Natural Products for the Prevention and Treatment of Common Cold and Viral Respiratory Infections

The common cold is generally considered a usually harmless infectious disease of the upper respiratory pathway, with mostly mild symptoms. However, it should not be overlooked, as a severe cold can lead to serious complications, resulting in hospitalization or death in vulnerable patients. The treatment of the common cold remains purely symptomatic. Analgesics as well as oral antihistamines or decongestants may be advised to relieve fever, and local treatments can clear the airways and relieve nasal congestion, rhinorrhea, or sneezing. Certain medicinal plant specialties can be used as therapy or as complementary self-treatment. Recent scientific advances discussed in more detail in this review have demonstrated the plant’s efficiency in the treatment of the common cold. This review presents an overview of plants used worldwide in the treatment of cold diseases.


Introduction
The common cold is a conventional term for a mild upper respiratory illness (nose, sinuses, pharynx, and larynx), the catarrhal disorder, which may be viral or a mixed infection. The severity and type of symptoms vary depending on the immune status of the patient and the pathogen causing the infection. It generally involves a set of lessspecific symptoms that include nasal stuffiness and discharge, sneezing, sore throat, cough, headache, malaise, and low-grade fever. The mucosal inflammation may involve the nasal mucosa, throat, sinuses, and larynx [1]. There is not a single cause for the illness; rather, it is a heterogeneous group of diseases caused by numerous viruses that belong to several different families. Occasionally, the common cold may spread to the lower respiratory tract, as well as predispose to bacterial complications [2][3][4][5][6].
Cough medications, both expectorants (productive cough) and antitussives (dry cough), are frequently used [26]. They reduce the viscosity of tenacious secretions by irritating the gastric vagal receptors that stimulate respiratory tract fluid, thus increasing the volume but decreasing the viscosity of respiratory tract secretions [26]. ure 1 A and B).
Mucilage is an active compound as an antitussive [26]. It inhibits the cough reflex suppressing the response of the cough center, via the demulcent effect of afferent vagus nerves. The blockade of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 1 (TRPV1) by mucilage represents a therapy for the treatment of dry cough. The TRPA1 agonists with antitussive activity are monoterpenes as borneol, 1,8-cineole, eugenol, menthol, thymol, and camphor (all in low concentrations) [42] (Figure 1A,B).

Most Commonly Used Medicinal Plants for the Treatment of the Common Colds
To meet our objective, which is the use of natural herbal medicine to treat the common cold, we conducted a scientific bibliographic search of articles published from the year 2000 onwards in the following databases: Medline, PubMed, and Scopus. We used the following keywords: "plant", "treatment", and "cold" (Tables 2 and 3).   Table 3. Herbal combinations used in the treatment of the common cold.
Garlic Allium sativum L. (A. sativum) has been widely known for centuries to influence health and to provide benefits to almost all physiologic systems including immunity. The antioxidant properties of A. sativum have also been also studied for their impact on human health, especially against tissue damage and inflammation [48]. Garlic is considered an antimicrobial and antiviral product that could relieve common cold viruses such as the human rhinovirus. A bibliometric study was performed to determine the effect of A. sativum on either the prevention or treatment of the common cold. However, data are limited to one clinical trial. The trial reported 24 occurrences of the common cold in the garlic intervention group (allicin content) compared with 65 in the placebo group (p < 0.001), resulting in fewer days of illness in the garlic group compared with the placebo group (111 versus 366). The authors of the clinical trial suggest that using garlic as a supplement to allicin can prevent the onset of common cold infections. However, the clinical data published in the bibliometric study were insufficient to validate the effect of garlic in the prevention or treatment of the common cold [49,50].
3.2. Echinacea angustifolia DC., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench The medicinal herbal echinacea species have clinical properties essentially as an immune-modulator in the case of common colds and respiratory infections [51]. The immunological effects of echinacea have been investigated extensively in vitro and in vivo. Echinacea products are made from the roots, the whole plant, or aerial parts of Echinacea angustifolia (E. angustifolia), Echinacea pallida (E. pallida), or Echinacea purpurea (E. purpurea) [51,52].
The E. purpurea has been recommended as a medicinal plant for the treatment of the common cold, cough, bronchitis and upper respiratory infections [53]. In vitro experiments with human macrophages found that fresh-pressed juice and dried juice from the aerial parts of E. purpurea stimulated the production of cytokines including IL-1, IL-10, and TNF-α [54]. In addition, evidence pointed out the effective activity of E. purpurea towards Coronavirus disease 2019 (COVID- 19) in an organotypic cell culture model [55][56][57].
The effectiveness of E. purpurea against colds was investigated by a randomized clinical trial performed on a total of 79 healthy children, designed to treat upcoming cold episodes with either 3 or 5 Echinaforce Junior tablets (EFJ) (contains the same herbal extract of freshly harvested E. purpurea) daily for up to 10 days. A total of 130 cold episodes were reported in 68 children overall during the 5.3 months of observation, encompassing a full cold and flu season. Results showed the treatment with EFJ had an excellent safety profile for the acute treatment of common cold symptoms [58]. In addition, in a randomized, double-blind, placebo-controlled trial, 282 subjects aged 18-65 years with a history of 2 or more colds in the previous year were recruited to evaluate the benefits of the treatment against cold symptoms. Among people who developed a cold, a significant decrease in symptoms was observed in the group that was under Echinacea treatment compared to the placebo group [59]. These findings confirmed the results of a randomized, double-blind, placebo-controlled clinical trial realized on 80 volunteers who had experienced the first symptoms of a cold. After a period of treatment with E. purpurea herb, this plant remains clinically efficient to relieve symptoms faster than a placebo [60]. However, Echinacea therapy represents an effective alternative to standard symptomatic medications in the acute treatment of the common cold [61].

