Artemisia Species with High Biological Values as a Potential Source of Medicinal and Cosmetic Raw Materials

Artemisia species play a vital role in traditional and contemporary medicine. Among them, Artemisia abrotanum, Artemisia absinthium, Artemisia annua, Artemisia dracunculus, and Artemisia vulgaris are the most popular. The chemical composition and bioactivity of these species have been extensively studied. Studies on these species have confirmed their traditional applications and documented new pharmacological directions and their valuable and potential applications in cosmetology. Artemisia ssp. primarily contain sesquiterpenoid lactones, coumarins, flavonoids, and phenolic acids. Essential oils obtained from these species are of great biological importance. Extracts from Artemisia ssp. have been scientifically proven to exhibit, among others, hepatoprotective, neuroprotective, antidepressant, cytotoxic, and digestion-stimulating activities. In addition, their application in cosmetic products is currently the subject of several studies. Essential oils or extracts from different parts of Artemisia ssp. have been characterized by antibacterial, antifungal, and antioxidant activities. Products with Artemisia extracts, essential oils, or individual compounds can be used on skin, hair, and nails. Artemisia products are also used as ingredients in skincare cosmetics, such as creams, shampoos, essences, serums, masks, lotions, and tonics. This review focuses especially on elucidating the importance of the most popular/important species of the Artemisia genus in the cosmetic industry.


Introduction
Over the past few years, Artemisia species have gained huge research interest due to their chemical composition and biological activities. This increase in interest is undoubtedly due to the award of the Nobel Prize in medicine in 2015 for the discovery of artemisinina sesquiterpenoid lactone effective in the treatment of malaria, which is found in Artemisia annua. In addition to A. annua, Artemisia abrotanum, Artemisia absinthium, Artemisia dracunculus, and Artemisia vulgaris are also popular worldwide. Their applications are even found in historical traditional medicine. Today, their chemical composition and biological properties have been extensively studied. Of particular importance is the increase in interest in the application of these species in cosmetic products [1,2].
The habitats of different Artemisia ssp. differ from one another and are widely distributed. Natural habitats of these species are found in Europe, Asia, North Africa, North and South America, and Australia [1,2].
For years, plants have been used as remedies mainly in areas where they occurred naturally. Today, their ethnobotanical and ethnopharmacological indications have been proved by scientific studies. There are known species, such as Matthiola incana and Daphne mucronata as well as the plants from genus Aronia, Mimosa, Schisandra, and many others, that

Phytochemical Characteristics of Artemisia Species
The Artemisia species discussed here differ from each other in their chemical composition; although there are some common classes of compounds, variable chemical composition has been reported for different species.

Ethnopharmacological Uses of Artemisia Species
Artemisia ssp. have for long been used in the traditional European, Asian (mainly Chinese and Hindu medicine), and South American medicines ( Table 4). The uses of infusions, extracts, and tinctures, as well as dried parts of plants, are here reported. In the traditional medicines of China and South America, A. abrotanum, A. annua, and A. vulgaris have been used, especially in malaria treatment [8,71,156].
In the European traditional medicine, Aboratani herba has been used in liver diseases, such as atony, the contractile states of the bile ducts, and the stagnation of or insufficient bile secretion. Artemisia ssp. infusions are recommended as an aid in cases of anorexia, flatulence, and hypoacidity [157]. A. abrotanum leaves have been used to stimulate menstruation [20].
The flowers of A. absinthium have been used in the European folk medicine to treat parasitic diseases and digestive ailments. The herb of this species was used to treat jaundice, constipation, obesity, splenomegaly, anemia, insomnia, bladder diseases, menstrual cramps, and injuries and nonhealing wounds [8][9][10]. The tincture of A. absinthium is a valuable tonic and digestive aid. Similarly, A. absinthium is used in the traditional Hindu medicine (Unani), in the drug "Afsanteen", which is used to treat chronic fever, hepatitis, and edema [9].
All the parts of A. annua are used in the traditional medicines of China and India, such as flowers, leaves, stems, seeds, and essential oils. They are used to treat jaundice, bacterial dysentery, fever, bleeding wounds, and hemorrhoids [71,158].
