The Safety of Medicinal Plants Used in the Treatment of Vitiligo and Hypermelanosis: A Systematic Review of Use and Reports of Harm

Introduction

Vitiligo is disfiguring and devastating condition that can make humans feel stigmatic and devalued.¹ Melasma is a general condition of hyperpigmentation and particularly involves the face.² The pigmentation disorders of vitiligo (hypopigmentation or de-pigmentation) and melasma (Hypermelanosis) are common among the world’s population (around 1% for vitiligo). The exact cause of both of the diseases is unclear, though various factors have been suggested in predisposition of vitiligo and melasma. Both of the conditions negatively effect the physical image of the affected individual, and there have been major cosmetic concerns, particularly for females. This affects them psychologically and economically by increasing their visits to dermatology/skin care clinics.^1,2 The use of natural products (complimentary/alternative medicines) for chronic health conditions is common and individuals may seek this approach for the treatment of vitiligo and melasma. Natural health products are promoted for use in these conditions. For the past few decades these products have been gaining popularity and there is an increase in demand because of their vast chemical diversity. These are believed to be relatively safe, reliable, easily accessible, and affordable to the public.³ There have been studies regarding the use of medicinal plants in the conditions of vitiligo and hypermelanosis, but these were found to have limited evidence to support their efficacy in these uses.^4,5 Generally, public perception, particularly in under-developing countries, that topical/oral use of herbs has no untoward effects and thus there is lack of proper rules and regulations regarding the monitoring of manufacturing and sales of these natural pharmaceutical products. Plenty of beauty creams/ointments are advertized in print/electronic media and are available over the counter and many herbal practitioners use for them.⁶ There are fewer clinical investigations of medicinal plants with respect to their safety when used in the vitiligo and hypermelanosis. To the best of the author's knowledge there has been no systematic research previously published. Thus, the novel systematic review has focused on exploring reports relating to possible harm associated with medicinal plants and some of the constituents derived from plants (psoralens) used in the treatment of vitiligo and hypermelanosis. The aims of the project were to identify and summarize harm associated with the medicinal plants used in the treatment of vitiligo and hypermelanosis through literature searches from databases.

Methods

Time Frame

Six months.

Setting

School of Pharmacy, University of Auckland, New Zealand.

Procedure

1. The following procedure was adopted to identify medicinal plants used in the treatment of vitiligo and hypermelanosis and their mode of use (topical or oral) for this treatment.

1a. The first step was to conduct a literature search to identify medicinal plants used in vitiligo/melasma (V/M). A systematic review of the literature was carried out using biomedical databases, including Medline, EMBASE, Scopus, International Pharmaceutical Abstracts, and so on to identify medicinal plants used in the treatment of vitiligo and hypermelanosis. Once the results were obtained (August 7, 2017), a search of the titles and abstracts to find the papers which discussed medicinal plants in V/M. The title and the abstract of the particular research paper was viewed to extract the key words representing the botanical or common name of that plant used to treat V/M. The plants included were either those having reports of clinical usage or those having in vitro anti-vitiligo/anti-melasma activity. After doing this, there was compilation of a table (medicinal plants used in vitiligo and/or melasma) listing the names of the medicinal plants used in V/M, and some other details (e.g., other names for the plants, use in V/M, the reference, method of preparation/delivery, i.e., topical or internal.

1b. Some other sources were also searched (e.g., authoritative medicinal plant textbooks, publicly available websites and pharmacopoeia) where possible to see if other medicinal plants were listed as being used in V/M and added them to the Table.

Books to be searched were those available at MedicinesComplete especially Herbal Medicine, Stockley’s Herbal Medicines Interactions, Clarke’s Analysis of Drugs and Poisons, Martindale and Melasma and vitiligo in brown skin. Pharmacopoeias to be searched out were Indian pharmacopoeia (IPC) and Hamdard pharmacograph.

Publicly Available Websites

There had been a general look on publicly available websites and the following sites (see Table 1) have been found leading, informative and relevant to retrieve the information on safety and harm of medicinal plants.