Eucalyptus globulus Labill.
Evidence has been shown that a selection of natural herbs improves the relief of symptoms of upper respiratory tract infections and that their inhalation has antitussive and expectorant effects [62].
The genus Eucalyptus encompasses more than 900 species and subspecies. Different species of Eucalyptus are used in alternative medicine as antiseptics due to their antimicrobial and antioxidant properties to treat the common cold and respiratory infections [63][64][65].
In addition, a recent study was able to determine that a formula containing hyaluronic acids, Eucalyptus oil, copper, and manganese salts is effective for safe nasal irrigation and therefore for alleviating symptoms associated with the common cold such as nasal congestion [66]. Additionally, the Eucalyptus plant is often used as a compound in an ointment containing camphor, menthol, and Eucalyptus oils for topical application, which lessens the symptoms of colds [67,68]. A meta-analysis published in 2022 was able to synthesize the clinical trials that demonstrate the effectiveness of Eucalyptus in relieving cough. However, six studies have been published. Four randomized controlled trials have shown that Eucalyptus globulus Labill. (E. globulus) used in a formula significantly reduces cough compared to the placebo group. This study supports the idea of using the medicinal plant Eucalyptus as a remedy for cold symptoms primarily for cough and runny nose [69].
3.4. Grindelia robusta Nutt./Grindelia squarrosa (Pursh) Dunal, Grindelia humilis Hook. et Arn., Grindelia camporum Greene EMA has pointed to the non-pharmaceutical value of several conger herbs in postviral infection cough. The Grindelia plant is one of them [15]. However, it has been shown that Grindelia squarrosa (G. squarrosa) has an anti-inflammatory effect in inhibiting proinflammatory cytokines such as IL-8, TNF-α, IL-1β, and IL-6 in culture cells such as macrophage, neutrophil, and respiratory epithelial cell line [70,71]. The researchers suggest that the anti-cold activity of Grindelia comes down to the composition of the medicinal plant formula used, and that G. squarrosa could have an essential effect on the treatment of inflammatory diseases of the respiratory tract [70,71]. Moreover, G. robusta has been demonstrated to be effective as an expectorant, antitussive, and anti-inflammatory remedy in children, but no clinical trial has confirmed its efficiency [72].
3.5. Glycyrrhiza glabra L., Glycyrrhiza inflata Bat., Glycyrrhiza uralensis Fisch The Glycyrrhiza plant is known for its anti-inflammatory and immunomodulatory properties during upper respiratory infections, targeting respiratory symptoms such as sore throat or cough. Its action is mediated by interfering with the Toll-like receptor 4 (TLR4) signaling and decreased production of pro-inflammatory cytokines including nuclear factor-κB, tumor necrosis factor, IL-1, and IL-6 [73].
The effect of Glycyrrhiza alone as an herbal remedy in the treatment of common colds is not yet clear, but several herbal preparations containing Glycyrrhiza have long been used to treat upper respiratory tract infections. In contrast, there are herb mixes containing Glycyrrhiza: Siji-kangbingdu, Maxing Shigan decoction, Lianhua-Qingwen capsules, and Macmoondongtang, which are used in China and Korea to treat upper respiratory tract infections [74,75].
A mixture of ASMATUSTM herbs has been used to relieve symptoms of asthma in children, and its activity has been evaluated as a remedy for colds. For example, a study has been conducted on 46 children with asthma and onset of cold symptoms. Patients received either the herbal mixture (composed of Matricaria chamomilla L., Althaea officinalis L., Malva sylvestris L., Hyssopus officinalis L., Adiantum capillus-veneris L., G. glabra and Ziziphus jujube Mills), or a placebo daily for 5 days. Indeed, the herbal mixture significantly decreased the severity of coughing and nocturnal awakenings compared to the placebo [76].
is one of the herbs most widely used as a remedy for common colds [77,78]. The antiviral and anti-inflammatory activities of M. × piperita leaves have been investigated in the case of respiratory infection. In the in vitro model, M. piperita decreases the production of proinflammatory cytokines such as TNF-α, IL-6, and PGE2, and has antiviral activity against the respiratory syncytial virus (RSV) [79].
According to EMA, M. × piperita essential oil (inhalation) could be used as a treatment of cough and cold symptoms by stimulating cold receptors in the respiratory tract [80,81] A prospective randomized double-blind controlled trial was assessed to investigate the effects of essential oils in patients with upper respiratory tract infections based on a sore throat, hoarseness, or cough. Mentha × piperita was investigated in an herbal mixture containing E. citriodora, E. globulus, Origanum syriacum L., and Rosmarinus officinalis L. A spray containing essential oils of plant mixture was applied five times a day for 3 days and compared with a placebo spray. Spray application reported an immediate improvement in the symptoms of upper respiratory ailments [82].