In European traditional medicine, A. dracunculus is used to treat ailments of the digestive system and as an appetite and digestive stimulant [54,159]. According to the Hindu traditional medicine (Ayurveda), A. dracunculus is effective in the treatment of helminthiasis and intestinal smooth muscle spasms and in the regulation of the menstrual cycle [54,160]. In Arabic countries, A. dracunculus is used in the treatment of gingivitis and foot and mouth disease, whereas in Central Asia, including Russia, it is used to treat irritation, allergic rashes, and gastritis [11,12].
In European folk medicine, the oral administration of A. vulgaris stimulates the secretion of gastric juice. The species A. vulgaris is also used as a relaxant for the gastrointestinal tract and bile ducts and for relieving colic [55], whereas its laxative effect is observed in the treatment of obesity. In traditional Hindu medicine (Unani), many preparations based on A. vulgaris are used. These preparations are recommended for liver inflammation and obstruction, treating enlarged liver or spleen and nephrolithiasis, chronic fever, and dysmenorrhea [161]. In the Asian medicine, A. vulgaris is often used in the treatment of gynecological diseases [162,163]. Furthermore, A. vulgaris is recommended for inducing labor or miscarriage [164].

Contemporary Phytotherapy
There are many monographs published by the European Medicines Agency (EMA) on the homeopathic preparations of A. abrotanum [165]. Moreover, A. abrotanum is included in homeopathic medicine according to the French Pharmacopoeia. These preparations are recommended for the treatment of the inflammation of the colon, rosacea, frostbite, inflammation of the lymph nodes, mucous membranes, and anxiety [166][167][168].
Among Artemisia ssp., A. absinthium herb (Absinthii herba) alone has the pharmacopoeial monograph in the newest tenth edition of the European Pharmacopoeia [59]. The raw material is the herb collected from young plants-in their first year of vegetation, buttend leaves are cut off-and from older plants with sparsely leaved, flowering shoot tips. The essential oil content of this raw material is standardized; this content must not be less than 2 mL/kg in the dried herb. Moreover, the bitterness index of the raw material must not be less than 10,000 [59]. In addition, the European Pharmacopoeia and the French Pharmacopoeia have classified the fresh, flowering herb of A. absinthium as a homeopathic raw material. The tincture produced should contain a minimum of 0.05% (w/w) of derivatives of hydroxycinnamic acid, expressed in terms of chlorogenic acid [169]. In the homeopathic medicine, the plant is recommended for hallucinations, nightmares, nervousness, insomnia, dizziness, and epileptic seizures [170]. Additionally, A. absinthium herba has been discussed in a monograph in the German Pharmacopoeia. The herb of A. absinthium is indicated for the loss of appetite, digestive problems, and bile secretion disorders [171][172][173]. Furthermore, the German Pharmacopoeia also mentions a tincture from the herb [174]. Homeopathic preparations from the herb of A. absinthium have been discussed in monographs published by EMA [165]. The species A. absinthium herba is recommended as the raw material in the temporary loss of appetite, mild dyspepsia, and gastrointestinal disorders. It can be used in different forms, e.g., finely divided or powdered herbal substance, fresh juice, or tincture from the herb. Commercial herbal preparations are made in solid or liquid forms, and the finely divided herb is used in herbal teas. Moreover, the herb of A. absinthium has been discussed in a monograph of the ESCOP (European Scientific Cooperative on Phytotherapy). It can be used in digestive disorders and anorexia [175].
There are no monographs in European pharmacopeias describing A. annua. However, monographs of Artemisiae annuae folium are found in the Chinese Pharmacopoeia and the Vietnamese Pharmacopoeia [176,177]. The raw material of Artemisiae annuae folium is standardized for the artemisinin content, which cannot be lower than 0.7% of dry weight. It is recommended for the treatment of fever of various origins and malaria [10]. It is worth noting that Artemisiae annuae herba is included in the International Pharmacopoeia published by the WHO [10].
It must be noted that A. dracunculus is not a pharmacopoeial species, and it is used only in the traditional medicine.
