A Review and Evaluation of the Data Supporting Internal Use of Helichrysum Italicum

plants Review A Review and Evaluation of the Data Supporting Internal Use of Helichrysum italicum Katja Kramberger 1,2 , Saša Kenig 1 , Zala Jenko Pražnikar 1, Nina KoˇcevarGlavaˇc 3 and Darja Barliˇc-Maganja 1,* 1 Faculty of Health Sciences, University of Primorska, 6310 Izola, Slovenia; [email protected] (K.K.); [email protected] (S.K.); [email protected] (Z.J.P.) 2 Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia 3 Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; [email protected] * Correspondence: [email protected]; Tel.: +386-5-662-6467 Abstract: Helichrysum italicum is a Mediterranean plant with various pharmacological activities. Despite extensive reports on the bioactivity of the plant, its clinically studied applications have not yet been reviewed. The aim of our study was to gather information on the internal use of H. italicum and its bioactive constituents to determine its efficacy and safety for human use. We reviewed research articles that have not been previously presented in this context and analyzed relevant clinical studies with H. italicum. Cochranelibrary.com revealed six eligible clinical trials with H. italicum that examined indications for pain management, cough, and mental exhaustion. Although the efficacy of H. italicum has been demonstrated both in in vitro tests and in humans, it is difficult to attribute results from clinical trials to H. italicum alone, as it has usually not been tested as the sole component. On the other hand, clinical trials provide positive information on the safety profile since no adverse Citation: Kramberger, K.; Kenig, S.; effects have been reported. We conclude that H. italicum is safe to use internally, while new clinical Jenko Pražnikar, Z.; KoˇcevarGlavaˇc, studies with H. italicum as a single component are needed to prove its efficacy. Based on the recent N.; Barliˇc-Maganja,D. A Review and trend in H. italicum research, further studies are to be expected. Evaluation of the Data Supporting Internal Use of Helichrysum italicum. Keywords: Helichrysum italicum; biological activity; internal use; clinical studies Plants 2021, 10, 1738. https:// doi.org/10.3390/plants10081738 Academic Editors: Sofia Rhizopoulou, 1. Introduction Maria Karatassiou and Efi Levizou Plants have a long history of use in medicine and have been used by all cultures or ethnic groups throughout history to improve human health [1]. They are considered Received: 23 July 2021 to be the oldest form of medicine known to humankind but are, on the other hand, also Accepted: 18 August 2021 Published: 23 August 2021 an important source of modern medicines and govern synthetic drug development [1,2]. According to the World Health Organization (WHO), 70–95% of the world’s population Publisher’s Note: MDPI stays neutral rely on traditional medicine for their primary health care [2]. This is especially true for the with regard to jurisdictional claims in Mediterranean countries, where plants play a vital role in the diet habits, and sometimes published maps and institutional affil- there is no clear dividing line between food and medicinal plants, particularly in indigenous iations. and local traditions [3]. The plants belonging to the genus Helichrysum (family Asteraceae) are known as everlasting flowers and are widely used in traditional medicine worldwide [4]. The plant species of this genus typically have inflorescences of a bright yellow color [5], which retain their form and color when dried, hence the name “everlasting” or “immortal” [4]. The Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. stems are woody at the base and can reach 30–70 cm in height. The plant is well adapted This article is an open access article to environments that lack water as it naturally grows on alkaline, dry, sandy and poor distributed under the terms and soil at the altitude from the sea level up to 2200 m [6]. The Helichrysum Miller genus conditions of the Creative Commons includes more than a thousand of taxa, among them the most well-known and studied Attribution (CC BY) license (https:// species are Helichrysum italicum (Roth) G. Don [7] (Figure1), Helichrysum stoechas (L.) creativecommons.org/licenses/by/ Moench [8], and Helichrysum arenarium (L.) Moench [9]. H. italicum and H. stoechas are 4.0/). distributed throughout the Mediterranean [10] but are especially characteristic to Adriatic Plants 2021, 10, 1738. https://doi.org/10.3390/plants10081738 https://www.mdpi.com/journal/plants PlantsPlants2021 2021, ,10 10, 1738, x FOR PEER REVIEW 22 of of 17 17 regionIberian [11 Peninsula] and Iberian [12], Peninsularespectively, [12 ],whereas respectively, H. arenarium whereas isH. mostly arenarium foundis mostlyin the Central found inEurope the