Origanum dictamnus L.
As noted in the previous section, Origanum dictamnus L. (O. dictamnus) was used among the herbal mixture that showed an effect on improving symptoms of upper respiratory infections [82,83]. EMA announced in its report related to this plant that the Committee on Herbal Medicinal Products stated that it can be used as a remedy for the symptoms of the common cold, but no clinical trial has been published to date [84].

Pelargonium sidoides DC, Pelargonium reniforme Curt
Pelargonium sidoides DC (P. sidoides) (family Geraniaceae) is a plant native to South Africa whose roots have been used as herbal remedies for respiratory and gastrointestinal infections for many centuries by the local South African populations [85]. A number of studies highlighted the activity of the proanthocyanidin-rich extract EPs 7630 from the roots of P. sidoides. It is considered effective against a variety of respiratory viruses such as HCoV (HCo-229E), influenza A virus (H1N1, H3N2), respiratory syncytial virus (RSV), and parainfluenza virus by limiting the symptom severity and disease duration of these infections [86,87].
A total of 120 patients with a common cold and at least 2 out of 10 common cold symptoms received one film-coated 20 mg tablet of EPs 7630 thrice daily for 10 days in an uncontrolled, interventional multicenter trial (ISRCTN65790556). Common-cold-associated symptoms and treatment satisfaction were evaluated after 5 days and at the treatment end. In 61 patients, viral nucleic acids were detected. Of these, 23 (37.7%) tested positive for at least 1 HCoV (HCoV subset) and 38 (62.3%) for other viruses only (non-HCoV subset). Patients of both subsets showed a significant improvement in common cold symptoms already after 5 days of treatment. EPs 7630 treatment outcomes of common cold patients with confirmed HCoV infection were as favorable as in patients with other viral infections [86]. Another clinical trial has evaluated the efficacy of EPs 7630, compared with the placebo for the treatment of the common cold. Of 207 patient participants, 103 were included in the standard dose of EPs 7630 (received 3 × 30 drops per day), 104 participated in the high dose group (received treatment with 3 × 60 drops per day), and the control group received a placebo. The study was conducted over a period of 10 days. The active EPs 7630 is an effective, well-tolerated, and safe treatment for the common cold. It significantly reduced the severity of symptoms [88]. The effectiveness of the extract roots of P. sidoides was also evaluated and confirmed by Lizogub [89] and Ross [90].
The Committee on Herbal Medicinal Products and EMA suggest that Pimpinella anisum L. (P. anisum) can be used as an expectorant (a medicine that helps bring up phlegm) for coughs associated with colds [91]. This evidence could be reinforced by the study of Iannarelli et al. [92]. The authors of this study evaluated the anti-inflammatory activity and the effect on mucin secretion of P. anisum essential oil in primary airway bronchial and tracheal epithelial cells (HBEpC and HTEpC, respectively). The data indicated that P. anisum essential oil showed a significant anti-inflammatory effect on both HBEpC and HTEpC cells together with mucus hypersecretion, which indicates that P. anisum could be used as an expectorant during cold periods [92]; however, on the other hand, there is no published clinical trial which confirms the expectorant effect of this plant. Official therapeutic indications are based on traditional use and include use as an expectorant in the cough due to a cold for both the preparations from flower and roots [93,94].
Parts of the plant used in official phytotherapy are flowers and/or roots. Flowers can be dried whole or cut and can or cannot include calyx [95]. The main constituents in flowers are triterpenic saponins, which are predominantly present in the sepals (up to 2%); flavonoids, which are predominantly present in the petals (up to 3%); carotenoids; essential oil (trace amounts); rosmarinic acid; D-volemitol; and other saccharide alcohols [95]. Roots may be whole or cut and dried [96]. The main constituents in roots are triterpenic saponins (3-12%), phenolic glycosides, saccharides, and D-volemitol (primulitol) [96].
According to the European Union herbal monograph, flowers are used as a herbal substance, comminuted and prepared as tea, or a liquid extract (prepared with 25% ethanol) [94,95]. The roots may be used as a herbal substance for the production of herbal preparations: dry extract (prepared with 40-50% ethanol), liquid extract (prepared with 70% ethanol), tincture (prepared with 70% ethanol), soft extract (prepared with water; 20-55% ethanol; 50% methanol; or a mixture of methanol, water, and ammonia), and comminuted herbal substance [93].
Since Primula flowers are usually used in combinations with other herbal substances (Primula content in teas is typically 10-30%, 1% in liquid, and 8% in solid dosage forms), assessing their effectiveness in the treatment of cough is challenging [95]. There are no clinical trials published in which only Primula flower or root preparation are used in the treatment group. However, combinations with thyme preparations show effectiveness on cough in clinical trials [97].
Primula preparations are generally safe to use, but their effectiveness in the treatment of cough is questionable. The mechanism of action for this indication is unclear and there is a lack of relevant clinical studies.