The species A. vulgaris is classified as a homeopathic raw material in the tenth edition of the European Pharmacopoeia [178] and in the French Pharmacopoeia [179]. Its preparations are recommended for the treatment of irregular menstrual cycles and menopausal symptoms [66], and nervous disorders such as sleepwalking, seizures, epilepsy, and anxiety [170]. In addition, A. vulgaris herba has been discussed in a monograph in the German Pharmacopoeia. It abovementioned uses are listed only in the traditional medicine, and it has been emphasized that the effectiveness of A. vulgaris preparations had not been confirmed; hence, they are not recommended for therapeutic uses [172]. Furthermore, A. vulgaris has been described in a monograph published by the European Food Safety Authority (EFSA) [148].
Antitumor activity was confirmed in A. abrotanum leaf extracts and essential oil components [20,168]. Flavonoids from A. abrotanum are reported to relieve the symptoms of allergic rhinitis [117]. The extract from the leaves has shown antiparasitic activity [192].
Scientifically proven biological activities and mechanisms of action of Artemisia ssp. are presented in detail in Table 5. In vivo Relief of symptoms of allergic rhinitis with possible concomitant allergic conjunctivitis, symptoms of bronchial obstruction, and symptoms of exercise-induced asthma by using a nasal spray with a mixture of essential oils and flavonoids present in A. abrotanum.
[117]         Caruifolin D in Absinthii herba inhibits the production of proinflammatory microglia mediators and reactive oxygen species and also inhibits protein C kinase and stress-activated kinases. [130]

From the History of Cosmetic Uses of Artemisia Species
In the twenty-first century, the terms "cosmetics" and "cosmetology", meaning "the art of body care", refer to not only a wide range of products and application techniques but also a multisector industry for which modern medical laboratories work, exclusively focusing on the beautifying aspect of the manufactured preparations. For this reason, the analysis of the historical sources in terms of possible cosmetic uses must be adapted to the time when the preparation was made or described.
In the therapeutic portrait of mugwort A. vulgaris, three forms of external application are shown, which can now be treated also as elements of cosmetic care: sit-ups, diaphoretic baths, and leg compresses [222][223][224][225].
Diaphoretic baths are used to regulate menstrual bleeding, especially in women experiencing trouble becoming pregnant.
Leg wraps, in the form of ointments or compression dressings, have the longest history of indication and are described in all epochs. They eliminate leg fatigue, reduce exercise pain in the lower limbs, and maintain the condition of the skin in these areas.
It is worth noting that although the use of A. vulgaris monopreparations without any admixtures is considered sufficient for each of the above indications, some authors have also provided recipes with an extended composition, e.g., with the addition of mugwort, chamomile flowers, mint pour, or lemon balm.
Most of the sources confirming the cosmetic use of Artemisia spp. refer to mugwort wormwood (A. absinthium).
In ancient Rome, wormwood ("artemisia" in Latin) was an ingredient in hair dyes. The use of wormwood ash, mixed with rose ointment, to anoint the hair to make it black, was mentioned by Pliny the Elder in Historia Naturalis (HN 15.87) [226].
Elagabalus, the Roman emperor who reigned from 218 to 222 AD, provided information about bathing in water flavored with rose petals and wormwood in another ancient work Scriptores Historiae Augustae [226].
According to Dioscorides (first century), a Greek physician and botanist, who is the author of the work on medicinal substances "Peri hyles iatrikes" ("De materia medica"), mugwort wormwood ("Apsinthion bathypicron" in Greek) should be used with water for blemishes formed at night and mixed with honey for bruises, eye problems, and rheumy ears. Wormwood cooked in raisin wine ("passum" in Latin) helped to ease eye pain, which was applied in the form of a soothing poultice and rubbed with oil to protect against insect bites [227].