1. The following procedure was performed to undertake a literature review on harm associated with the use of medicinal plants in the treatment of vitiligo and hypermelanosis. 2a. Once part 1a/1b was finished, the list of medicinal plants was used in the table to do another literature search. This involved entering all the plant names (as well as their common names) and combine with “OR„. To findclinical information on harm, the search was limited to all the clinical information types (i.e., all the clinical trial, case reports, systematic reviews, etc.). The results of this search were combined using “AND„ with the list obtained by combining the disease terms with “OR„ to get the relevant data. Other limits were applied at this stage, e.g., “human„, and in the English language. Then the pooled medicinal plants group were combined with the “clinical” group with “AND„. This then provided the set of literature to work on for Aim 2, i.e., the systematic review on harms associated with the use of med plants in V/M. Psoralens were included in the review by adding the search terms for these into plant names at this stage (Figure 1).

Table 1 Publicly Available Websites

Figure 1 Flow chart of study selection process.

2b. To look through the titles and abstracts of this group and to select the papers that contained information on harms/adverse effects came from clinical trial reports, or from case reports with these medicinal plants, or other types of papers. Using the relevant papers to summarise the information on harms/adverse effects for each of the medicinal plant.

1. Using the list of medicinal plants in the Table from 1b above, there was a search of the ADR databases to find reports of suspected adverse drug reactions (ADRs) submitted to national medicines agencies/pharmacovigilance centres. Systematic searches of WHO VigiAccess database (the publicly available version of the WHO’s individual case safety report database) and other databases containing data from spontaneous reporting schemes for ADRs, such as EudraVigilance (the European database of suspected ADR reports), SMARS (Suspected Medicine Adverse Reaction Scheme (NZ).

Inclusion Criteria

Articles containing information on adverse events or other safety-related information associated with the use of medicinal plant preparations for the treatment of of vitiligo and hypermelanosis in humans.

Exclusion Criteria

Publications where full length articles were not available, articles other than English language and articles describing preclinical studies only. Journals discontinued/articles not found online from journal archives.

Results

The results have been summarized in Tables 3, Tables 2–4.