Sambucus nigra L.
Sambucus nigra or elderberry belongs to the family Adoxaceae [98]. The part of elderberry used in traditional and rational phytotherapy is the flower. Elderberry flowers are used dried and the herbal substance contains at least 0.80% flavonoids according to the European Pharmacopoeia [99]. Flavonoid content may be up to 3%. Other important compounds are triterpenes essential oil, 3% caffeic acid derivatives, 0.11% sterols, 8-9% minerals (especially potassium), and other (e.g., tannins, mucilages, pectins and saccharides, plastocynin) [99,100].
According to the European Union herbal monograph, elderberry flowers are used as an herbal substance and herbal preparations, i.e., comminuted, as a liquid extract (25% ethanol used as an extraction solvent) or as a tincture (25% ethanol used as extraction solvent). These can be further processed into tea or liquid oral dosage formulations. The EMA has approved the indication for "the relief of early symptoms of common cold", which is based solely on traditional use [101].
In some cases, fruit is also used. Dried, ripe berries are the herbal substance, but fresh berries are also used in some preparations [102]. Fresh fruits contain anthocyanins and flavonoids. The dried seeds contain hemagglutinin (lectins, e.g., S. nigra agglutinin III), while S. nigra agglutinin Vf lectin is present in fresh fruits. Other constituents are essential oil (trace amounts), vitamins, minerals, and saccharides [102]. The seeds of the unripe fruits also contain cyanogenic glycosides, sambunigrin, prunasin, zierin, and holocalin [103]. Other traditional uses of elderberry fruit preparations are as a laxative, diaphoretic, diuretic, analgesic, and sedative, to alleviate headache, dental, heart, nerve pain and neuralgia, and against cough and cold, to name a few [102]. However, the EMA monograph on elderberry fruit is not available yet.
To conclude, the data from clinical studies and mechanistic studies are too scarce to unambiguously support the evidence-based use of elderberry preparations for the relief of the symptoms of the common cold. However, the use of flower preparations is safe and has an approved indication based on long-standing use. Elderberry fruit, although safe to consume if ripe, was not granted an indication by the EMA due to the lack of relevant data.
The Committee on Herbal Medicinal Products and EMA reported that the three species are used as a remedy for cold symptoms and primarily for cough prevention in Albania, Greece, and Bulgaria [104]. Other evidence noted that Sideritis scardica Griseb (S. scardica) has been used in traditional medicine as a remedy for improving symptoms during respiratory infections such as bronchitis and bronchial asthma. Additionally, this plant is known for its effectiveness against colds and coughs [105,106], but there is no published clinical trial which confirms these effects.
The genus Thymus or thyme (family Lamiaceae) numbers about 400 species. This species is a common perennial shrub, native to southern Europe and the western Mediterranean.
Thyme is a traditional Mediterranean aromatic plant used for centuries in cooking, medicine, and perfume preparations. Consequently, thyme has spread worldwide, as has its uses, and this has led to many varieties. Nowadays, thyme cultivation is economically important to producing essential oils for the perfume industry, monoterpene production, and medicinal use. Thyme could also be used as a preservative for food products. Thyme leaves are also used as a fresh or dry condiment. The EMA published two monographs about the use of thyme for cough and cold, one for the herb and the second for the essential oil. The herbal substances and the herbal preparation(s) are composed of the leaves and/or flowers separated from the dried stems of the plant. The essential oil is obtained by steam distillation from fresh flowering aerial parts of T. vulgare or T. zygis [107,108].
In the recent article by Silva et al. on phenolic acids, tannins, rosmarinic and salvianolic acid, flavonoids, and polyphenols also enter frequently the chemical composition of Thymus.
Its therapeutic properties derive mainly from the essential oil with antitussive, expectorant, antiseptic, antimicrobial, and anthelmintic properties. Traditional uses also report Pharmaceuticals 2023, 16, 662 14 of 25 hepatoprotective properties. No genotoxicity has been reported. However, considering the growth area of the plant, it could be contaminated with pollutants such as trace metals such as lead (Pb). Additionally, the chemical stability of essential oils is low [109]. Flavonoids from thyme do not seem to have a strong pharmacological potential [109].