Similar descriptions of the cosmetic uses of mugwort were also reported in the socalled renaissance Polish herbaria (herbaria), which were based on the works of ancient and medieval botanists. Szymon Syreński (Syrenius), the author of the Herbarium published in 1613, provided much information on the nurturing and healing properties of A. absinthium L. According to him, fresh wormwood, grated with honey and ground caraway seeds, removes dark circles below the eyes and bruises all over the body; in the case of bruises covered with blood, crushed wormwood, sprinkled with wine on a hot brick, should be used. It helps with itchy pimples, scabies, and lichens when grated with coating, cumin, and white pepper and served with white wine. A daily intake of wormwood juice mixed with wine and drunk is reported to remove skin problems (impetigo). Wormwood is also effective in eye ailments, such as redness, swelling, and pain. For bloodshot eyes, either a poultice of mashed wormwood mixed with the white of fresh egg or eye drops made of wormwood with breast milk and a little rose vodka was used. The hair care benefits of wormwood are listed in the Herbarium of Syrenius: washing with wormwood boiled in water can remove dandruff and scabs on the head and frequent washing with wormwood cooked with a tree (A. abrotanum L.) can treat baldness. Wormwood also repels lice, fleas, and clothing moths. Mermaid also wrote that wormwood cooked in vinegar can be used as a mouthwash to remove unpleasant odors [228].
Information on the use of A. absinthium in cosmetology was also found at the beginning of the nineteenth century. In 1805, a work by a pharmacist, professor of chemistry, and pharmacognosy, J.B. Trommsdorf (1770-1837), was published, entitled "Kallopistria, oder die Kunst der Toilette für die elegante Welt" (Wien, 1805), containing the first monographs on A. absinthium with regard to their cosmetic use. Trommsdorf mentioned wormwood (A. absinthium) leaves, used in perfume production, and tarragon vinegar (A. dracunculus) as raw materials for cosmetic products [229].

CosIng Database
Of late, Artemisia ssp. raw materials have been increasingly appearing in cosmetic products.
Information about forms of Artemisia available in cosmetology is provided in the European Union Special Cosmetic Ingredients database CosIng (Table 6) [230].  Two forms of A. abrotanum are listed in the CosIng database, which show skin conditioning, skin protecting, and moisturizing activities.
In cosmetics, six forms of A. absinthium are reported, and they are reported as having antimicrobial, perfuming, skin conditioning (emollient), and hair conditioning activities. Moreover, A. absinthium filtrate obtained after fermentation of the leaves by Lactobacillus spp. is used in cosmetology.
Eleven forms of A. annua are listed in CosIng, which show skin conditioning, fragrance, perfuming, antiseborrheic, antioxidant, and skin protecting activities. In addition, it has been reported in CosIng that A. annua can be used as a cosmetic ingredient in the callus culture extracts of antimicrobial, antioxidant, hair conditioning, skin protecting, and skin conditioning activities. After the fermentation of its leaves by a microorganism, e.g., Aspergillus spp., Bacillus spp., Lactobacillus spp., and Leuconostoc spp., A. annua herb extracts are also used as a filtrate. Essential oils possessalso the important position.
According to CosIng, A. dracunculus can be used in six forms, which have skin conditioning, perfuming, and fragrance properties.
In cosmetology, A. vulgaris can be used in nine forms as skin conditioning, perfuming, antioxidant, and skin protecting ingredients. In addition, original cosmetic ingredients, such as filtrates obtained by fermentation with bacteria (Bacillus spp., Lactobacillus spp.) or fungi (Saccharomyces spp.) deserve attention [230] (Table 6).
From a cosmetic point of view, a very interesting scientifically proven activity against P. acnes strains has been reported for the extracts from the herb of A. abrotanum and A. absinthium. Studies have shown that these extracts can be used to create new therapeutic and cosmetic products for the treatment of acne and for skincare [233].
It has also been demonstrated that the antioxidant activity of Artemisia ssp. extracts is conditioned mainly by the presence of flavonoids and other polyphenol compounds. This antioxidant activity is very important as it is related to the antiaging effect in cosmetic products [20,[38][39][40][41].
Moreover, A. vulgaris herb extracts have been reported to help in decreasing skin and eye sensitivity [244].
In the Philippines, A. absinthum and A. vulgaris are traditionally used to treat skin diseases and ulcerative sores. An entire plant is made into a decoction and is used as a wash for many kinds of wounds and skin ulcers. The dried leaves are cut into small fragments to help induce a more rapid healing of wounds and are used in eczema, herpes, and purulent scabies [245].
The methanolic extracts of aerial parts of A. absinthium have been tested for the sun protection activity. Studies have indicated that A. absinthium extracts have a higher value of SPF in comparison with other species, such as Sambucus nigra, Sambucus ebulus, Orobanche orientalis, Vicia faba, Albizzia julibrissin, Danae racemosa, and Echium amoenum. These activities are significantly correlated with the phenolic and flavonoid content, which was also studied [246].