Table 2 Summary of Clinical Studies on Vitiligo and Melasma

Table 3 Summary of Clinical Case Reports on Vitiligo and Melasma

Table 4 Brief Summary of Adverse Events from VigiAccess56

Discussions

The study included all types of clinical trials and case reports retrieved according to protocol and the literature search strategy. It was found that adverse effects were poorly reported in most of the studies. Some research papers mentioned safety in abstract but did not provide details, some trials did not report safety information, some did report, but not very well. The topical gel Aloe vera was reported safe without any significant dermatological reactions by Masoumech and Ali⁷ in a randomized double blind controlled trial. On Aloe vera VigiAccess reported 204 cases of total adverse events including 29 reports on skin and subcutaneous reactions and 1 report on pigmentation disorders specifically the discoloration of skin. The report about discoloring/hypopigmentation effect of Aloe vera pointed out the use of Aloe vera in skin care and anti-aging effects. Debbie⁹ worked on topical lotion of Coffea Arabica; fruit, vegetables extract in hyperpigmentation and and reported no side effects. The study was on a limited number of patients (40 females) for a short period of time (5 weeks). Hussain et al¹¹ reported skin irritation effects with topical ointment contained powdered form of Psoralea corylifolia (PC). Maurice and Cream,⁵⁰ a case report concerning the use of herbal infusion containing powdered seeds of Psoralea corylifolia, mentioned the adverse effects of photosensitivity, itching of hands, erythema, and blistering. The reversal of ADR after stoppage of the infusion it was related to the use of PC. Deborah and MacDonald⁵⁴ reported a case of serious ADR with the oral use of PC seeds. The adverse effects were cholestatic acute hepatitis, jaundice, abdominal pain, lethargy, vomiting, dark urine, and pale stools. Acute hepatitis was reversed after stopping the use of seeds of PC. Acute hepatitis was a potential ADR of PC and manufacturers of such products should label a warning to highlight this harmful effect of hepatitis. A study recommending no significant side effects of PC did not include the biochemistry of liver function tests, thus hepatitis was unlikely to be observed in this research.⁵⁷ There is need for the proper recommendation of daily dosing of PC as current recommendations are referenced from customs instead of science.⁵⁸ The trials to establish formal dosing is needed. VigiAccess⁵⁶ reported 16 cases of total adverse events with PC including 3 reports on skin and subcutaneous tissue disorders of blister, pruritus and rash. PC is believed to have its local arterial pharmacological action on plexus of the capillaries, dilating them by stimulating melanoblasts to produce pigments. The pigment penetrates in the white vitiliginous patches on skin.⁵⁹ Orest et al,¹² Ahmed et al¹³ and Parsad et al¹⁴ studied Ginkgo biloba clinically in vitiligo patients. There were infrequent reports on side effects related to gastrointestinal problems. Ginkgo biloba has been widely used in many indications. VigiAccess⁵⁶ reported Ginkgo biloba 4016 cases of total adverse events including 66 reports on skin and subcutaneous reactions and 7 reports related to pigmentation disorders (skin discoloration). Interestingly the information of skin discoloration derived from VigiAccess is opposing the use of Gingko biloba in vitiligo for the purpose of acquiring skin coloration (pigmentation). Patients using Ginkgo biloba are pron to be more risk of increased bleeding.⁶⁰ Bedi et al¹⁶ has not monitored the safety of Picrorhiza kurroa in self controlled trials on 30 patients. Some animals studies have reported the drug as potent liver protecting agent to counter the toxicities of poisons by improving the bile flow and rectifying the liver functions.^61,62 Eduardo²⁰ used Polypodium leucotomos (PL) orally adjuvant to PUVA to treat generalized vitiligo, on the other hand, Lucy et al¹⁹ tried the same plant alone in the management of melasma. Adverse effects were not monitored by Lucy et al¹⁹ while no side effects were reported by Eduardo et al.²⁰ Martiza et al²¹ in an open trial conducted on 10 patients only reported PL plus PUVA as chemophotoprotective along with adverse effects of low grade erythema. Due to its pronounced antioxidative properties PL has protective effect against the UV and PUVA induced damage to skin. It thereby decreases sun burn cells when administered orally or topically to decreases phototoxicity and erythema of psoralens.^63,64 Colucci et al²³ in an adjunct therapy for non-segmental vitiligo reported no side effects for Phyllanthus emblica when used orally while in another adjunct therapy for melasma reported by Adilson et al,²⁴ adverse effects of burning, erythema, and erythematous papules were observed with topical use of the herb. VigiAccesss⁵⁶ reported one adverse event of rash erythematous related to skin and subcutaneous reactions. Khellin has been widely studied as adjunct therapy for its anti-vitiligo effects. Adverse effects reported with adjuvant topical therapy of khellin were erythema, burning sensation and perilesional hyperpigmentation as reported by Saraceno et al²⁹ in the study for vitiligo patients. Whilst no side effects of topical khellin treated patients in vitiligo is observed by Valkova et al³⁰ or Orecchia et al.³¹ Subjects receiving a combination of topical and oral khellin were observed to have episodes of mild nausea, some orthostatic complaints and mild derangement of liver transaminases. A case reported by Dushet et al⁴⁸ regarding oral plus topical administration of khellin, showed that there was marked elevation of liver transaminases along with slight hepatomegaly. The liver functions were reversed to normal after the treatment was stopped thus confirming the khellin-related ADR. It has been reported previously that use of khellin can raise the transaminases in the first two months of treatment.