Leaves are mostly used as an infusion, or as tea, ointment, and syrup. The reported properties of thyme infusion are as a general stimulant, anti-flatulent, cough depressant, common cold treatment, and antibacterial [109,111,113]. The anti-microbial properties are used in mouth, gastrointestinal, and urinary tract infections, as well as respiratory diseases (cough, bronchitis, asthma). The most important medicinal use relies on thymol, p-cymene, and carvacrol.
It is suggested that thymol antiviral activity may occur at a different level of the viral cycle, from cell penetration and viral envelope interference to protein inhibition [17].
Boskabady et al. [118] described a relaxant effect on the tracheal chain on guinea pigs as efficient as theophylline, and Wienkotter et al. [119] described a β 2 agonist activity (molecular binding and biological effects), suggesting an interesting therapeutic activity at both symptomatic and viral levels in the case of upper respiratory tract infections such as the common cold and flu. Additional anti-inflammatory activities lead Thymus sp. to have strong potential in upper respiratory tract viral infections. Patil et al. [111] reported an inhibition of the 5-lipooxygenase at a low concentration of thyme essential oil (IC 50 at 0.005 µg/mL), suggesting the latter could reduce leukotrienes synthesis during inflammation.
Lenz et al. [120] also showed antiviral activity of thyme extract (in a commercial preparation, where the active compound is thymol according to the authors) against the human rhinovirus 1a (HRV1a, MDCK/A549 cells, MOI 1).
From a clinical point of view, Kemmerich et al. [22] published a clinical trial (doubled blind, placebo controlled, multicenter, with 363 patients including 182 with herbal treatment and 181 in the placebo group) which showed the efficacy and tolerability of a fluid extract of thyme herb (mixed with Ivy) on acute bronchitis. The herbal treatment significantly reduced cough compared to placebo (77.6% vs. 55.9%; p < 0.0001) after 9 days and reduced the severity of bronchitis (evaluated with BSS score). The authors also reported the superiority of the herbal treatment on sleep disturbance, and general well-being. They also reported that adverse effects were low and similar to those in the placebo group (3.8% and 4.5% respectively). All adverse effects had been resolved at the end of the study and the authors concluded the very good tolerability of the treatment [22].
Thymol is the most studied essential oil constituent from thyme and show good activity against several viruses (rhinoviruses, influenza viruses) in vitro, in vivo, and in clinical trials. The latter also shows the efficiency as well as the safety of thyme extracts in symptom reduction. The mechanism of action is not yet fully understood. However, several studies showed that thyme could reduce inflammation, enhance bronchodilatation via β2 agonism, and directly reduce viral replication. Thus, finally, thyme showed a direct and indirect strong potential in upper viral tract infections [121,122].
To conclude, regarding the safe traditional use of thyme herbal preparation and essential oils in productive cough and common cold associated with in vitro, in vivo, and clinical data, common thyme is safe and efficient in this indication, as mentioned in the revised final opinion of the EMA.
3.14. Tilia cordata Miller, Tilia platyphyllos Scop., Tilia × vulgaris Heyne In an assessment report relating to EMA and the Committee on Herbal Medicinal Products, it was reported that the plants Tilia cordata Miller (T. cordata), Tilia platyphyllos Scop (T. platyphyllos), and Tilia × vulgaris Heyne (T. vulgaris) could be used as a remedy for cold symptoms in Germany and Poland in association with other plants such as Salicis cortex, Thymi herba, Foeniculi amari fructus and Lichen islandicus [125].
Verbascum spp. is one of the natural botanical remedies used to alleviate cold-related symptoms [126]. It is known to relieve respiratory system ailments such as hoarseness, tonsillitis, colds, coughs, asthma, or bronchitis, and this data are supported by EMA and Committee on Herbal Medicinal Products [127,128].
Experimental studies have demonstrated the anti-inflammatory effect of the plant Verbascum thapsum L. (V. thapsum) by the fact that it has the ability to reduce the secretion of proinflammatory mediators in human myelomonocytic leukemia cells [129] and by its antiviral activity against the H1N1 infection in a mouse model [130].