Recent studies have investigated the efficacy and safety of a nail gel containing glycerin and A. abrotanum extract in the treatment of nail plate surface abnormalities. The findings of these studies have confirmed a significant reduction in roughness and an increase in smoothness. These values were observed after 2 and 8 weeks of using the preparation [247].
Studies of A. vulgaris extracts have focused on the antioxidant effect against the oxidative stress caused by UV radiation, which was tested on hairless mouse skin. The A. vulgaris extract and, for comparative purposes, a lotion as well as ascorbic acid were applied on mouse skin before exposure to UV radiation. The animals were then irradiated with increasing doses of UV-B for 4 weeks. Results suggested that the A. vulgaris extract was more effective than ascorbic acid extract in protecting hairless mouse skin from photoirradiation and that it can be used as a potential antiaging cosmetic ingredient [248].   [20]       A. absinthium essential oil has the ability to scavenge radicals in DPPH and ABTS (2,2'-azobis(3-ethylobenzotiazolino-6-sulfonian)) tests.

Artemisia ssp. in Cosmetology
Artemisia ssp. are used as ingredients in skincare cosmetics, such as creams, shampoos, essences, serums, masks, lotions, and tonics. Different cosmetic brands based on Artemisia spp. extracts or essential oils are available worldwide.
The species A. abrotanum is used in the products of Australian, German, Japanese, Polish, and US cosmetic companies, whereas A. absinthium is very often used in the cosmetics from South Korean, Canadian, French, Russian, and USA. Furthermore, A. annua is used as a cosmetic ingredient in Malaysia, Swiss, Singapore, South Korea, and US cosmetic products, while A. dracunculus is primarily used by UK, South Korea, and US cosmetic companies ( Table 8).
The essential oil of A. dracunculus obtained by steam distillation is widely used as an ingredient in perfumes [2]. It is also used in aromatherapy during massages and baths and in facial masks and compresses [113,145]. The essential oil of A. dracunculus is also very often used by prestigious fashion brands, such as the Italian Prada, Versace, Dolce & Gabbana; the French Givenchy and Chloé; the American Calvin Klein and Tom Ford; and many others.
The use of A. vulgaris is widespread in the cosmetic industry. Various companies from Canada, France, the United Kingdom, New Zealand, Norway, Russia, Indonesia, Israel, and South Korea use the A. vulgaris herb extract and A. vulgaris essential oil in the production of different cosmetics (Table 7). An original form of A. vulgaris-the filtrate obtained as a result of fermentation by bacteria (Bacillus sp., Lactobacillus sp.) or fungi (Saccharomyces sp.)-is used in cosmetic products. During fermentation, Bacillus sp. produces valuable physiologically active substances, such as peptides, viscous compounds (with polysaccharide structure), antioxidants, and fibrins. A combination of A. vulgaris and Bacillus sp. has been shown to enhance the effects of fermentation and to increase the antiaging and antiwrinkle effects by inhibiting the production of matrix metalloproteinase-1 and metalloproteinase-9 enzymes (decomposed of collagen) and increasing cell regeneration and collagen synthesis [35,76,84,121,122].

Safety of Artemisia ssp. Use
Artemisia ssp. may have limitations in use depending on other ingredients used along with them or depending on the oral intake of other ingredients simultaneously, due to which various side effects could occur.
Studies on patients taking homeopathic remedies, herbal mixtures, or single-ingredient preparations from A. abrotanum extracts have reported no serious adverse effects. In a previous study, only two patients out of the 236 studied showed side effects. The intake of a preparation composed of A. abrotanum and Matricaria recutita extracts was reported to cure ailments such as stomach pain and allergy [299].
