adverse events observed.⁴⁰ Another study demonstrated that mild-to-moderate plaque psoriasis patients who applied turmeric microemulgel (containing 30 µg/mL curcumin) for nine weeks experienced mild adverse effects: 6% reported a burning sensation, 6% reported dryness, and 3% reported irritation.⁸⁴ However, the study suggested that these adverse events were more likely due to other ingredients in the formulation rather than curcumin itself. Although these topical formulations are reported to be safe in previous studies, the lack of standardized assessments for skin irritation or sensitization poses challenges in drawing definitive conclusions about their safety. Future studies should incorporate standardized safety assessments and include participants with varied skin sensitivities to account for a broader spectrum of potential skin reactions to curcumin-based topical treatments. Given the chronic nature of psoriasis and the likelihood of prolonged administration, rigorous long-term safety studies are essential to thoroughly evaluate the risk-benefit profile of these formulations.

Conclusion

Curcumin exerts an anti-psoriatic effect through multi-targeted actions, including inhibiting cell proliferation, inducing apoptosis, suppressing pro-inflammatory cytokines, exhibiting antioxidant effects, and enhancing skin barrier protein expression. Through these mechanisms of action, curcumin significantly improves psoriasis lesions, such as reducing thickened and scaly plaques. Additionally, its multi-targeted actions may offer a more comprehensive approach to managing psoriasis, especially when used in conjunction with other treatment modalities, potentially reducing the risk of adverse effects associated with high-dose monotherapies. Despite its therapeutic potential, both oral and topical curcumin formulations face challenges related to low bioavailability and limited skin penetration, emphasizing the need for advanced formulations. Novel topical curcumin formulations, such as liposome, nanosponge, nanoemulsion, and liposphere, have been developed to enhance its anti-psoriatic effects by improving skin penetration, protecting it from degradation, and facilitating sustained release. Moreover, curcumin has demonstrated a favorable safety profile in both clinical and non-clinical studies. However, current clinical evidence remains limited, with small sample sizes, short durations, and a lack of comprehensive assessments, thereby warranting further investigation. Overall, curcumin and its novel formulations may be promising candidates for psoriasis treatment; however, further studies, particularly large-scale clinical trials, are needed to fully assess their efficacy and safety.