Aloe qrborescens Mill.
Aloe arborescens Mill. (A. arborescens) has been used mostly in the treatment of upper respiratory tract infections. Preclinical and clinical data showed that this medicinal plant has immunomodulatory and antiviral effects in the case of upper respiratory tract infections [135,136]. A. arborescens extract mixed with Vitamin C (1920 mg of the extract and 51 mg Vitamin C per 5 mL) "Biaron C ® " has been tested against a panel of viruses that cause upper respiratory infections [137]. Human rhinovirus B (HRV14), influenza A virus (H1N1) and (H3N2), influenza B, respiratory syncytial virus (RSV), parainfluenza type 3 virus (Para 3), coxsackievirus (CA9), adenovirus C (Adeno 5) were cultivated in specific cells (such as MDCK, Hep-2, and HeLa-cells), and were treated by Biaron C ® at 2-0.006% of final concentration. Data demonstrated that the Biaron C ® was effective against the RNA viruses tested. The antiviral activity was more selective against Picornaviridae and Orthomyxoviridae. This confirms its known therapeutic antiviral effect [137].

Camellia sinensis (L.) Kuntze, Camellia qssamica var. Kucha
Tea is a vegetable infusion containing antioxidants and other beneficial nutrients such as L-theanine (known to stimulate human T lymphocytes to secrete IFN-γ), a powerful antimicrobial cytokine. There are hundreds of varieties of the tea species such as Camellia sinensis (C. sinensis). Numerous observational studies suggest that tea drinking is beneficial to health. A randomized, double-blinded study demonstrated the effect of C. sinensis (as green tea) on cold and flu symptoms by enhancing immunity response [139]. The results of this study show that the ingestion of two capsules containing C. sinensis daily decreased by about a third the number of subjects who presented cold and flu symptoms. In addition to its effect on the incidence of cold and flu symptoms, C. sinensis ingestion enhanced the production of IFN-γ by γ/δ T cells challenged in vitro [139].
Compounds isolated from tea were evaluated for their cytotoxicity and inhibitory effects on human influenza virus A/Puerto Rico/8/34 by analyzing viral protein expression The Cistus incanus (C. incanus) is a shrub of the Cistaceae family, a hybrid between C. albidus and C. crispus, evergreen which gives gray-green leaves and beautiful pink-purple flowers. It is mainly found in arid Mediterranean regions with soils rich in magnesium. This plant is the richest in polyphenols (antioxidants), and it is used in particular for its powerful antiviral and antibacterial properties [141,142].
The leaves of this plant (family Cistaceae) are traditionally used. It was reported that a Cistus extract (CYSTUS052) was more effective than an extract of green tea against infections of the upper respiratory tract [143]. Furthermore, in the case of the latter infections, a randomized, placebo-controlled clinical study was performed to evaluate the effect of a Cistus extract (CYSTUS052) in a total of 160 patients by comparing symptoms and by dosing inflammatory markers in either group: CYSTUS052 treatment and placebo. However, common cold symptoms and C-reactive protein were significantly reduced in CYSTUS052 treated group compared to the placebo group [144]. In addition, the antiviral activity of this extract ( Cinnamomum cassia (C. cassia) is a common traditional Chinese herbal medicine that has been used in the case of different respiratory tract diseases including the common cold. Antiviral activity of the hot water extract of C. cassia against HRSV was evaluated against both human upper (HEp-2) and lower (A549) respiratory tract cell lines. This study demonstrates that Cinnamomum cassia at 10 µg/mL could inhibit HRSV-induced plaque formation on A549 and HEp-2 cells by inhibiting viral attachment and penetration. Furthermore, C. cassia could decrease the expression of viral F protein to inhibit viral spread into other cells. The authors suggest that C. cassia could be an antiviral agent used in therapeutic ways to manage HRSV infection [147].