The species A. absinthium is rich in compounds that have toxic effects, of which αand β-thujone deserve particular attention, with α-thujone being thought to be two to three times more harmful [300]. The EFSA listed αand β-thujone, absinthin, and anabsinthin as potentially dangerous. However, the conclusions of the EFSA report regarding A. absinthium contain information that the plant can be safely used as a basic substance. Furthermore, A. absinthium has a known toxicological profile, and its compounds that were previously considered harmful are currently being investigated as medicinal substances [300]. Nonetheless, A. absinthium should not be recommended if the patient has gastric or duodenal ulcers, biliary obstruction, or liver disease or if he/she is allergic to plants of the family Asteraceae. It should not be used during pregnancy and breastfeeding [171,175]. Studies confirmed no skin irritation after the application of undiluted A. absinthium essential oil [301]. The dangers of drinking absinthe are worth mentioning. Absinthe consumption initially causes the feeling of well-being and hallucinations, slowly leading to a depressive stage. In recent years, it has been speculated that absinthe causes misdiagnosed alcoholism. The symptoms characteristic of absinthism can be attributed to ethanol itself [302]. The FDA (US Food and Drug Administration) has listed A. absinthium as an allergenic species. The source of allergens is the pollen, which can also be present in the extracts of the plant [303].
The species A. annua can cause inflammation of the skin, and due to its highly allergenic pollen, susceptible people may develop allergies. Adverse effects after consumption of preparations with A. annua extracts are as follows: abdominal pain, bradycardia, diarrhea, nausea, vomiting, decreased appetite, flu-like symptoms, reticulocytopenia, and fever. The use of A. annua products is contraindicated in patients with ulcers and gastrointestinal disorders [8,304,305]. The EFSA listed A. annua leaves as a raw material that is not healthneutral due to the high concentration of camphor (2.58-37.5%) in the essential oil [306].
The FDA has listed A. dracunculus and the essential oils and extracts derived from this species as safe for use [307]. However, there have also been reports of the potential toxicity of the main components of the essential oil of A. dracunculus -estragole and methyl eugenol [54]. In animal studies, these components showed the adverse effects of causing, inter alia, liver tumors and neuroendocrine tumors in the glandular stomach, kidneys, and mammary glands [308]. After analyzing the available data, the EFSA has classified estragole and methyl eugenol as genotoxic and carcinogenic compounds. However, a safe threshold for the consumption of estragole and methyl eugenol has not yet been established. The EFSA recommends limiting the use of both compounds [308].
Herbal extracts of A. vulgaris used in therapeutic doses may not have any side effects. However, A. vulgaris can cause allergies, as confirmed by the FDA. Its pollen contains allergenic glycoproteins that cause type I (immediate) allergic reactions. In addition, in a few individuals, anaphylactic shock has been observed after swallowing the pollen [55,303]. The species A. vulgaris is also considered to be the primary cause of hay fever and allergic asthma in Northern Europe, North America, and a few regions of Asia [148,309]. People allergic to herbal ingredients from other plants of the Asteraceae family should avoid contact with these preparations. It has been reported that A. vulgaris cross-reacts with pollen from other plants as well as with food substances, such as birch, cabbage, grasses, hazelnuts, honey, pollen of the European olive, and sweet pepper, as well as with royal jelly, sunflower, kiwi, peach, mango, apple, celery, and carrot [148,310]. Apart from respiratory system ailments, allergic skin lesions have also been observed and allergic skin reactions, such as dermatitis and urticaria, may also occur [309,[311][312][313].
The EFSA classified the essential oil components of A. vulgaris, such as α-thujone, β-thujone, camphor, and 1,8-cineol, as having potentially adverse effects on human health when taken with food or dietary supplements [306]. Therefore, A. vulgaris should be used with caution in patients with diabetes as it can increase blood glucose levels [148].

Conclusions
The multidirectional ethnopharmacological indications and recent popularity of artemisinin resulted in a huge increase in interest in the chemism of Artemisia species and in the biological activity of extracts obtained from these plants and essential oils. Research studies have confirmed their many valuable directions of biological activity, such as hepatoprotective, neuroprotective, and antidepressant effects. Some of the proven biological properties, e.g., antibacterial, antifungal, and antioxidant activities, are of particularly utility from the perspective of the cosmetic industry. In the data presented by the European Commission, in the CosIng database, the number of cosmetic raw materials approved for the production of cosmetics includes as many as 37 raw materials based on the five species characterized in this review. Cosmetics based on these raw materials are becoming more popular not only in European but also in North American and East Asian countries.