Central [9,10]. Europe Despite [9 the,10]. long Despite tradition the long in treatment tradition inof treatmentvarious disorders of various for disorders all three forbefore all three-mentioned before-mentioned species, their species, traditional their traditionaluse for treating use for digestive treating problems digestive problems(e.g., full- (e.g.,ness fullnessand bloating) and bloating) has been has approved been approved by the WHO by the and WHO the andEuropean the European Medicines Medicines Agency Agency(EMA) for (EMA) the species for the speciesH. arenariumH. arenarium alone [8]alone. Nevertheless, [8]. Nevertheless, H. italicumH. italicumhas beenhas recently been recentlyinvestigated investigated quite extensively, quite extensively, especially especially in the Balkan in the Balkancountries. countries. The focus The of focus this ofrev thisiew reviewarticle articlewill be willfrom be herein from hereinafter on after H. onitalicumH. italicum only. Amongonly. Among the H. the italicumH. italicum speciesspecies,, there thereare also are alsoseveral several subspecies subspecies (abbreviated (abbreviated ssp.) ssp.),, which which are are difficult difficult to todistinguish distinguish due due to to a astrong strong polymorphism polymorphism in in morphology morphology [10] [10].. The The explanation of H. italicumitalicum classificationclassification isis beyondbeyond thethe scopescope ofof thisthis reviewreview article,article,but butthe the namename ofof subspeciessubspeciesis isincluded, included,if ifavailable available inin thethe referencedreferenced article. article. FigureFigure 1. 1.Cultivated CultivatedHelichrysum Helichrysum italicum italicumplant plant in in flowering flowering stage stage (Photo: (Photo: Katja Katja Kramberger). Kramberger). CharacteristicCharacteristic yellowyellow fade-resistantfade-resistant inflorescencesinflorescences (seen in Figure Figure 11)) as well as veg-vege- etativetative aerial aerial organs organs of H. italicum are aa treasurytreasury ofof bioactivebioactive secondarysecondary metabolitesmetabolites thatthat resultresult from from the the plants’plants’ adaptationadaptation to to thisthis challengingchallenging environment. environment. Apart Apart from from the the volatile volatile terpenesterpenes presentpresent inin essentialessential oils,oils, absolutesabsolutes andand supercritical supercritical CO CO22 extracts,extracts, H.H. italicumitalicumis is alsoalso veryvery richrich inin phenolicphenolic compounds,compounds, whichwhich areare recognizedrecognized asas healthhealth promotingpromoting agentsagents duedue toto antioxidant antioxidant properties properties they they exert exert and and their their probable probable role role in thein the prevention prevention of various of vari- diseasesous diseases associated associated with with oxidative oxidative stress, stress, such assuch cancer, as cancer, cardiovascular cardiovascular and neurodegen- and neuro- erativedegenerative diseases diseases [13]. The [13] health-beneficial. The health-beneficial potential potential of H. of italicum H. italicumhas has been been reported reported in ethnopharmacologicalin ethnopharmacological surveys surveys and and supported supported by by numerous numerousin in vitro vitroand andin in vivo vivo exper-exper- imentsiments [[7]7].. In In the the Greek Greek-Roman-Roman system system of of medicine, medicine, H.H. italicum italicum waswas used used as asan an anti anti--in- inflammatoryflammatory and and anti anti-infective-infective plant, plant, and and both both uses uses are arestill stillwell well rooted rooted in traditional in traditional med- medicineicine today today [14]. [Antunes14]. Antunes Viegas Viegas et al. [7] et al.emphasized [7] emphasized that, in that, contrast in contrast to animal to animalstudies, studies,there is therea severe is a lack severe of clinical lack of studies clinical investigating studies investigating the effects the of effects the H. of italicum the H. italicumextracts, extracts,which undermines which undermines the possibility the possibility of validating of validating the traditional the traditional uses of usesthis plant of this. One plant. of Onethe reasons of the reasons why clin whyical clinical and other and comprehensive other comprehensive studies studies with herbal with herbal products products are scarce are scarceprobably probably lies in liesthe indifficulty the difficulty of interpret of interpretinging the results the results of such of studies such studies [2]. [2]. TheThe aim aim of of our our study study was was to gatherto gather all informationall information reported reported in the in literature the literature on internal on in- applicationsternal applications of H. italicum of

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