Larix decidua Mill.
This tree from the family Pinaceae produces the Larch arabinogalactan possessing an anti-common cold effect [148]. Larch arabinogalactan seems to be implicated specifically in the activation of immune cells as well as the secretion of pro-inflammatory cytokines during common cold diseases [149]. This scientific evidence could be confirmed by a clinical trial that enrolled a total of 199 healthy participants who had common cold infections in the last 6 months. A group of 101 participants were given Larch arabinogalactan (4.5 g) compared to the placebo group (98 participants). Subsequently, the results revealed that Larch arabinogalactan decreased significantly the incidence of common cold infections and reduced the number of seasonal common cold episodes [150]. Larch arabinogalactan seems to be implicated specifically in the activation of immune cells as well as the secretion of pro-inflammatory cytokines during common cold diseases [149].

Hedera helix/Primula vulgaris/Thymus vulgaris
Thymus vulgaris is indicated mostly for the treatment of respiratory diseases [118], and a double-blind, randomized study identified the efficacy and tolerability of ivy leaves for the treatment of acute bronchitis with improving symptoms: cough, sputum, rales/rhonchi, and chest pain during coughing and dyspnea [153]. A combination of thyme and ivy leaves has been studied in the case of acute bronchitis with productive cough [21,22]. The efficacy of combination of thyme and ivy treatment was evaluated by a double-blind, placebo-controlled, multicenter Phase IV study performed on 361 outpatients with acute bronchitis and coughing fits. Coughing fits intensity and the symptoms of acute bronchitis improved rapidly in the group under the thyme-ivy combination [22,119]. Metanalysis demonstrated that different herbal mixtures are effective against the common cold such as vy/primrose/thyme, essential oils GeloMyrtol ®, and Tsumura bakumondoto (Table S1) [23]. This study highlighted that the combination of ivy/primrose/thyme has been effective to reduce coughing. Furthermore, RCT demonstrated also the effectiveness of GeloMyrtol ® and Tsumura bakumondoto [23].

Tsumura Bakumondoto
A study performed on 19 patients compared the effects of a bakumondoto preparation in combination with conventional medication to conventional medication alone [154]. The effect of bakumondoto on the intensity of the patient's coughs was significantly stronger on days 4 and 5 of intake. No serious adverse events were reported [154].

GeloMyrtol ® (Myrtol ® )
This is a mix of plant medicine syrup produced by distillation of essential oils (Table S1). Myrtol ® 300 mg was investigated as treatment in a double-blind, parallel-group enrolling about 413 patients with bronchitis. The patients responded positively to this treatment with an improvement in their clinical state of health [155]. Myrtol ® was also confirmed to be effective against acute bronchitis. A study by Mattys et al. studied the effectiveness of the myrtol stand on 676 patients with acute bronchitis. The responder rate was significantly higher in the myrtol stand group and superior in terms of efficacy compared to other tested treatments and placebo; it is even considered as an alternative to antibiotics for acute bronchitis treatment [156].