⁶⁵ The dramatic increase in values of liver enzymes was not observed in a trial on 60 patients. It was surprising that the increase in liver transaminases was reported by Dushet et al⁴⁸ with topical application of the khellin although systematic absorption as well as serum level of the drug was not monitored. One cannot expect the systematic absorption of the drug merely due to its topical application on vitiliginous lesions.⁶⁶ No liver toxicity was reported with several years' use of Khellin with a daily dosage of up to 300 mg in treatment of cardio patients.⁶⁷ Although some later studies have mentioned the elevation of liver enzymes with the use of Khellin plus UVA.⁶⁸ The results of KUVA are comparable to the findings reported with the use of PUVA but the major advantages of khellin were no side effects of mutations and phototoxic skin erythema in contrast to PUVA.⁶⁹ VigiAccess⁵⁶ reported 7 adverse effects of khellein in general and 2 of these were related to skin and subcutaneous reactions, i.e., pruritis and 4 cases related to hepatobiliary disorders. The hepatotoxicity remains the potential concern with the use of khellin. In the current systematic review Psoralens have been observed as good choice alone or in combination with phototherapy in the management of vitiligo with common adverse effects of pruritis, phototoxic reactions, erythema (mild-severe), itching, scaling, giddiness, nausea, depigmented macules, hyperpigmentation and gastrointestinal disturbances. Concerning the reports of adverse events of psoralens, VigiAccess⁵⁶ reported 34 cases of total adverse events including 6 cases of skin and subcutaneous reactions (macule, psoriases, skin disorder, skin exfoliation, skin hyperpigmentation, skin lesion, skin toxicity and urticaria). Over the centuries it has been believed that medicinal plants containing psoralens when combined with phototherapy can successfully benefit vitiligo patients⁷⁰ However most of the observers came across the negative results of blisters, pruritis, itching, urticaria and erythema, etc., by adopting this therapeutic strategy.⁷¹ Lentigines (little brown patches on skin) a side effect has been associated with extensive use of PUVA therapies in old males of skin type V and VI. Once appeared, these PUVA induced lentigines do not subside after the discontinuation of PUVA therapy although it has been believed to be reversed with cryotherapy (cold therapy with an instrument called cryoprobe using liquid nitrogen or nitrous oxide where abnormal tissues are frozen and destroyed with the therapy).^72. Dilute solution of PUVA in water is termed as bath PUVA having promising advantages over topicals and oral uses of PUVA. Its delivery to the skin is uniform thus avoidance of localized phototoxic reactions as well as uneven pigmentation.⁷³ Bath PUVA reduces the long term risk of squamous cell carcinoma by reducing cumulative doses of UVA, trade off is the incidence of more common phototoxic reactions.⁷⁴ There are some reports of inflammatory hyperpigmentation induced by Demodex mites (Demodex folliculorum and Demodex brevis) hence the researcher may also keep in mind the such hyperpigmentation when monitoring the clinical studies related to herbs.⁷⁵ Friction has been mentioned as a distinct aetiology of hyperpigmentation in Indian patients⁷⁶ and Demodex inflammation has been associated to induce the frictional melanosis in influencing the hyperpigmentation.⁷⁷ Herbal Taraxaci, Herba Agrimoniae and Cortex Phellodendri et al have remarkable anti-mites potential along with human skin safety versus the Demodex folliculorum.^78,79 Based on in vivo melanocyte proliferation potential of Piper nigrum extract (containing piperine)⁸⁰ there has been a clinical human study on few patients using the piperine extract, piperine alone or piperine extract associated with prostaglandins. Pigmentation effects were reported with such therapies and latter combination speeded up the pigmentation with changed pigmentation pattern.⁸¹ The results provide a clue of future benefits of such uses if the controlled clinical studies are carried out on larger batches of patients as the existing data involve few patients (3 patients only) and 1 patient of the 3 had withdrawn from the study due to intense burning sensations, irritation and local redness. The 2 remaining patients reported a slight burning sensation on first use under an occlusive dressing. The clinical study was not controlled and the application of ointment with rubbing can give false results due to frictional melanosis. Furthermore the formulation development and characterization of the ointment before loading the drug has not been mentioned in this study on two patients.

Limitations of the Literature Search

It is possible that not all plants were identified (in Phase 1) and that not all relevant papers were found in the second phase literature search.

Conclusion

Primarily the retrieved clinical studies were efficacy oriented and safety parameters were secondary in priority whilst the general protocol of clinical trials requires the screening of drugs/medicinal plants on the basis of safety studies before testing the clinical aspect of efficacy. Thereby it is recommended that efficacy studies may be followed once the safety has been established for a particular medicinal plant in treating vitiligo and hypermelanosis.

Recommendations

The author recommends similar studies related to safety of medicinal plants and reports of harm for skin ailments other than vitiligo and hypermelanosis.