Soshiho-Tang
Soshiho-tang is a widely used Oriental herbal formulation for treating the common cold in East Asian countries (Table S1). According to the meta-analysis of Jung et al. [157], Soshiho-tang is mainly used in the treatment of pediatric cough, nasal congestion, and runny nose, and because of the herbs that compose it, there could be an anti-inflammatory effect [157]. A recent review suggests that Soshiho-tang could be used in the treatment of COVID-19 symptoms [158].

Kang Jang ®
Kang Jang ® is an herbal mix constitute (Table S1) including harms root used in Scandinavia for the treatment of respiratory tract diseases [159]. Bath et al. facilitated a clinical trial to test the effectiveness of Kang Jang ® as an antitussive remedy. Among 177 patients enrolled in the parallel-group, randomized, double-blinded, placebo-controlled trial, the group which had undertaken Kang Jan (30 mL/day; 762 mg genuine extracts with standardized contents of 0.2 mg/mL vasicine, 0.8 mg/mL chicoric acid, and 0.03 mg/mL eleutherosides B and E) showed a faster symptom improvement compared to other groups (placebo and bromhexine) [159].  (Table S1), Socheong-ryong-tang and Yeon-gyo-pae-dok-san in the treatment of the common cold [160]. In this study, 480 patients who presented symptoms of the common cold within 48 h were recruited. The clinical trial was double blinded, and So-cheong-ryong-tang and Yeongyo-pae-dok-san were administrated separately in parallel groups orally 3 times per day. Evaluation of symptoms after mix herbal intake showed that each of the herbal blends used resulted in their improvement [160].

Combination of Echinaceae radix, Baptisiae radix, Thujae herba
The efficacy of the herbal combination Echinaceae radix, Baptisiae radix, and Thujae herba was evaluated in a randomized double-blind placebo-controlled study. A total of 238 valid patients with common cold symptoms were included [24]. The results showed that more than half of the patients taking the herbal combination responded positively to the treatment compared to patients taking a placebo. The therapeutic benefit of the herbal remedy appeared on day 2 and reached significance on day 4, continuing until the end of treatment while following the evolution of the symptoms of bronchitis and rhinitis [24]. The efficacy of this herbal medication in common cold treatment was also demonstrated by Naser et al. [161]. The authors evaluated in their clinical trial the effect of the mixture of Echinaceae radix, Baptisiae radix, and Thujae herba on runny nose symptoms. A total of 60 patients suffering from the common cold were treated with the mixture (19.2 mg and 9.6 mg) versus 31 patients who received a placebo, three times daily for 3-12 days. Test evaluation of common cold symptoms showed that the two groups that took the two doses (high and low) of the herbal mixture responded well to the treatment compared to the placebo [161]. Thus, both studies showed that this herbal remedy is effective and safe in common cold treatment.

Ma-Xing-Shi-Gan-Tang
Ma-xing-shi-gan-tang is a Chinese herbal mix (Table S1) used for the treatment of the common cold, fever, and influenza virus infections. The antiviral activity of nontoxic concentrations of Ma-xing-shi-gan-tang against influenza virus A/WSN/33 (H1N1) was examined in MDCK cells. Ma-xing-shi-gan-tang exhibited an antiviral activity with EC 50 of 0.83 ± 0.41 mg/mL against influenza virus A/WSN/33 (H1N1). In addition, this combination of medicinal herbs appeared to have an inhibitory effect on the synthesis of both viral RNA and proteins in treating cells. These data supported that Ma-xing-shi-gantang could be used in the treatment of influenza virus infections [162].

Conclusions
To date, there is no specific treatment for the common cold. The only treatments that exist are aimed at relieving cold symptoms such as cough, fever, and runny nose. The development of research on medicinal plants has demonstrated their effectiveness against respiratory infections and in particular the common cold. Various clinical trials have established herbal syrups or herbal combinations that can be used for self-medication to relieve certain cold-related symptoms. A. sativum, Echinacea family, and T. zygis are considered antimicrobial natural products that can relieve common cold. Further future studies are recommended to determine alternative herbal remedies to prevent and treat other respiratory infections (viral and bacterial), primarily those for which vaccines and treatments are not yet well developed.
The use of medicinal plants to alleviate cold symptoms would be very interesting because they are more easily accessible to patients than drugs and compliance is generally better.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ph16050662/s1, Chapter 1: Other medicinal plants with EMA monography with potential effects on common cold. Table S1: Herbal combinations used in the treatment of the common cold.